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Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo. [ABSTRACT FROM AUTHOR]

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[ 18 F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[ 18 F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Background: Extracellular renal interstitial guanosine cyclic 3',5'-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na + ) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na + transport similar to ouabain-a cardiotonic steroid., Methods: Urine Na + excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 μg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA., Results: Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated Src Tyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2) Thr202/Tyr204 ; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 μM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 μM)+ouabain (10 μM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N 3 -PET-8-biotin-11-cGMP (2 μM); 8-N 3 -6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N 3 -PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non-cross-linked samples and cross-linked or non-cross-linked 8-N 3 -6-biotin-10-cAMP RPTs. Ouabain (10 μM) reduced NKA in cross-linked 4-N 3 -PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N 3 -PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA., Conclusions: cGMP can bind to NKA and thereby mediate natriuresis.

Background: How signals from activated angiotensin type-2 receptors (AT 2 R) mediate inhibition of sodium ion (Na + ) reabsorption in renal proximal tubule cells is currently unknown. Protein phosphatases including PP2A (protein phosphatase 2A) have been implicated in AT 2 R signaling in tissues other than kidney. We investigated whether inhibition of protein phosphatase PP2A reduced AT 2 R-mediated natriuresis and evaluated changes in PP2A activity and localization after renal AT 2 R activation in normal 4- and 10-week-old control Wistar-Kyoto rats and 4-week-old prehypertensive and 10-week-old hypertensive spontaneously hypertensive rats., Methods and Results: In Wistar-Kyoto rats, direct renal interstitial administration of selective AT 2 R nonpeptide agonist Compound-21 (C-21) increased renal interstitial cyclic GMP (cGMP) levels, urine Na + excretion, and simultaneously increased PP2A activity ≈2-fold in homogenates of renal cortical tubules. The cyclic GMP and natriuretic responses were abolished by concurrent renal interstitial administration of protein phosphatase inhibitor calyculin A. In renal proximal tubule cells in response to C-21, PP2A subunits A, B55α and C, but not B56γ, were recruited to apical plasma membranes together with AT 2 Rs. Calyculin A treatment abolished C-21-induced translocation of both AT 2 R and PP2A regulatory subunit B55α to apical plasma membranes. Immunoprecipitation of AT 2 R solubilized from renal cortical homogenates demonstrated physical association of AT 2 R with PP2A A, B55α, and C but not B56γ subunits. In contrast, in spontaneously hypertensive rats, administration of C-21 did not alter urine Na + excretion or PP2A activity and failed to translocate AT 2 Rs and PP2A subunits to apical plasma membranes., Conclusions: In renal proximal tubule cells of Wistar-Kyoto rats, PP2A is activated and PP2A subunits AB55αC are recruited to C-21-activated AT 2 Rs during induction of natriuresis. This response is defective in prehypertensive and hypertensive spontaneously hypertensive rats, presenting a potential novel therapeutic target for treating renal Na + retention and hypertension.

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Background In spontaneously hypertensive rats (SHR) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. In this study, we evaluated whether metformin improved myocardial metabolic abnormalities and simultaneously prevented contractile dysfunction and left ventricular hypertrophy in SHR. Methods and Results SHR and control Wistar-Kyoto rats were treated with metformin from 2 to 5 months of age, when SHR hearts exhibit metabolic abnormalities and develop cardiac dysfunction and left ventricular hypertrophy. We evaluated the effect of metformin on myocardial glucose uptake rates with dynamic 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography. We used cardiac MRI in vivo to assess the effect of metformin on ejection fraction, left ventricular mass, and end-diastolic wall thickness, and also analyzed metabolites, AMP-activated protein kinase and mammalian target-of-rapamycin activities, and mean arterial blood pressure. Metformin-treated SHR had lower mean arterial blood pressure but remained hypertensive. Cardiac glucose uptake rates, left ventricular mass/tibia length, wall thickness, and circulating free fatty acid levels decreased to normal, and ejection fraction improved in treated SHR. Hearts of treated SHR exhibited increased AMP-activated protein kinase phosphorylation and reduced mammalian target-of-rapamycin activity. Cardiac metabolite profiling demonstrated that metformin decreased fatty acyl carnitines and markers of oxidative stress in SHR. Conclusions Metformin reduced blood pressure, normalized myocardial glucose uptake, prevented left ventricular hypertrophy, and improved cardiac function in SHR. Metformin may exert its effects by normalizing myocardial AMPK and mammalian target-of-rapamycin activities, improving fatty acid oxidation, and reducing oxidative stress. Thus, metformin may be a new treatment to prevent or ameliorate chronic hypertension-induced left ventricular hypertrophy.

Rationale: Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl 1 -angiotensin II])-elicited AT 2 R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR)., Objective: This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT 2 R signaling and renal sodium (Na + ) retention by utilizing the selective AT 2 R agonist compound-21 (C-21)., Methods and Results: Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic AT 1 R (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng/[kg·min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na + excretion from 0.023±0.01 to 0.064±0.02, 0.087±0.01, and 0.089±0.01 µmol/min ( P =0.008, P <0.0001, and P <0.0001, respectively) and renal interstitial fluid levels of AT 2 R downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91±0.3 to 3.1±1.0, 5.9±1.2 and 5.3±0.5 fmol/mL ( P =nonsignificant, P <0.0001, and P <0.0001, respectively). In contrast, C-21 did not increase urine Na + excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced AT 2 R translocation to apical plasma membranes of renal proximal tubule cells, internalization/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na + /K + ATPase (sodium-potassium-atpase) and phosphorylation of AT 2 R-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na + transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane AT 2 R recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or AT 2 R recruitment in SHR., Conclusions: The results demonstrate a primary renal proximal tubule cell AT 2 R natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension. Visual Overview: An online visual overview is available for this article.

Extracellular vesicles (EVs) have been described as novel biomarkers and bioactivators in vascular dysfunction in hypertension. However, the mechanism(s) by which EVs affect vascular function is unknown. To examine the effects of EVs on endothelial-dependent vasodilation (acetylcholine), we isolated circulating EVs from platelet-poor plasma using a low centrifugation speed (17 000 g ) and mesenteric resistance arteries from 12-week-old normotensive WKYs (Wistar-Kyoto rats) and SHRs (spontaneously hypertensive rats). Arteries were cannulated on a pressure myograph, and EVs were added to the vessel lumen and circulating bath. We found that circulating EVs from normotensive WKY reduced vasodilation of normotensive WKY arteries but had no effect on hypertensive SHR arteries. In contrast, EVs from hypertensive SHR failed to reduce vasodilation of arteries from both WKY and SHR. The restraining effect on vasodilation by EVs from normotensive WKY may be mediated by inhibition of eNOS (endothelial NO synthase), as addition of L-nitro-arginine methyl ester did not provide any additive effect. Moreover, circulating EVs from normotensive 6-week-old SHR-an age where SHRs have not yet developed hypertension-had similar restraining effect on vasodilation. In addition, delipidation of EVs did not alter the restraining effect of EVs from WKY but did restore the restraining effect of EVs from SHR. Finally, EVs from normotensive humans also restrained vasodilation of normotensive mouse arteries-an effect not observed in EVs from hypertensive humans. Taken together, our data support a vasoactive role of EVs that is altered in hypertension.

Intrarenal ghrelin infusion activates ghrelin receptors in the kidney collecting duct (CD) to increase α epithelial sodium (Na + ) channel ( α E Na C)-dependent Na + reabsorption in vivo , but the underlying mechanisms are unknown. Seventy-two hours following uninephrectomy, 12-week-old female Sprague-Dawley rats received the following renal interstitial (RI) infusions for 1 hour after a 1-hour control: vehicle (n = 10), ghrelin (3 μg/minute; n = 8), ghrelin + phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 (0.1 μg/kg/minute; n = 7), ghrelin + protein kinase A (PKA) inhibitor adenosine 3'5'-cyclic monophosphorothioate, Rp-isomer (10 μg/kg/minute; n = 8), ghrelin + microtubule polymerization inhibitor nocodazole (0.3 μg/kg/minute; n = 7), or ghrelin + actin polymerization inhibitor cytochalasin D (0.3 μg/kg/minute; n = 6). Compared with vehicle infusion, RI ghrelin induced a significant anti-natriuresis (urine Na + excretion was reduced by 53.7% ± 6.8%; P < 0.001). This effect was abolished during concomitant PKA or microtubule inhibition (106.4% ± 9.4% and 109.7% ± 10.6% of vehicle infusion, respectively; P < 0.01 from ghrelin) but not during concomitant PI3K or actin inhibition (reduced by 48.6% ± 3.9% and 52.8% ± 12.7%, respectively; P < 0.001 and P < 0.01 from vehicle, respectively; P = not significant from ghrelin). Infusions had no effect on mean arterial pressure. Western blot analysis demonstrated that CD membrane but not total α E Na C expression increased in response to ghrelin infusion compared with vehicle, (0.39 ± 0.05 vs 0.12 ± 0.02 arbitrary units; P < 0.01). This effect was abolished during PKA or microtubule inhibition but persisted during PI3K or actin inhibition. Neural precursor cell expressed, developmentally down-regulated 4 isoform 2 (Nedd4-2) dependent internalization of α E Na C was not affected by ghrelin, indicating that microtubule-dependent forward trafficking of α E Na C is necessary for anti-natriuretic responses to ghrelin. Taken together, these studies highlight the importance of PKA and microtubule polymerization in ghrelin-induced α E Na C-mediated Na + reabsorption., (Copyright © 2019 Endocrine Society.)

Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type-2 receptor ( AT 2 R)-induced natriuresis in normal rats, and that hypertensive 12-week-old spontaneously hypertensive rats ( SHR ) lack natriuretic responses to Ang III . This study tested whether prehypertensive SHR already have defective Ang III -induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4-week-old SHR and Wistar Kyoto rats were studied after 24-hour systemic AT 1 R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang III (3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4-week-old Wistar Kyoto rats, renal interstitial Ang III increased urine sodium (Na + ) excretion but failed to induce natriuresis in 4-week-old SHR . Renal Ang III levels were similar between Wistar Kyoto rats and SHR , making increased Ang III degradation as a possible cause for defective natriuresis in SHR unlikely. In Wistar Kyoto rats, renal interstitial Ang III induced translocation of AT 2 Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang III induced retraction of the major Na + transporter Na + -H + exchanger-3 ( NHE -3) from apical membranes and internalization of Na + /K + ATP ase ( NKA ) from basolateral membranes of renal proximal tubule cells. Consistent with NHE -3 and NKA retraction, Ang III increased pS er 552 - NHE -3 and decreased pS er 23 - NKA . In contrast, in SHR , intrarenal Ang III failed to induce AT 2 R translocation, NHE -3 or NKA retraction, pS er 552 - NHE -3 phosphorylation, or pS er 23 - NKA dephosphorylation. Conclusions These results indicate impaired Ang III / AT 2 R signaling as a possible primary defect in prehypertensive SHR .

Playas are the often most noticeable surface water feature in the Southern High Plains. The purpose of our study is to provide local and timely reference data on playa water quality and quantity in drier and wetter weather conditions. Water quality parameters of three playas in Texas, in the summer of 2016, were monitored via weekly environmental sampling. Annual water volume-depth dynamics within the study playas were also estimated by water balance informed by climate and geospatial data. The results showed that both direct rainfall and runoff affect the volume of water within the playa where the volume of runoff entering into a playa is contingent upon the surrounding drainage area. In addition, water quality does vary substantially from playa to playa (conductivity 180-850 μS/cm, TOC 13-81 mg/L) and between playa and non-playa surface water. Differences were related to local soils, drainage area size/slope, and land use. It was also found from the water quality analysis that playas are capable of containing a quality of water that would make them an attractive habitat for wildlife. The greatest economic value of playas may be their ability to contain high quantities of biodiversity though the future of their capacity to do so is uncertain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl- and branched chain amino acid-derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 month-old SHR. Conclusions Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension-induced left ventricular hypertrophy.

The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells, where it increases epithelial Na + channel (αE Na C)-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in angiotensin II-dependent hypertension via reductions in αE Na C-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats ( n = 121) received subcutaneous osmotic pumps for chronic systemic delivery of angiotensin II or vehicle (5% dextrose in water). Rats also received intrarenal infusion of vehicle, GR siRNA, or scrambled (SCR) siRNA. In rats receiving intrarenal vehicle or intrarenal SCR siRNA, systemic angiotensin II infusion increased sodium retention and BP on day 1, and BP remained elevated throughout the 5-day study. These rats also demonstrated increased CD GR expression after 5 days of infusion. However, intrarenal GR siRNA infusion prevented angiotensin II-mediated sodium retention on day 1, induced a continuously negative cumulative sodium balance compared with angiotensin II alone, and reduced BP chronically. Glomerular filtration rate and renal blood flow remained unchanged in GR siRNA-infused rats. Systemic angiotensin II infusion also increased serum aldosterone levels, CD αE Na C, and phosphorylated serum and glucocorticoid-inducible kinase 1 expression in rats with intrarenal SCR siRNA; however, these effects were not observed in the presence of intrarenal GR siRNA, despite exposure to the same systemic angiotensin II. These data demonstrate that chronic inhibition of intrarenal GR activity significantly reduces αE Na C-dependent sodium retention, resulting in a negative cumulative sodium balance, thereby ameliorating angiotensin II-induced hypertension in rats. Renal GRs represent a novel therapeutic target for the treatment of hypertension and other sodium-retaining states.

One challenge for gerontology is getting more students interested in aging at an earlier point in their academic career. This study evaluated the impact of an interdisciplinary course on aging designed for first-year undergraduate students. The course aimed to expand students' appreciation of the personal and professional relevance of aging issues, with the goal of expanding their aging-related curricular and career interests. Main outcome variables of the study included knowledge of older adults and aging, attitudes toward older adults, and anxiety about personal aging. Participants included an intervention group enrolled in the course and a control group not enrolled in the course. Compared to baseline, at the end of the semester students in the class had more knowledge about aging and more positive explicit attitudes toward older adults, but their implicit attitudes toward older adults and anxiety about aging did not change. Control students showed no changes. These findings suggest that objective knowledge of aging and explicit attitudes improve with curricular intervention, but implicit attitudes and anxiety might be more difficult to change. Gerontology education is a complex undertaking whose diverse goals must be clearly articulated in order to guide curricular interventions and incite curiosity among young undergraduate students.

Rationale: Compound 21 (C-21) is a highly selective nonpeptide angiotensin AT2 receptor (AT2R) agonist., Objective: To test the hypothesis that chronic AT2R activation with C-21 induces natriuresis via an action at the renal proximal tubule (RPT) and lowers blood pressure (BP) in experimental angiotensin II (Ang II)-dependent hypertension., Methods and Results: In rats, Ang II infusion increased both sodium (Na(+)) retention and BP on day 1, and BP remained elevated throughout the 7-day infusion period. Either intrarenal or systemic administration of C-21 prevented Ang II-mediated Na(+) retention on day 1, induced continuously negative cumulative Na(+) balance compared with Ang II alone, and reduced BP chronically. The effects of C-21 are likely to be mediated by action on the RPT as acute systemic C-21-induced natriuresis was additive to that induced by chlorothiazide and amiloride. At 24 hours of Ang II infusion, AT2R activation with C-21, both intrarenally and systemically, translocated AT2Rs from intracellular sites to the apical plasma membranes of RPT cells without altering the total cellular pool of AT2Rs and internalized/inactivated major RPT Na(+) transporters Na(+)-H(+)-exchanger-3 and Na(+)/K(+)ATPase. C-21 lowered BP to a similar degree whether administered before or subsequent to the establishment of Ang II-dependent hypertension., Conclusions: Chronic AT2R activation initiates and sustains receptor translocation to RPT apical plasma membranes, internalizes/inactivates Na(+)-H(+)-exchanger-3 and Na(+)/K(+)ATPase, prevents Na(+) retention resulting in negative cumulative Na(+) balance, and lowers BP in experimental Ang II-induced hypertension. Acting uniquely at the RPT, C-21 is a promising candidate for the treatment of hypertension and Na(+)-retaining states in humans., (© 2016 American Heart Association, Inc.)

A 9-year water dataset from the Houston Ship Channel (HSC) was analyzed to understand partitioning in polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/Fs). Total PCBs had more mass as dissolved (74%) whereas total PCDD/Fs did not (11%). Generally, the limited number of PCDD/Fs (only 2378 substituted) explained these differences though differences in chemical behavior beyond log K ow also likely influence partitioning. The particular fractionation seen in the HSC also seemed related to a wide variation in particulate organic carbon (POC)/dissolved organic carbon (DOC) ratio (0.42-180%). Published and unaltered linear free energy and linear solvation energy relationships for DOC, POC, and particulate black carbon (BC) resulted in predictions that were at best 27% (PCB) and 25% root-mean-square error (RMSE) (PCDD/F) partition fraction compared to observed (using estimated BC/POC fractions of 10 and 25%, respectively). These results show, at least in light of the uncertainties in this data (e.g., precise fraction of BC), that a 25% accuracy in model prediction of operationally dissolved or suspended fraction for any one PCB or PCDD/F congener is the best prediction that may be expected. It is therefore recommended that site-specific data be used to calibrate most any water column-partitioning model if it is to be expected to describe what actually occurs in field conditions.

Rationale: Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist., Objective: To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice., Methods and Results: In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension., Conclusions: AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension., (© 2014 American Heart Association, Inc.)

Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD-induced hypertension. Dahl salt-sensitive rats received standard diet or HFD for 6 weeks. Rats underwent uninephrectomy and osmotic minipump implantation for chronic intrarenal delivery of vehicle (0.25 μL/h × 28 d), selective GHSR antagonist [D-Lys-3]-growth hormone releasing peptide-6 (0.2μM/d), or GHSR inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (SUB-P) (3.6μM/d). HFD rats with vehicle pumps had significantly increased renal GHSR expression compared with standard diet (0.092 ± 0.005 vs 0.065 ± 0.004 arbitrary units; P < .05), whereas acyl ghrelin levels were similar (16.3±6.2 vs 15.7±8.7 pg/g tissue). HFD rats with vehicle pumps became hypertensive after 2 weeks (P < .05) and showed a significant reduction in 24-hour urine Na(+) before hypertension. At this time, these rats showed an increase in collecting duct α-epithelial Na(+) channel, thereby providing a potential mechanism for the excess Na(+) reabsorption. In contrast, HFD rats with [D-Lys-3]-growth hormone releasing peptide-6 or SUB-P pumps never became hypertensive and did not show the reduction in urine Na(+). Because SUB-P blocks the constitutive, but not ghrelin-dependent, activity of the GHSR, and HFD-induced α-epithelial Na(+) channel up-regulation was abolished during GHSR antagonism, these data suggest that HFD increases the constitutive activity of renal GHSR to increase Na(+) reabsorption and induce hypertension in rats.

Wastewater effluent samples were collected in the summer of 2009 from 16 different locations which included municipal and industrial wastewater treatment plants and petrochemical industrial outfalls in the Houston area. The effluent samples were analyzed for all 209 polychlorinated biphenyls (PCBs) congeners using high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) using the USEPA method 1668A. The total PCBs (∑209) concentration in the dissolved medium ranged from 1.01 to 8.12 ng/L and ranged from 2.03 to 31.2 ng/L in the suspended medium. Lighter PCB congeners exhibited highest concentrations in the dissolved phase whereas, in the suspended phase, heavier PCBs exhibited the highest concentrations. The PCB homolog concentrations were dominated by monochlorobiphenyls through hexachlorobiphenyls, with dichlorobiphenyls exhibiting the highest concentration amongst them at most of the effluent outfalls, in the suspended phase. Both total suspended solids (TSS) and various organic carbon fractions played an important role in the distribution of the suspended fractions of PCBs in the effluents. The log Koc values determined in the effluents suggest that effluent PCB loads might have more risk and impact than what standard partitioning models predict., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation., Methods and Results: Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice., Conclusions: Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.

The main distal nephron segment sodium transporters are the distal tubule chlorothiazide-sensitive sodium chloride cotransporter (NCC) and the collecting duct amiloride-sensitive epithelial sodium channel (ENaC). The infusion of ghrelin into the renal interstitium stimulates distal nephron-dependent sodium reabsorption in normal rats, but the mechanism is unknown. Here we localize renal ghrelin receptors (GR) to the cortical collecting duct (CCD). Ghrelin significantly increased phosphorylated serum/glucocorticoid-regulated kinase-1 (pSGK1), a major upstream signaling intermediate regulating ENaC. To test whether increased apical membrane αENaC induced the antinatriuresis, ghrelin was infused in the presence of acute and chronic amiloride, a selective inhibitor of ENaC. In the presence of amiloride, renal interstitial ghrelin failed to reduce urine sodium excretion, suggesting that ghrelin-induced sodium reabsorption is dependent on intact ENaC activity. While the main sodium transporter of the CCD is ENaC, NCC is also present. In response to renal interstitial ghrelin infusion, neither total nor phosphorylated NCC levels are altered. Ghrelin-induced sodium reabsorption persisted in the presence of chlorothiazide (selective inhibitor of NCC), indicating that intact NCC activity is not necessary for ghrelin-induced antinatriuresis. Finally, renal interstitial ghrelin infusion significantly increased interstitial cAMP levels and adenylyl cyclase blockade abolished ghrelin-induced antinatriuresis. Thus, GRs expressed in the CCD regulate sodium reabsorption by cAMP-induced trafficking of ENaC to the apical membrane.

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.

cGMP functions as an extracellular (paracrine) messenger acting at the renal proximal tubule and is an important modulator of pressure-natriuresis (P-N). The signaling pathway activated by cGMP in the tubule cell basolateral membrane remains unknown. We hypothesized that renal interstitial microinfusion of cGMP (50 nmol/kg per minute) or P-N would be accompanied by increased renal protein levels of phospho-Src (Tyr 416) and that the natriuresis would be decreased by Src inhibition. Renal interstitial cGMP-induced natriuresis was blocked by Src inhibitor PP2 (2.0±0.4 versus 0.5±0.01 μEq/g per minute; P<0.001). The inactive analog of PP2, PP3, had no effect on cGMP-induced natriuresis. SU6656, another Src inhibitor, also inhibited cGMP-induced natriuresis (2.0±0.4 versus 1.02±0.01 μEq/g per minute; P<0.001). Renal interstitial cGMP infusion increased phospho-Src protein levels 5.6-fold at 15 minutes and 6.8-fold at 30 minutes compared with vehicle infusion but returned toward basal levels after 60 minutes. PP2 also blunted P-N (3.1±0.1 versus 1.1±0.3 μEq/g per minute; P<0.01) despite a similar increase in blood pressure. PP3 had no effect on P-N. Phospho-Src protein levels increased during P-N in vehicle- (1.8-fold) and PP3-treated (2.1-fold) groups compared with the sham-operated group. PP2 blocked the pressure-induced increase in renal phospho-Src protein levels. PP2 had no effect on renal hemodynamics but decreased both fractional excretion of Na(+) and lithium. Both extracellular cGMP and increased renal perfusion pressure increased renal phospho-Src protein levels and induced natriuresis in an Src-dependent manner, demonstrating that Src is an important downstream signaling molecule for extracellular cGMP-induced natriuresis.

All 209 PCB congeners are quantified in water in both dry and wet weather urban flows in Houston, Texas, USA. Total water PCBs ranged from 0.82 to 9.4ng/L in wet weather and 0.46 to 9.0ng/L in dry. Wet weather loads were 8.2 times higher (by median) than dry weather with some increases of over 100-fold. The majority of the PCB load was in the dissolved fraction in dry weather while it was in the suspended fraction in wet weather. Dissolved PCB loads were correlated with rain intensity and highly developed land area, and a multiple linear regression (MLR) equation was developed to quantify these correlations. PCA generated five PCB components with nearly all positive loadings. They were interpreted as DOC-associated A1248, wet weather primarily suspended fraction A1254/A1260 likely from building sealants, truly dissolved-associated wastewater dechlorination, watershed-sourced PCB 11, and monochlorinated PCBs (likely connected to a different state or source of dechlorination). The PCB 11 component was statistically higher in wet versus dry weather when no other component showed such clear distinctions. Hierarchical cluster analysis (HCA) did not always group dry and wet weather samples from the same location together illustrating the different congener composition that often exists between dry and wet conditions. Four wet weather samples from high percentage developed land (>90%) watersheds had nearly the same fingerprint suggesting a generic "urban" signature in runoff, which in this case was caused by residual A1254/A1260 PCB stocks and currently produced PCB 11 in consumer goods., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Renal dopamine receptor function and ion transport inhibition are impaired in essential hypertension. We recently reported that caveolin-1 (CAV1) and lipid rafts are necessary for normal D(1)-like receptor-dependent internalization of Na-K-ATPase in human proximal tubule cells. We now hypothesize that CAV1 is necessary for the regulation of urine sodium (Na(+)) excretion (U(Na)V) and mean arterial blood pressure (MAP) in vivo. Acute renal interstitial (RI) infusion into Sprague-Dawley rats of 1 μg·kg⁻¹·min⁻¹ fenoldopam (FEN; D(1)-like receptor agonist) caused a 0.46 ± 0.15-μmol/min increase in U(Na)V (over baseline of 0.29 ± 0.04 μmol/min; P < 0.01). This increase was seen in Na(+)-loaded rats, but not in those under a normal-sodium load. Coinfusion with β-methyl cyclodextrin (βMCD; lipid raft disrupter, 200 μg·kg⁻¹·min⁻¹) completely blocked this FEN-induced natriuresis (P < 0.001). Long-term (3 day) lipid raft disruption via continuous RI infusion of 80 μg·kg⁻¹·min⁻¹ βMCD decreased renal cortical CAV1 expression (47.3 ± 6.4%; P < 0.01) and increased MAP (32.4 ± 6.6 mmHg; P < 0.001) compared with vehicle-infused animals. To determine whether the MAP rise was due to a CAV1-dependent lipid raft-mediated disruption, Na(+)-loaded rats were given a bolus RI infusion of CAV1 siRNA. Two days postinfusion, cortical CAV1 expression was decreased by 73.6 ± 8.2% (P < 0.001) and the animals showed an increase in MAP by 17.4 ± 2.9 mmHg (P < 0.01) compared with animals receiving scrambled control siRNA. In summary, acute kidney-specific lipid raft disruption decreases CAV1 expression and blocks D(1)-like receptor-induced natriuresis. Furthermore, chronic disruption of lipid rafts or CAV1 protein expression in the kidney induces hypertension.

PCDD/F and PCB field data (1041 samples) in five media (dissolved, suspended sediment, bed sediment, catfish, and blue crab) were studied to explore dual contaminant patterns in the Houston Ship Channel, Texas, USA. PCDD/Fs showed greater concentration than PCBs in suspended sediments while PCBs were higher in apparent dissolved (truly dissolved+DOC-associated), fish, and crab. PCDD/Fs at nearly all locations contributed more strongly to dioxin-like toxicity. The fraction of PCB TEQ was, however, enriched in biotic over abiotic media due in large part to the presence of PCB 126, which was mostly undetected in water and sediment and yet exhibited a BAF three times greater than 2,3,7,8-TCDD. Dissolved-suspended sediment and suspended-bed sediment relationships showed that (1) observed apparent dissolved concentration differences (as fraction of total water were mean 10% PCDD/Fs and 63% PCBs) can reasonably be explained by a four-phase partition model (truly dissolved, DOC-associated, suspended OC, and suspended BC) for PCBs but not for PCDD/Fs and (2) the contaminants behaved similarly in bed to suspended sediment concentration ratios (C(bed)/C(susp)) upstream of a major confluence but not downstream. PCA-cluster analysis pointed to the possibility that suspended sediment PCB contamination originates from resuspended bed sediment while PCDD/Fs in suspended sediment originates more probably from other sediment sources such as upstream wash load or air deposition. Finally, examinations of a congener marker ratio (PCB 209/206) seemed to indicate that a source of pure PCB 209 may exist in bed sediment near Patrick Bayou though the source was not completely localized., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Ghrelin is a 28-amino acid peptide hormone that exerts powerful orexigenic effects. Ghrelin receptor expression has been reported in the kidney, but the role of ghrelin in the kidney is unknown. The present studies confirmed ghrelin receptor mRNA expression in the kidneys of normal Sprague Dawley rats (n=6) using reverse transcription polymerase chain reaction (PCR) and sequencing of the 588-bp PCR product. To test intrarenal ghrelin action, uninephrectomized rats received 3 cumulative 1-hour renal interstitial (RI) infusions of 5% dextrose in water (vehicle, n=21), ghrelin (n=10), ghrelin plus specific ghrelin receptor antagonist [D-Lys-3]-GHRP-6 (n=24), or [D-Lys-3]-GHRP-6 alone (n=32). Mean arterial pressure (MAP), urine sodium excretion rate (U(Na)V), glomerular filtration rate (GFR), fractional excretion of sodium (FE(Na)), and fractional excretion of lithium (FE(Li)) were calculated for each period. RI ghrelin infusion significantly decreased U(Na)V to 86 ± 4.9% (P<0.05), 74 ± 6.5% (P<0.01), and 62 ± 10% (P<0.01) of baseline during periods 1 to 3, respectively. Ghrelin also significantly decreased FE(Na) to 68 ± 11% (P<0.05), 57 ± 8.6% (P<0.001), and 59 ± 12% (P<0.01) of baseline, without changing GFR or FE(Li). Identical ghrelin infusions in the presence of [D-Lys-3]-GHRP-6 failed to permit reductions in U(Na)V or FE(Na). Following [D-Lys-3]-GHRP-6 infusion alone, U(Na)V increased from 0.06 ± 0.01 to 0.18 ± 0.03 μmol/min (P<0.0001). Concomitant increases in FE(Na) were also observed (0.23 ± 0.03% to 0.51 ± 0.06% [P<0.001]), without changes in MAP, GFR, or FE(Li). Together, these data introduce a novel intrarenal ghrelin-ghrelin receptor system, which, on activation, significantly increases Na(+) reabsorption at the level of the distal nephron.

An on-going study in the Houston Ship Channel (HSC) characterized polychlorinated biphenyl (PCB) levels in sediment, water, and tissue in 2002-2003 and 2008. The observed PCB concentration ranges in all media were higher than those measured in other PCB-impacted water bodies in the world, with the highest concentrations occurring within the industrialized segments. Contrary to polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/PCDF) observations, the PCB concentrations in the dissolved phase were greater than the suspended phase. Possible explanations include passage of colloids, competition for adsorption sites from other hydrophobic contaminants, and continuing current sources. The PCB homologue distributions were similar for suspended water, sediment and tissue with the profile normalized around penta-chlorobiphenyls, while the dissolved phase profile normalized around tri-chlorobiphenyls. PCB-209 was detected in the suspended water phase and in sediment (10%) prompting interest into its sources to the HSC since PCB-209 was present only in rare commercial mixtures and is a byproduct in very few manufacturing processes. Inter-media analyses showed a significant correlation and transfer of PCBs. Dioxin-like PCBs contributed significant toxicity to total equivalent in tissue (33%), while they were insignificant in water (<10%) and sediment (<5%). The PCB concentrations over time showed a significant decrease in suspended water, sediment and tissue, while dissolved water concentrations showed insignificant change. The homolog distribution, however, showed a significant change in dissolved water and fish, a minor change in sediment and insignificant change in suspended water. Furthermore, an analysis for six representative congeners showed that they were accurate in predicting the total PCB concentrations and could be thus used as indicator PCBs., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (U(Na)V), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs). Although renal interstitial infusion of Ang II type 1 receptor blocker candesartan increased U(Na)V in WKYs from a baseline of 0.05+/-0.01 to 0.17+/-0.04 micromol/min (P<0.01), identical infusions failed to increase U(Na)V in hypertensive SHRs. Coinfusion of AT(2)R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT(2)R-mediated effect. AT(2)R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.05+/-0.01 to 0.11+/-0.03 micromol/min; P<0.05). The defects in sodium excretion were present before the onset of hypertension in SHRs, because young WKYs demonstrated double the U(Na)V of SHRs (0.04+/-0.006 versus 0.02+/-0.003 micromol/min; P<0.01) at baseline. The increased U(Na)V of young WKYs was attributed to reduced renal proximal tubule sodium reabsorption, because increases in fractional excretion of sodium were paralleled by increases in fractional excretion of lithium. Renal interstitial PC-18 infusion ameliorated defective AT(2)R-mediated natriuresis in young SHRs by increasing fractional excretion of sodium and fractional excretion of lithium without changing the glomerular filtration rate. Thus, increased renal proximal tubule sodium retention is observed before the onset of hypertension in SHRs, and inhibition of the metabolism of Ang III ameliorates this pathophysiologic defect in sodium excretion.

This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-natriuresis.

In Sprague-Dawley rats, renal angiotensin (Ang) type 2 receptors (AT(2)Rs) mediate natriuresis in response to renal interstitial (RI) D(1)-like receptor stimulation or RI Ang III infusion. After D(1)-like receptor activation, apical membrane (AM) but not total renal proximal tubule cell AT(2)R expression is increased, suggesting that AM AT(2)R translocation may be important for natriuresis. The onset of hypertension in spontaneously hypertensive rats (SHRs) is preceded by defects in renal sodium excretion. The present study examines AT(2)R-mediated natriuresis in response to RI Ang III infusion in Wistar-Kyoto rats (WKYs) and SHRs. WKYs and SHRs received RI Ang III infusion after 24 hours of systemic AT(1)R blockade with candesartan. In WKYs, urine sodium excretion rate increased from 0.043+/-0.01 to 0.191+/-0.06 micromol/min (P<0.05) in response to Ang III infusion, but identical conditions failed to increase the urine sodium excretion rate in SHRs. The increase in the urine sodium excretion rate was blocked by coinfusion of PD-123319, a selective AT(2)R antagonist. On confocal microscopy images, Ang III-infused WKYs demonstrated greater renal proximal tubule cell AM AT(2)R fluorescence intensity compared with SHRs (5385+/-725 versus 919+/-35; P<0.0001), and Western blot analysis demonstrated increased AM (0.050+/-0.003 versus 0.038+/-0.003; P<0.01) but not total cell AT(2)R expression in WKYs. In SHRs, AM AT(2)R expression remained unchanged in response to RI Ang III infusion. Thus, RI Ang III infusion elicits natriuresis and renal proximal tubule cell AT(2)R translocation in WKYs. Identical manipulations fail to induce natriuresis or AT(2)R translocation in SHRs, suggesting that defects in AT(2)R-mediated natriuresis and trafficking may be important to the development of hypertension in SHRs.

Extracellular renal interstitial (RI) cGMP modulates NO- and pressure-induced natriuresis in vivo in the rat. The present study objective was to test the hypothesis that an intact microtubulin network is required for transport of cGMP from intracellular sites into the extracellular compartment in vivo and that this transport is required for natriuresis induced by NO and increased renal perfusion pressure. After a 1-hour control period, uninephrectomized rats received an RI infusion of NO donor S-nitroso-N-acetylpenicillamine (SNAP), SNAP+microtubule inhibitor nocodazole (NOC), SNAP+NOC+cGMP, or NOC alone for 2 consecutive 1-hour collection periods. SNAP alone increased RI cGMP (P<0.05 during both experimental periods) and urinary sodium excretion (P<0.05 at 1 hour and P<0.005 at 2 hours). In contrast, when SNAP+NOC were coinfused, there was no increase in either RI cGMP or urinary sodium excretion. However, when cGMP was coinfused with SNAP+NOC, the natriuretic response to SNAP was fully restored. Similarly, NOC abolished SNAP-induced increases in the fractional excretion of Na(+) and Li(+). NOC also prevented the increase in both RI cGMP and natriuresis engendered by raising renal perfusion pressure in uninephrectomized rats, and pressure-natriuresis was re-established by coadministration of RI cGMP. As demonstrated by confocal microscopy after in vivo renal perfusion fixation, beta-tubulin was disrupted in renal cortical nephrons of kidneys infused intrarenally with NOC. These observations indicate that a functioning microtubulin network is required for the transport of cGMP into the extracellular space to modulate NO- and pressure-induced natriuresis.

In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA). In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN). Renal interstitial (RI) infusion of Ang III, but not Ang II, results in angiotensin type-2 receptor (AT(2)R)-mediated natriuresis. This response is augmented by coinfusion of PC-18, a specific inhibitor of APN. The present study addresses the hypotheses that Ang II conversion to Ang III is critical for the natriuretic response. Sprague-Dawley rats received systemic angiotensin type-1 receptor (AT(1)R) blockade with candesartan (CAND; 0.01 mg/kg/min) for 24 hours before and during the experiment. After a control period, rats received either RI infusion of Ang II or Ang II+PC-18. The contralateral kidney received a RI infusion of vehicle in all rats. Mean arterial pressure (MAP) was monitored, and urinary sodium excretion rate (U(Na)V) was calculated separately from experimental and control kidneys for each period. In contrast to Ang II-infused kidneys, U(Na)V from Ang II+PC-18-infused kidneys increased from a baseline of 0.03+/-0.01 to 0.09+/-0.02 micromol/min (P<0.05). MAP was unchanged by either infusion. RI addition of PD-123319, an AT(2)R antagonist, inhibited the natriuretic response. Furthermore, RI addition of EC-33, a selective APA inhibitor, abolished the natriuretic response to Ang II+PC-18. These data demonstrate that RI addition of PC-18 to Ang II enables natriuresis mediated by the AT(2)R, and that conversion of Ang II to Ang III is critical for this response.

Polychlorinated biphenyls (PCBs) were quantified in water, sediment, and catfish and crab tissue collected from the Houston Ship Channel (HSC) in Texas. The total concentrations of the 209 PCB congeners ranged from 0.49 to 12.49 ng l(-1), 4.18 to 4601 ng g(-1) dry wt, 4.13 to 1596 ng g(-1) wet wt, and 3.44 to 169 ng g(-1) wet wt, in water, sediment, catfish and crab tissue, respectively. All media showed maximum concentrations greater than studies in other regions with the highest concentrations occurring in the most industrialized segments of the channel. Inter-media correlations suggested that sediment is a source to water. Galveston Bay sediment concentrations compared to a previous study showed a declining trend though the rate of the decline may be slowing. Detailed homolog profiles revealed that the industrialized part of the channel may be receiving PCB-laden sediment from its tributaries. An unusually high fraction of the deca-chlorinated congener (PCB-209) was found in all media. Seen in only a few other studies and in previous air concentrations in the channel, this may point to unusual Aroclor mixtures used in the history of the HSC or to contemporary sources from local industry. A comparison of PCB concentrations obtained using Aroclor, representative congener, and all congener methods, indicated that Aroclors are not an appropriate surrogate for total PCBs and that the NOAA NST method is more representative than the NOAA EPA method.

This study addresses the hypothesis that NO- and pressure-induced natriuresis are inhibited when guanosine cyclic 3',5'-monophosphate (cGMP) is prevented from being transported outside its renal synthesizing cells in vivo. Rats received a renal interstitial (RI) infusion of NO donor S-nitroso-N-acetylpenicillamine (SNAP) or SNAP+organic anion transporter inhibitor probenecid (PB) or SNAP+PB+cGMP. SNAP alone increased U(Na)V (P<0.05 at 1 hour and P<0.005 at 2 hours). In contrast, SNAP failed to increase U(Na)V when coinfused with PB, but cGMP coinfused with SNAP+probenecid restored the natriuretic response. SNAP alone increased RI cGMP (P<0.05) during the second experimental period. PB abolished the increase in RI cGMP in response to SNAP (P<0.01), but cGMP levels were restored by coinfusion with cGMP. PB also abolished SNAP-induced increases in fractional excretion of Na(+) (FE(Na)) and lithium (FE(Li)) (both P<0.01). PB also abolished the rise in RI cGMP and natriuresis induced by raising renal perfusion pressure (RPP) from 100 to 160 mm Hg in rats subjected to a standard pressure-natriuresis protocol and the natriuretic response was rescued by coinfusion with cGMP. RI administration of phosphodiesterase type V (PDE V) reduced both RIcGMP and U(Na)V in parallel (both P<0.01) without altering RIcAMP. The data demonstrate that export of cGMP from its renal synthesizing cells into the extracellular RI compartment is critical for the natriuretic action of NO donor SNAP or increased RPP and that RI cGMP controls basal Na(+) excretion. Extracellular cGMP modulates NO- and pressure-induced natriuresis.

The renal angiotensin angiotensin type 2 receptor has been shown to mediate natriuresis, and angiotensin III, not angiotensin II, may be the preferential angiotensin type 2 receptor activator of this response. Angiotensin III is metabolized to angiotensin IV by aminopeptidase N. The present study hypothesizes that inhibition of aminopeptidase N will augment natriuretic responses to intrarenal angiotensin III in angiotension type 1 receptor-blocked rats. Rats received systemic candesartan for 24 hours before the experiment. After a 1-hour control, cumulative renal interstitial infusion of angiotensin III at 3.5, 7, 14, and 28 nmol/kg per minute (each dose for 30 minutes) or angiotensin III combined with aminopeptidase N inhibitor PC-18 was administered into 1 kidney. The contralateral control kidney received renal interstitial infusion of vehicle. In kidneys infused with angiotensin III alone, renal sodium excretion rate increased from 0.05+/-0.01 micromol/min in stepwise fashion to 0.11+/-0.01 micromol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=3.68; P<0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05+/-0.01 to 0.32+/-0.08 mumol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=6.2; P<0.001). The addition of intrarenal PD-123319, an angiotensin type 2 receptor antagonist, to renal interstitial angiotensin III plus PC-18 inhibited the natriuretic response. Mean arterial blood pressure and renal sodium excretion rate from control kidneys were unchanged by angiotensin III +/- PC-18 + PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA F=16.9; P=0.0001). Aminopeptidase N inhibition augmented the natriuretic response to angiotensin III, suggesting that angiotensin III is a major agonist of angiotensin type 2 receptor-induced natriuresis.

We explored the effects of direct renal interstitial stimulation of dopamine D(1)-like receptors with fenoldopam, a selective D(1)-like receptor agonist, on renal sodium excretion and angiotensin type-2 (AT(2)) receptor expression and cellular distribution in rats on a high-sodium intake. In contrast to vehicle-infused rats, sodium excretion increased in fenoldopam-infused rats during each of three 1-hour experimental periods (<0.001). Blood pressure was unaffected by vehicle or fenoldopam. In plasma membranes of renal cortical cells, fenoldopam increased D(1) receptor expression by 38% (P<0.05) and AT(2) receptor expression by 69% (P<0.01). In plasma membranes of renal proximal tubule cells, fenoldopam increased AT(2) receptor expression by 108% (P<0.01). In outer apical membranes of proximal tubule cells, fenoldopam increased AT(2) receptor expression by 59% (P<0.01). No significant change in total AT(2) receptor protein expression was detectable in response to fenoldopam. Fenoldopam-induced natriuresis was abolished when either PD-123319, a specific AT(2) receptor antagonist, or SCH-23390, a potent D(1)-like receptor antagonist, was coinfused with F (P<0.001). In summary, direct renal D(1)-like receptor activation increased urinary sodium excretion and the plasma membrane expression of AT(2) receptors in renal cortical and proximal tubule cells. D(1)-like receptor-induced natriuresis was abolished by intrarenal AT(2) receptor inhibition. These findings suggest that dopaminergic regulation of sodium excretion involves recruitment of AT(2) receptors to the outer plasma membranes of renal proximal tubule cells and that dopamine-induced natriuresis requires AT(2) receptor activation.

This study addressed factors associated with six-month post-acute dispositions (continuous community stay, medical hospitalization, psychiatric rehospitalization, nursing home placement, death) for older adults hospitalized for depression and discharged to the community. The sample included 199 older adults; and data were collected via medical records, interviews with discharge planners, patients, and family members. Over half of the sample remained in the community throughout the observation period; 23% experienced psychiatric re-admission and 10% entered a nursing home. Several factors associated with nursing home placement were identified: less improvement in depression during the hospitalization, lower Global Assessment of Functioning (GAF) scores at discharge; and less mental health service use in the post-acute period. Those at higher risk of psychiatric re-admission had more previous psychiatric hospitalizations and were marginally more likely to be married and have lower Brief Psychiatric Rating Scale (BPRS) scores at discharge. Differentiating those at risk for nursing home placement may be easier than differentiating those at risk of psychiatric readmission.

Using the SF-12 to measure physical and mental functioning, the authors examine the intra-individual changes in health-related quality of life (HRQOL) 6 months post-discharge for depressed older adults. In addition, they examine three sets of predictors that might influence these changes. The sample of depressed older adults was recruited from an inpatient geropsychiatry unit. Although their physical and mental health scores on the SF-12 were lower than comparable norms, the sample showed an average increase in their mental functioning but a decrease in the physical functioning over the 6 months. Negative life-events were significant predictors of people who reported no change in their mental health functioning and decreases in their physical health functioning. Interestingly, those who experienced positive life events were more likely to report declines and younger participants were more likely to report no change in their physical functioning. The findings indicate that the effects of depression on HRQOL can have enduring effects on a sample of previously hospitalized older adults. The significance of life event changes might signify the importance of taking into account non-traditional areas of medical interventions. Further, the findings indicate the usefulness of the SF-12 quantifying HRQOL outcomes.

Whereas angiotensin (Ang) II is the major effector peptide of the renin-angiotensin system, its metabolite, des-aspartyl1-Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT1) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT2) blocker, on Na+ excretion (UNaV) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on UNaV with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na+ intake, RI CAND increased UNaV from 0.07+/-0.08 to 0.82+/-0.17 micromol/min (P<0.01); this response was abolished by PD. During Na+ restriction, CAND increased UNaV from 0.06+/-0.02 to 0.1+/-0.02 micromol/min (P<0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter UNaV. However, with systemic CAND infusion, RI Ang III increased U(Na)V from 0.08+/-0.01 micromol/min to 0.18+/-0.04 micromol/min (P<0.01) at 3.5 nmol/kg per minute, and UNaV remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter UNaV at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT1 receptor blockade engenders natriuresis by activation of AT2 receptors. AT2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT1 receptor blockade.

Objective: The authors examined physical illness among elderly patients hospitalized for treatment of major depression, the impact of comorbidity on functional status, and the burden of comorbidity on post-discharge service needs., Methods: Data for this cross-sectional study were derived from patient interviews and abstracted from hospital charts. The sample comprised 195 older adults hospitalized for treatment of depression on the geropsychiatric unit of a large urban teaching hospital and discharged to home. Medical comorbidity was measured with the Cumulative Illness Rating Scale for Geriatrics. A psychiatrist confirmed DSM-IV for Axis I diagnosis of depression, and the Geriatric Depression Scale measured depression severity. Unit nurses administered the Mini-Mental State Exam. They assessed functional dependency via the OARS Multidimensional Functional Assessment Questionnaire. Service needs post-discharge were measured from physician discharge orders and patient scores on standardized tests., Results: Almost three-fourths of depressed elderly patients had at least one comorbid condition requiring first-line treatment; nearly half had two, and one-fourth had three or more. Comorbid physical illness and cognitive impairment was significantly and negatively associated with elderly patients' functional impairment at discharge. Depressed patients with higher medical comorbidity had significantly more needs for services after they left acute care., Conclusion: Medical comorbidity needs to be assessed and considered in planning for post-acute care for depressed elderly patients discharged home.

The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT(2) receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 microL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109+/-4 to 130+/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9+/-0.8 to 3.6+/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05+/-0.05 to 0.18+/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had approximately 40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.

Using a microdialysis technique, we monitored changes in right and left renal interstitial fluid angiotensins in anesthetized and conscious dogs (both n = 5) in response to right renal interstitial epinephrine (0.2 mg/kg per minute) administration. Renal interstitial and plasma angiotensin levels also were monitored in conscious dogs (n = 4) in response to dietary sodium deprivation (10 mmol/d) for 5 consecutive days. Changes in renal interstitial and plasma angiotensins in response to interstitial administration of a specific renin inhibitor, ACRIP (0.5 micrograms/kg per minute for 20 minutes), were monitored on day 5 of sodium depletion. At basal levels, there were no significant differences between the right and left renal interstitial immunoreactive angiotensin levels in anesthetized dogs. Renal interstitial epinephrine administration caused a significant increase in renal interstitial immunoreactive angiotensin concentrations in both anesthetized and conscious dogs (P < .01). However, anesthetized dogs had significantly higher renal interstitial immunoreactive angiotensin levels basally and in response to epinephrine than conscious dogs (P < .05). Renal interstitial immunoreactive angiotensin concentrations increased significantly and progressively during exposure to a low sodium diet from 3.9 +/- 1 nmol on day 1 to 740 +/- 332 nmol on day 5 (P < .01). Renal interstitial immunoreactive angiotensin decreased significantly to 124 +/- 37 nmol (P < .01) in response to intrarenal renin inhibition at the end of day 5 of sodium depletion. Plasma immunoreactive angiotensin increased significantly (P < .01) in response to sodium depletion, and no change occurred during intrarenal renin inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine is synthesized by the kidney, and dopamine-2 (DA2) receptors are present in the renal glomerulus. However, no role for DA2 receptors in the kidney has been defined. We investigated the possible role of DA2 receptors in control of renal function by intrarenal infusion of a highly specific DA2 antagonist YM-09151 (YM), in conscious uninephrectomized dogs (n = 5) in metabolic balance at Na intake 40 meq/day. YM infused at 0.01 pmol.kg-1.min-1 did not cause any changes in urinary flow rate or Na excretion. Administration of YM (infusions from 0.1 to 10.0 pmol.kg-1.min-1) caused a significant dose-dependent diuresis (F = 20.3; P less than 0.001) and natriuresis (F = 35.2; P less than 0.0001) and an increase in glomerular filtration rate (F = 45.4; P less than 0.0001), renal plasma flow (F = 209.3; P less than 0.0001), and filtration fraction (F = 11.2; P less than 0.0001). No significant changes in plasma renin activity, plasma aldosterone concentration, or mean arterial blood pressure occurred with any of the doses of YM infused into the renal artery. Coinfusion of LY-171555, a specific DA2 agonist, at a dose that itself did not affect renal function, completely abrogated the renal hemodynamic and excretory changes induced by YM. The data suggest that dopamine produced intrarenally may act at renal vascular and/or glomerular DA2 receptors to control renal function.

Dopamine (DA), a catecholamine produced in the kidney, is a renal vasodilator and natriuretic substance, but its action at dopamine-1 (DA-1), dopamine-2 (DA-2) and alpha- and beta-adrenergic receptors limits its effectiveness as a heuristic tool and pharmacologic agent. We have studied the effects of highly selective DA-1 and DA-2 receptor agonists and antagonists in normal human subjects and experimental animals to determine the precise physiological role of renal dopamine at DA-1 and DA-2 receptors within the kidney. We studied fenoldopam, a selective DA-1 agonist, in normal human subjects in metabolic balances at high (300 mEq/day) and low (10 mEq/day) sodium (Na) intake. Selective DA-1 receptor stimulation during high Na intake resulted in renal vasodilation, natriuresis and diuresis in a sustained manner for 3 hours. The natriuresis was mediated by a reduction in Na reabsorption at both proximal and distal tubular sites. In contrast, during low Na intake, DA-1 receptor stimulation did not engender a natriuretic or diuretic response. Thus, sodium depletion may inhibit the function of renal tubular cells in response to DA-1 stimulation. DA-1 receptors are present in the medial layer of the renal vasculature, proximal tubule and cortical collecting duct; DA-2 receptors are localized to the glomerulus, the renal nerves surrounding renal blood vessels and possibly the renal vascular endothelium. We have performed studies in conscious dogs with indwelling renal arterial catheters to identify the physiological role of renal DA to DA-1 and DA-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

We produced maximal or near-maximal acute intrarenal blockade of the renin-angiotensin system (RAS) by combining inhibitors. Intrarenal infusion of the renin inhibitor, ACRIP, the converting enzyme inhibitor, teprotide, and saralasin were administered individually or combined in random order. The inhibitors were infused for 20 min in doses that did not produce systemic effects in uninephrectomized conscious dogs in sodium balance at 10 meq/day. Significant increases in urine flow rate (UV; F = 97, P less than 0.0001), urinary sodium excretion (UNaV; F = 220, P less than 0.0001), glomerular filtration rate (GFR; F = 64, P less than 0.0001), and renal plasma flow (RPF; F = 108, P less than 0.0001) were observed with each blocker, whether alone or in combination except that ACRIP alone did not alter GFR or RPF. The increase in renal function was related to the number of blockers (3 greater than 2 greater than 1). With the three blockers combined UV increased approximately sixfold (from 0.5 +/- 0.06 to 2.9 +/- 0.03 ml/min), UNaV approximately 10-fold (from 3 +/- 0.4 to 34 +/- 2.8 mueq/min), GFR from 31 +/- 2 to 49 +/- 2 ml/min, RPF from 59 +/- 1 to 120 +/- 4 ml/min, and fractional excretion of sodium from 0.06 +/- 0.01 to 0.5 +/- 0.4% (all P less than 0.001). These changes did not occur where the inhibitors were infused systemically and the changes during intrarenal blocker administration were blocked completely with co-administration of angiotensin II intrarenally. The intrarenal RAS is a potent physiological regulator of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptors are classified to DA-1 and DA-2 and are characterized in renal tissue by radioligand binding and by the response of renal adenylate cyclase to dopaminergic agonists and antagonists. DA-1 receptors are localized in the renal tubules, the medial layer of renal microvessels, and the juxtaglomerular apparatus. DA-1 receptor stimulation causes dilation of renal, mesenteric, coronary, and cerebral vessels. In the present study, we tested the hypothesis that dopamine is a paracrine substance in the control of renal function. We employed a potent specific DA-1 receptor antagonist, SCH, to evaluate the role of intrarenal DA-1 receptor in the maintenance of renal function. Intrarenal DA-1 receptor blockade with SCH caused a highly significant dose-dependent antidiuresis and antinatriuresis, and decreased FENa. A rebound diuresis and natriuresis above control values were observed after cessation of DA-1 receptor blockade. There were no changes in renal hemodynamic function during DA-1 receptor blockade. These results strongly suggest that the antinatriuresis and antidiuresis induced by DA-1 receptor blockade are mediated by an action at the renal tubule. The infusion rate of SCH administered intrarenally was sufficiently low to produce no measurable systemic effects including PRA, PAC, and MAP. Thus, these results can be interpreted as due to intrarenal DA-1 blockade. In summary, we have demonstrated that renal excretory function is highly sensitive to DA-1 receptor blockade within the kidney and appears to be mediated by renal tubular events. This study provides strong evidence that DA-1 receptors play a physiological role in the control of renal function.

Dopamine is synthesized within the kidney and dopamine 1 (DA1) receptors are associated with the proximal tubule. In pharmacological doses, dopamine increases renal blood flow and sodium excretion. It is possible that dopamine formed intrarenally acts locally via renal dopamine receptors to control renal function. We investigated the possible paracrine action of renal dopamine by intrarenal administration of a specific DA1 antagonist, Sch 23390, in doses confined to the kidney in conscious uninephrectomized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Changes (mean +/- SE) in renal excretory and hemodynamic function in response to cumulative infusions of several doses of Sch 23390 (0.01, 0.1, 1.0, 5.0, and 10.0 pmol.kg-1.min-1) were studied. Sch 23390 at 0.01 pmol.kg-1.min-1 did not cause any changes in urinary flow rate or sodium excretion. Sch 23390 in doses from 0.1 to 10.0 mol.kg-1.min-1 caused a significant dose-dependent antidiuresis (F = 44.9, P less than 0.0001) and antinatriuresis (F = 42.1, P less than 0.0001) and a decrease in fractional sodium excretion (F = 44.2, P less than 0.0001). No changes in estimated renal plasma flow, glomerular filtration rate, plasma aldosterone concentration, plasma renin activity, or systemic arterial pressure occurred with any dose of intrarenal Sch 23390 infused into the renal artery. Rebound diuresis and natriuresis occurred after cessation of the DA1 blockade.(ABSTRACT TRUNCATED AT 250 WORDS)