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Clinical studies have demonstrated that estrogen replacement therapy suppresses stress-induced increases in plasma catecholamines. The present study determined whether normal circulating levels of estrogen can modulate hypoglycemia-induced increases in plasma epinephrine (EPI). In anesthetized female rats, insulin-induced hypoglycemia (0.25 U/kg) increased plasma EPI concentration to a significantly greater extent in 14-day ovariectomized (OVEX) rats compared to that in sham-operated controls. In 17β-estradiol (E2)-replaced OVEX rats, the hypoglycemia-induced rise in plasma EPI was reduced significantly when compared to that in vehicle-replaced OVEX rats. OVEX and E2 replacement had no effect on tyrosine hydroxylase or phenylethanolamine N-methyltransferase mRNA levels in the adrenal medulla. In isolated adrenal medullary chromaffin cells, agonist-induced increases in intracellular Ca2+ were unaffected by 48-hr exposure to 10 nM E2. In contrast, acute (3-min) exposure to micromolar concentrations of E2 dose-dependently and reversibly inhibited agonist-induced Ca2+ transients. In addition, in OVEX rats, a constant infusion of E2 significantly reduced the insulin-induced increase in plasma EPI concentration compared to that in vehicle-infused controls. These data demonstrate that physiologic levels of circulating E2 can modulate hypoglycemia-induced increases in plasma EPI. This effect seems independent of steroid influence on adrenal medullary secretion or biosynthesis. In contrast, acute exposure to high levels of E2 can also suppress hypoglycemia-induced increases in plasma epinephrine, due at least in part to inhibition of stimulus-secretion coupling. © 2004 Wiley-Liss, Inc.

Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Background Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na + , K + , and Cl − transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c ), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C (−/−) null). Results In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C (−/−) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C (−/−) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na + /K + ATPase γ-subunit and the Cl − channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C–independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na + /K + ATPase and ClC-K2.

Guanylin and uroguanylin are newly discovered intestinal peptides that have been shown to affect NaCl transport in both the intestine and kidney. The present study tests the hypothesis that guanylin and uroguanylin mRNA expression in each major region of the intestine is regulated by NaCl intake. Semiquantitative multiplex RT-PCR analysis was used to determine the molecular expression of guanylin and uroguanylin in the duodenum, jejunum, ileum, and colon in rats maintained on low (LS), normal (NS), or high (HS) NaCl intake for 4 days. LS intake reduced the expression of uroguanylin, and to a lesser degree, guanylin mRNA in all intestinal segments compared to NS intake. The duodenum was the site of the greatest decrease for both. In contrast, HS intake significantly increased the expression of guanylin mRNA only in the duodenum and jejunum and had minimal effect on uroguanylin mRNA. The minimum time required for altered gene expression was determined by delivering an oral NaCl challenge directly to the gastrointestinal tract by oro-gastric administration to LS or NS animals. In LS rats, NaCl oro-gastric administration significantly increased mRNA expression of both peptides in all intestinal segments. Furthermore, the increases in guanylin and uroguanylin mRNA were detected within 4 h and plateaued by 8 h. Conversely, acute oro-gastric administration of the same NaCl solution to NS rats caused elevations of guanylin mRNA only in the duodenum and jejunum, and of uroguanylin mRNA only in the ileum and colon. In conclusion, the data demonstrate that variations in NaCl intake lead to intestinal segment-specific changes in guanylin and uroguanylin mRNA expression.

Guanylin (GN) and uroguanylin (UGN) are two recently identified peptides that have been shown to affect water and electrolyte transport in both the intestine and the kidney. Mechanistically, the effects of both peptides are thought to be mediated by intracellular cGMP which results from ligand binding to a plasma membrane guanylyl cyclase-C (GC-C) receptor. To date, the specific intrarenal site(s) of GN and UGN action have not been established. To begin to address this issue, the present studies utilized semi-quantitative RT-PCR to assess the distribution of GC-C mRNA in specific microdissected segments of the rat nephron. GC-C mRNA expression was highest in the cortical collecting tubule, followed by the proximal convoluted tubule, medullary thick ascending limb and collecting tubule, and thin limbs of Henle's loop. Expression levels were significantly lower in all other segments tested, including the glomerulus. The renal tubular expression pattern for cGMP-dependent protein kinase II (cGK-II) mRNA, which is activated in response to GN/UGN-dependent cGMP accumulation, was similar to that for GC-C. Notably, both GN and UGN mRNAs were also expressed along the nephron. The highest levels of expression for both peptides were detected in the medullary collecting tubule. Lower, but comparable levels of GN and UGN expression also occurred in the cortical collecting tubule, cortical and medullary thick ascending limb, and thin limbs of Henles loop. In the proximal convoluted tubule, GN mRNA expression was also quite high, while UGN mRNA was almost undetectable. The presence of renal GC-C and cGK-II in the kidney are consistent with a proposed endocrine function for GN and UGN. In addition however, the present data suggest that intrarenally synthesized GN and UGN may also contribute to the regulation of renal tubular transport.

The aim of the present study was to determine whether dopamine affects NaCl reabsorption in the medullary thick ascending limb of the loop of Henle. Basolateral dopamine (10(-6) M) significantly inhibited Cl- reabsorption in the in vitro microperfused rat medullary thick ascending limb by 21 +/- 2% (P0.01). The response to 10(-6) M dopamine was completely blocked by pretreatment with the dopamine D1 receptor antagonist R(+)-SCH-23390 (5 x 10(-5) M), and was mimicked by the dopamine D1 receptor agonist A-77636 (10(-6) M; delta - 36 +/- 2%; P0.05). In contrast, basolateral administration of the dopamine D2 receptor agonist (+)-bromocriptine (10(-6) M) transiently increased Cl- reabsorption by 49 +/- 18% (P0.05). Neither the D1 nor the D2 agonist affected Cl- reabsorption when selectively administered to the luminal membrane. These data suggest that the predominant effect of dopamine on the medullary thick ascending limb of the rat is to inhibit the reabsorption of NaCl, a response which is mediated by dopamine D1 receptors.

The aim of the present study was to determine whether vasopressin affects NaCl reabsorption in the medullary thick ascending limb of the loop of Henle when administered selectively to the luminal membrane. At 5 x 10(-6) M and 10(-8) M, luminal [Arg8]vasopressin significantly inhibited Cl- transport in the in vitro microperfused rat medullary thick ascending limb by 46.4 +/- 5.9% (P0.01) and 32.4 +/- 2.0% (P0.05) respectively. The response to 10(-8) M luminal [Arg8]vasopressin was completely blocked by the vasopressin V1 receptor antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2,Arg8]vasopressin (10(-6) M), and was mimicked by the vasopressin V1 receptor agonist [Phe1, Ile5, Orn8]vasopressin (10(-8) M; delta -35.0 +/- 4.5%; P0.05). Luminal administration of the vasopressin V2 receptor agonist [deamino-Cys1, D-Arg8]vasopressin (5 x 10(-6) M) had no effect on transport. These data suggest that luminal vasopressin can inhibit NaCl transport in the medullary thick ascending limb of the rat via vasopressin V1 receptors.

Pharmacological blockade of the renin-angiotensin converting enzyme reportedly alters the heart rate (HR) power spectrum in conscious dogs, suggesting that these hormones contribute to the short-term regulation of arterial blood pressure. We tested this possibility using four independent procedures. First, HR power spectrum was determined in seven awake dogs before and after administration of enalaprilat (300 ng/kg), a converting-enzyme inhibitor. There were no significant changes in the average amplitude for the spectral peak between 0.003 and 0.1 Hz (i.e., the "low-frequency peak"). Second, the HR power spectrum was measured in 11 awake rabbits before and after treatment with deoxycorticosterone acetate (1 mg.kg-1.day-1) and salt (0.9% saline ad libitum) for 7 days to depress plasma renin levels. There were no significant changes in the amplitude of the HR power spectrum, although mean HR decreased from 206 +/- 3 to 184 +/- 4 beats/min after treatment. In the third experiment, another group of rabbits (n = 8) was tested after 2 wk on a low-salt diet to elevate plasma angiotensin levels and then after 2 wk on a normal salt diet. Once again there were no significant effects on the HR power spectrum. Finally, tranquilized dogs (n = 9) were subjected to sinusoidally varying lower body negative pressure at selected frequencies of 0.008-0.12 Hz. Tests were conducted in the control state and after administration of an angiotensin receptor antagonist (saralasin, 1 microgram.kg-1.min-1). Lower body negative pressure-induced fluctuations in arterial blood pressure were similar in both states. We find no evidence for the role of the renin-angiotensin system in the moment-to-moment regulation of arterial pressure and HR.

Embalming, the most common funeral practice in the United States, may expose the embalmer to infectious diseases and blood. We surveyed the 860 members of the National Selected Morticians in 1988 to estimate the incidence of self-reported occupational contact with blood and infectious disease, assess morticians' knowledge of acquired immunodeficiency syndrome (AIDS), determine their adherence to universal precautions, and identify predictors of practices designed to reduce risk of occupational exposure to infections. Of 539 (63%) respondents, 212 (39%) reported needle-stick injuries in the past 12 months, and 15 (3%) reported percutaneous exposures to the blood of a decedent with AIDS. Those rating the risk of occupationally acquired human immunodeficiency virus infection as very high or high (194/539 [36%]) were more likely to decline funerals of decedents with antemortem diagnosis of AIDS (59/194 [30%]) and/or to charge more for such funerals (133/194 [69%]) than those who rated the risk as low to moderate (31/345 [9%], 174/135 [51%]).

To test the hypothesis that impaired baroreflex control of heart rate in Dahl salt-sensitive (S) rats is due to an impairment of the parasympathetic limb of the bradycardic response, baroreflex sensitivity was evaluated in conscious, chronically instrumented Dahl S and salt-resistant (R) animals. Sensitivity was impaired in Dahl S rats when bolus doses of phenylephrine were administered (0.863 +/- 0.042 vs. 1.43 +/- 0.055 ms/mmHg), but it was not different than in R rats when tested with sodium nitroprusside. When the sensitivities before and after blocking the parasympathetic nervous system with atropine were compared, it was revealed that 82% of the reflex bradycardia resulting from bolus doses of phenylephrine was due to the parasympathetic nervous system, whereas the majority (73%) of the bradycardia induced by 5-min infusions of phenylephrine was due to withdrawal of sympathetic tone. Neither baroreflex sensitivity to infusions of phenylephrine (73% sympathetic) or to infusions after atropine (100% sympathetic) were significantly different between S and R rats. Therefore, the impairment of the heart rate reflex in Dahl S rats is due to an impairment of the parasympathetic limb of the response. In addition, a high-salt diet before the development of hypertension did not alter baroreflex sensitivity in either Dahl S or R rats.

Inhibition of plasma renin activity (PRA) by saline has been shown to be related to a specific effect of chloride. The purpose of this study was to test the hypothesis that inhibition of renin release by selective chloride infusion in the rat is related to increased chloride transport in the thick ascending limb of the loop of Henle (TALH). Measurements of loop of Henle function were obtained by micropuncture before and after a 5% body wt infusion of solutions containing either 0.15 mol/l NaCl, 0.15 mol/l lysine monohydrochloride (LysCl), or 0.15 mol/l Na-assorted anions (NaAA). Both NaCl and LysCl infusion lowered PRA (60.8 +/- 11.9 to 22.6 +/- 3.7 ng angiotensin I (ANG I).ml-1.h-1 and 53.3 +/- 6.8 to 34.5 +/- 4.6 ng ANG I.ml-1.h-1; P less than 0.05), whereas NaAA infusion had no effect on PRA (66.7 +/- 15.1 to 59.1 +/- 12.4 ng ANG I.ml-1.h-1). Analysis of late proximal and early distal fluid showed that chloride transport in the TALH was significantly elevated by infusion in all three groups, and there were no differences among the groups after infusion. Distal chloride concentration increased in the NaCl and LysCl groups (26 +/- 2 to 37 +/- 1 meq/l and 26 +/- 2 to 36 +/- 2 meq/l; P less than 0.05), but distal chloride concentration decreased in the NaAA group (28 +/- 2 to 22 +/- 1 meq/l; P less than 0.05). There was no correlation between PRA and fluid flow rate or chloride delivery to the distal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)

Our previous in vitro microperfusion studies established that dopamine inhibits sodium chloride transport in the rat medullary thick ascending limb. The present study was designed to determine the intracellular signaling pathway mediating this response. The dopamine D1 receptor agonist fenoldopam (1 microM) inhibited sodium chloride transport in the thick ascending limb by 42+/-5%. The dopamine D1 receptor antagonist R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH-23390) completely blocked this effect of fenoldopam. Suppression of protein kinase A activity using either myristoylated protein kinase inhibitor (PKI) or N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89), as well as suppression of phospholipase C activity using 1-(6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U-73122), had no effect on fenoldopam-dependent inhibition of transport. In contrast, inhibition of phospholipase A2 activity using E-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) significantly attenuated the effect of fenoldopam by 74%. The cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA) and the protein kinase C inhibitor staurosporine both significantly attenuated the effects of fenoldopam by 67%. Exposure to 20-Hydroxy-(5Z, 8Z, 11Z, 14Z)-eicosatetraenoic acid (20-HETE) inhibited transport by 31+/-5%, and this effect was significantly attenuated by 66% in the presence of staurosporine. We propose a signaling pathway in which dopamine activates a calcium-independent phospholipase A2 in the medullary thick ascending limb. Released arachidonic acid is then metabolized to 20-HETE which subsequently increases protein kinase C activity that acts as a final transport effector.

The aim of the present study was to determine whether a significant relationship exists between a student’s college (Allied Health, Arts and Science, Education, and Graduate School) and achievement in an advanced-level course in human physiology (PGY 412G). The mean percentage of correct answers on four multiple-choice tests, collectively totaling 400 points, was used to assess each student’s performance. A four (college)-by-three (academic year) analysis of variance was used for statistical comparisons among 660 students enrolled in PGY 412G from the fall semester of 1995 through the spring semester of 1998. Subsequent pairwise comparisons tests found that the College of Education students had a significantly lower mean percentage of correct answers (61%) compared with students in each of the other colleges ( P < 0.001). No significant differences in percentage scores were found among students enrolled in Allied Health (78%), Arts and Science (78%), or the Graduate School (77%). Also, percentages of correct answers averaged across all students were significantly lower during the 1997–1998 academic year than those in either the 1996–1997 year ( P < 0.001) or the 1995–1996 year ( P < 0.05). Students’ scores during these two earlier years did not differ significantly. Upward letter grade adjustments based on class distributions were made each semester, and more As and Bs and fewer Cs and Ds were given as course grades than expected from an absolute assessment scale. This grade inflation benefited low-scoring students from all colleges, particularly those students enrolled in the College of Education. To improve the understanding of human function of these low-scoring students may require special educational programs.

Recent studies from this laboratory demonstrated that bradykinin transiently elevates intracellular Ca2+ and inhibits Cl-reabsorption in the in vitro microperfused medullary thick ascending limb (mTAL) of the rat. The present study was designed to identify the intracellular signaling mechanism(s) that mediate this response. Preincubation with the intracellular calcium chelator BAPTA (10(-5) M) completely eliminated the bradykinin-dependent increase in intracellular Ca2+ and the suppression of Cl- transport. Preincubation with the cGMP-dependent protein kinase inhibitor H-89 (10(-5) M) had no effect on the transport response to bradykinin. In contrast, 17-octadecynoic acid (17-ODYA; 10(-5) M), a suicide-substrate inhibitor of renal cytochrome P450 omega-hydroxylase, completely blocked the transport response to bradykinin, while the cyclooxygenase inhibitor sodium meclofenamate (10(-5) M) had no effect. Finally, addition of the cytochrome P450 omega-hydroxylase metabolite 20-hydroxyeicosatetraenoic acid (20-HETE; 10(-8) M) to the bathing medium significantly inhibited Cl- transport in the mTAL (delta -39 +/- 6.0%; p0.05), while the epoxygenase metabolite 5,6-epoxyeicosatrienoic acid (5,6-EET; 10(-8) M) had no effect. These data suggest that the bradykinin-dependent inhibition of Cl- transport in the mTAL of the rat is mediated by cytochrome P450 dependent metabolite(s) of arachidonic acid.

Exposure to microgravity results in the loss of fluid and electrolytes.This study was designed to determine whether loss of fluid and electrolyte by the kidney occur by increased filtration or decreased tubular reabsorption and to investigate the mechanisms involved.Vascular and bladder catheters were implanted and the effects of preferential thoracic volume expansion were studied in conscious rats using a new hindlimb supported head-down tilt model designed to simulate the effects of microgravity. Control rats maintained at 0 degree tilt (NT) were compared to rats at 40 degrees head-down tilt (HDT).HDT immediately increased central venous pressure from 1.4 +/- 0.3 to 2.7 +/- 0.3 mm Hg (p0.01); which peaked after 8 h. Compared to NT, cumulative sodium excretion significantly increased within 6 h of HDT and remained increased at 24 h (198.8 +/- 40.3 vs. 72.8 +/- 18.4 microEq; p0.01). HDT also significantly increased glomerular filtration rate (GFR) at both 6 (p0.05) and 24 h (p0.01). In contrast, fractional proximal reabsorption (assessed by lithium clearance) was unchanged over the period of HDT, indicating an appropriate proximal tubule response to increased filtered sodium. HDT had no significant effect on plasma catecholamine or atrial natriuretic peptide concentration nor on plasma renin, while plasma aldosterone concentration was increased after 24 h (72.8 +/- 24.0 vs. 32.4 +/- 8.7 ng/dl; p0.05); presumably in response to sodium loss during HDT.HDT-induced thoracic volume expansion significantly increases sodium excretion, primarily as a result of an increase in GFR.

Elevated plasma atrial natriuretic peptide (ANP) levels and concomitant increases in renal sodium and water excretion are often encountered in respiratory diseases associated with increased airway resistance such as obstructive sleep apnea. The present study utilized an anesthetized rat model to determine the principal mechanism(s) responsible for stimulation of ANP release in this clinical syndrome. A 10-minute increase in external resistive loading, which reduced peak tracheal pressure to -15 to -17 mm Hg produced a significant increase in both central venous pressure and right atrial transmural pressure. This maneuver subsequently resulted in significant transient increases in glomerular filtration rate; urine flow; urinary Na+, K+, and Cl- excretion; and urinary cyclic guanosine monophosphate (cGMP) excretion, which was taken as an index of increased circulating levels of ANP. Similar changes in renal function and cGMP excretion occurred when arterial PO2 was lowered to a degree equivalent to that seen with increased resistive loading. Lowering arterial PO2 also significantly increased mean central venous pressure and right atrial transmural pressure. Conversely, the resistive loading-induced changes in renal function and cGMP excretion did not occur when the reduction in arterial PO2 was prevented by breathing a high O2 gas mixture during the resistive loading. Additionally, O2 supplementation prevented the increases in both mean central venous pressure and right atrial transmural pressure caused by increased resistive loading. These data indicate that the elevated ANP release that results from an acute increase in external resistive loading is not caused by a decrease in intrathoracic pressure but rather suggest that the elevated ANP release is primarily caused by an increased right atrial transmural pressure resulting from hypoxia-induced pulmonary vasoconstriction.

It is well established that the aminoglycoside antibiotics can adversely affect proximal tubule function. Predominantly indirect evidence suggests that aminoglycosides may also affect function of more distal nephron segments. The present study utilized whole kidney clearance, in vivo micropuncture and in vitro microperfusion to directly determine whether acute gentamicin treatment affects sodium chloride transport in the thick ascending limb of the loop of Henle. Gentamicin (25 mg/kg) significantly increased urine flow, as well as sodium, potassium and chloride excretion within 15 min of intravenous injection. Glomerular filtration rate and proximal tubule fluid reabsorption were not altered by acute gentamicin treatment. In contrast, both fractional and absolute loop chloride transport was significantly decreased. In the in vitro microperfused medullary thick ascending limb, luminal but not basolateral administration of gentamicin (1 mM) significantly decreased chloride reabsorption when compared to time controls. These data suggest that the increased urine and electrolyte excretion associated with acute gentamicin treatment is, at least in part, a consequence of decreased transport in the thick ascending limb of Henle's loop.

We have examined the effects of chronic gentamicin treatment on arginine 8 -vasopressin (AVP)-dependent cyclic AMP (cAMP) metabolism in rat medullary collecting tubules (oMCT) and medullary thick ascending limbs of Henle's loop (mTALH). Gentamicin attenuated AVP-stimulated cAMP accumulation to a greater extent in the mTALH (Δ −51%) than in the oMCT (Δ −25%). The mechanism of attenuation differed between segments, and could not be attributed to either direct inhibition of adenylate cyclase activity nor direct potentiation of cAMP-phosphodiesterase activity. These data suggest that the gentamicin-induced decrease in renal concentrating ability may be due at least in part to reduced AVP-dependent cAMP accumulation in the oMCT and mTALH.

We evaluated the effects of selective dietary chloride loading (without sodium) on plasma renin activity (PRA) and plasma aldosterone in the sodium-deprived Sprague-Dawley rat. Three groups of animals were fed one of the following diets for 13 days: 1) low NaCl; 2) high NaCl; or 3) low sodium, high chloride, provided as glycine hydrochloride. Compared with NaCl-deprived animals, PRA and plasma aldosterone were lower (P less than 0.01) in animals fed low sodium high chloride, whereas aldosterone in animals fed glycine hydrochloride was higher (P less than 0.01) than that of NaCl-deprived animals. In contrast, plasma concentrations of corticosterone and 18-hydroxycorticosterone were not increased by selective chloride loading. Glycine chloride-fed animals were acidotic and had elevated plasma concentrations of potassium and ionized calcium. Thus stimulation of aldosterone by selective chloride loading is not related to PRA or ACTH but may be due to a direct effect of acidosis or an indirect effect of acidosis on potassium and/or calcium. Additionally, selective chloride loading appears to stimulate the conversion of 18-hydroxycorticosterone to aldosterone.

To determine if alterations of electrolyte balance or sympathetic nervous system activity are present in Dahl salt-sensitive rats (DS) before the onset of hypertension, we compared electrolyte balances, extracellular fluid volume (inulin space), plasma volume (radiolabeled albumin), and norepinephrine turnover in peripheral tissues (heart and interscapular brown fat) in prehypertensive DS and Dahl salt-resistant rats (DR). Animals were maintained for 5 to 7 days on either a "normal" or high NaCl diet. Tissue norepinephrine turnover was evaluated by measuring the rate at which norepinephrine content decreased following tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine. Blood pressure was higher (p less than 0.05) in DS (135 +/- 2 [SE] mm Hg) than in DR (129 +/- 2 mm Hg) and was not affected by the diets. Extracellular fluid volume and net Na+ and Cl- balances did not differ between DS and DR. However, plasma volume was greater in DS than in DR (p less than 0.05). In both fat and heart, norepinephrine turnover was decreased by dietary NaCl loading in DR (p less than 0.01), but not in DS. Thus, the tendency of the DS to become hypertensive with high NaCl intake may be related to the combined effects of an increased plasma volume and the failure of high dietary NaCl to inhibit peripheral sympathetic nervous system activity.

The purpose of the present study is to determine whether changes of plasma renin activity (PRA) induced by dietary NaCl are mediated by a renal tubular mechanism or by a neural mechanism. Male Sprague-Dawley rats were placed on low-, normal-, or high-NaCl diets for 1 wk (n = 8 for each group). There were no group differences of glomerular filtration rate (GFR), renal plasma flow, Na+ or Cl- delivery to the loop, Na+ or Cl- reabsorption in the loop, Na+ or Cl- concentration in early distal tubular fluid, or Na+ or Cl- delivery to the early distal tubule. PRA of rats on normal NaCl (4.8 ng.ml-1.h-1 +/- 0.8) was greater (P less than 0.05) than that of rats on high NaCl (3.3 +/- 0.4) and less (P less than 0.05) than that of animals on low NaCl (9.1 +/- 1.8). To determine whether alterations of PRA by dietary NaCl might be related to low-pressure baroreceptors with vagal afferents, animals were bilaterally vagotomized after micropuncture. Forty-five minutes after vagotomy, PRA increased (P less than 0.05) on each of the diets, however, after vagotomy mean PRA in animals fed normal (10.9 +/- 1.8) and low NaCl (13.2 +/- 2.2) did not differ. Thus our results do not support the hypothesis that suppression of PRA by dietary NaCl loading is related to a renal tubular mechanism. A vagally mediated mechanism may contribute to renin suppression by dietary NaCl.

It has been reported that the concentration of chloride in the proximal tubule is greater than that in plasma in several mammalian species. Much of the theory concerning fluid and electrolyte reabsorption in the proximal tubule is based on data taken from in vitro isolated proximal tubules of the rabbit nephron. This study measured in vivo the rabbit proximal tubule fluid-to-ultrafiltrate chloride concentration ratio [(TF/UF)Cl] and its relationship to proximal tubule length as estimated by the tubule fluid-to-plasma inulin concentration ratio [(TF/P)In]. From six rabbits, 19 random proximal tubules were micropunctured and analyzed for inulin and chloride concentrations, the latter being measured by microelectrometric titration. Plasma ultrafiltrate was determined by correcting plasma chloride concentration for protein concentration. The average single nephron filtration rate was 20.2 +/- 0.8 nl/min. The (TF/UF)Cl ratio was 1.10 +/- 0.03, which was significantly different from unity. Furthermore, regression analysis yielded no significant correlation between the (TF/UF(Cl and (TF/P)In ratio. This study demonstrates that a tubule lumen-to-plasma chloride concentration gradient exists in the in vivo proximal tubule of the rabbit that is apparently established early and is not correlated with proximal tubule length.

Electromagnetic flow techniques and inulin clearance were used to determine the autoregulatory capabilities of the rabbit kidney in vivo. Renal blood flow was measured in 13 animals over a renal perfusion pressure range of 40–110 mmHg. Normal renal blood flow averaged 3.2 +/- 0.3 ml.min-1.g kidney-1 and was efficiently autoregulated above a renal artery pressure of 75 mmHg. For every 10 mmHg renal pressure change above 75 mmHg renal blood flow changed only 0.96%. Renal perfusion pressure was reduced from 102 +/- 3 to 74 +/- 2 mmHg in six animals. Over this pressure range glomerular filtration rate was not significantly decreased and averaged 4.2 +/- 0.5 ml/min at high pressure compared to 4.0 +/- 0.5 ml/min at low perfusion pressure. Results show that the rabbit kidney autoregulates renal blood flow and glomerular filtration rate efficiently above 75 mmHg. This range of autoregulation compares well with the autoregulatory range of the dog. The results also show that in the autoregulatory range the rabbit and the rat appear to autoregulate with equal efficiency but that the rabbit kidney begins to autoregulate at a low perfusion pressure than the average of approximately 100 mmHg usually found in the rat.

Flow of tubule fluid to the macula densa is part of a proposed feedback loop for autoregulation of glomerular filtration rate. In the present study, autoregulation of single nephron filtration rate was tested in the presence and the absence of flow to the macula densa in the rat. Filtration rates were measured at elevated arterial blood pressures caused by carotid occlusion and vagal section and at reduced renal perfusion pressures caused by partial aortic constriction. Measurements of single nephron filtration rate in the presence and the absence of flow to the macula densa were obtained by complete volume collections from the distal nephron beyond the macula densa and from the proximal tubule, respectively. Mean blood pressure was 130 ± 4 (SE) mm Hg for the initial collections, and renal perfusion pressure was 100 ± 1 mm Hg for the repeat collections (nine rats). Distal single nephron filtration rate was 42 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure; proximal single nephron filtration rate was 41 ± 1 nliters/min at elevated perfusion pressure and 41 ± 1 nliters/min at reduced perfusion pressure. Similarly, glomerular filtration rate was 4.6 ± 0.4 ml/min kg -1 body weight and 4.7 ± 0.3 ml/min kg -1 body weight at elevated and reduced perfusion pressures, respectively. Additional studies in seven dogs showed good correlation between autoregulation of single nephrons in the absence of flow to the macula densa and autoregulation of the micropunctured kidney. It is concluded that autoregulation of single nephron filtration rate is unaltered by interruption of tubule fluid flow to the macula densa.

In most cases blood pressure (BP) is directly related to NaCl intake. In some studies, BP is increased by low salt intake. The effect of Na and Cl deprivation or selective Na deprivation on BP in the normotensive Sprague-Dawley rat was investigated. In study 1, rats were uninephrectomized and fed low NaCl, normal NaCl, or low Na-normal Cl for 3 wk. BP was higher (P less than 0.05) in rats fed low NaCl and low Na-normal Cl than normal NaCl. Plasma renin activity was stimulated by low NaCl intake but was not different between the other two groups. After captopril treatment, BP was lower in the low NaCl group (73.1 +/- 3.6 mmHg) than in the normal-NaCl (99.2 +/- 6.7 mmHg) or low Na-normal Cl (92.0 +/- 6.7 mmHg) groups. In study 2, intact rats (n = 8 per group) were fed low (less than 0.01%), normal (1%), or high NaCl (4%) for 1 wk. BP and heart rate were higher in the low-NaCl group (P less than 0.05) than in the other two groups. Plasma volumes were not different among the groups. In study 3, two groups of eight rats were given either low NaCl or 2% NaCl for 2 wk. BP (131.4 +/- 3.6 mmHg) and heart rate (402 +/- 11 beats/min) were higher in the low-NaCl group than in the 2% NaCl group (121.1 +/- 3.2 mmHg and 369 +/- 9 beats/min, respectively). In the normotensive Sprague-Dawley rat, low NaCl intake elevated BP when compared with normal or high NaCl intake. Part of the increase in the uninephrectomized, Cl-supplemented group is not dependent on the renin-angiotensin system.

Preferential expansion of the plasma volume by infusion of salt-poor hyperoncotic albumin solution decreases sodium reabsorption by the proximal tubule. The present micropuncture studies test the thesis that albumin infusion depresses proximal reabsorption by an effect unrelated to expansion of the plasma volume, perhaps due to an effect of parathyroid hormone (PTH) on proximal sodium reabsorption. Infusion of salt-poor hyperoncotic albumin significantly decreased plasma ionized calcium, increased immunoreactive PTH (iPTH) in plasma, decreased sodium reabsorption by the proximal tubule, and increased phosphate clearance. In contrast, infusions of albumin, in which the ionized calcium was restored to normal plasma levels, had no significant effect on ionized calcium, iPTH, proximal reabsorption, or phosphate clearance in intact dogs. Similarly, in parathyroidectomized animals given a constant replacement infusion of PTH, albumin infusion had no significant effect on proximal reabsorption or phosphate clearance. Plasma volume was markedly expanded following albumin infusion in all groups of dogs. These findings (a) indicate that PTH plays a significant role in the decrease in sodium reabsorption by the renal proximal tubule after salt-poor hyperoncotic albumin infusion, and (b) dissociate preferential expansion of the plasma volume from decreases in sodium reabsorption by the proximal tubule.

The reason for the failure of glomerular filtration rate (GFR) to exhibit plasma flow dependency during pharmacologic vasodilation remains unclear although it has been suggested on the basis of experiments in rats that vasodilators may lead to a reduction in the glomerular filtration coefficient (Kf). To evaluate the applicability of this hypothesis to the dog, the effects of vasodilation with acetylcholine on glomerular dynamics and Kf were evaluated in two groups of dogs. One group (n = 19) was studied at spontaneous arterial pressures to allow maximum vasodilation to occur. In the other group (n = 5), renal arterial pressure was reduced and maintained at approximately 89 mmHg. Glomerular filtration rate and single nephron glomerular filtration rate were not altered significantly during acetylcholine infusion in either of the two groups. Both whole kidney and superficial filtration fractions decreased significantly. At spontaneous arterial pressures, transglomerular hydrostatic pressure was not altered significantly because of equivalent increases in proximal tubule pressure and in glomerular pressure. In the dogs studied at reduced renal perfusion pressure, glomerular capillary pressure did not change, but proximal tubule pressure increased slightly. Average effective filtration pressures and Kf were not significantly altered during the infusion of acetylcholine either at spontaneous or reduced renal perfusion pressures. These observations indicate that Kf in the dog is not significantly decreased by acetylcholine and that GFR is not affected during infusion of this agent because the effective filtration pressure is not significantly altered.

In eight intact, anesthetized dogs the aldosterone secretory rate averaged 13.8 ± 1.9 ng/min (mean ± SE ). One hour after nephrectomy and decapitation, the aldosterone secretory rate decreased to 2.3 ± 1.7 ng/min and failed to increase in response to hemorrhage. By 8 hours after surgery, the aldosterone secretory rate had returned to control levels. The serum potassium concentration gradually increased from 3.2 ± 0.5 mEq/liter in the control samples to 5.3 ± 0.5 mEq/liter in the 8-hour samples. Eight hours after nephrectomy and decapitation, the arterial blood pressure was lowered to 70 mm Hg by hemorrhage in six dogs. During the next 3 hours, the aldosterone secretory rate increased from 11.2 ± 2.1 ng/min to 27.3 ± 2.1 ng/min. Associated with the increase in the aldosterone secretory rate following hemorrhage was a further increase in the serum potassium concentration from 5.3 ± 0.5 mEq/liter to 6.8 ± 0.5 mEq/liter. The aldosterone secretory rate did not increase following hemorrhage when the rise in serum potassium concentration was prevented by hemodialysis. These data indicate that normal levels of aldosterone secretion can be maintained in the absence of the renin-angiotensin system and the pituitary secretion of adrenocorticotropic hormone. Also, hemorrhage will greatly enhance aldosterone secretion in the absence of the head and the kidneys but only if the serum potassium concentration is allowed to rise following the hemorrhage.

In general, phosphate is filtered at the glomerulus, a portion is reabsorbed by the renal tubules and the excess is excreted in the urine. This framework was demonstrated by Pitts in 1933 when he reported the relationship between phosphate reabsorption and the filtered load of phosphate [1]. Fig. I illustrates the curvilinear relationship between plasma phosphate concentration and the ratio of the clearance of phosphate to the clearance of a glomerular marker, in this case xylose. At low plasma concentrations, phosphate is reabsorbed from the filtrate, and as the plasma concentration is raised the phosphate clearance approaches the xylose clearance without exceeding it. Pitts concluded that phosphate was not secreted since the maximum phosphate clearance could be accounted for by filtration of phosphate.

Previous studies in rats have demonstrated that the concentration of chloride in proximal tubule fluid is greater than that in plasma. The gradient reaches a free-flow steady-state level in the early proximal tubule and is maintained throughout the accessible proximal tubule. On the other hand, studies in dogs are in conflict regarding either the existence of a gradient or the development of a free-flow steady-state level. Since a species difference of tubule fluid to plasma chloride (TF/PC1) may exist, the present study was done to systematically compare the tubule fluid to ultrafiltrate chloride ratio (TF/UFC1) in hydropenic rats and dogs during normal acid-base balance. Chloride was analyzed by microelectrometric titration. In the rat the TFC1 and UFC1 concentrations were 139 +/- 1.4 and 120 +/- 1.2 meq/1, respectively. In the dog the TFC1 and UFC1 concentrations were 138 +/- 1.3 and 121 +/- 1.5 meq/1, respectively. Thus, there was no significant difference in the TF/UFC1 ratio between the rat (1.17 +/- 0.02) and the dog (1.14 +/- 0.01). Furthermore, regression analysis indicates that there is no correlation between TF/UFC1 and TF/PIn in either the rat or dog, which suggests that the gradient originates early in the proximal tubule and is maintained throughout the accessible proximal tubule in both species.

Effects of chlorpropamide on loop of Henle function and plasma renin. We have suggested that inhibition of renin release by sodium chloride is related to increased absorptive solute transport in the loop of Henle. In the rat, we have shown that reduced chloride transport in the loop is associated with increased renin release. Based on indirect evidence, it has been suggested that chlorpropamide (CPMD) increases loop solute transport. This study directly evaluates the effect of CPMD on loop chloride transport and plasma renin activity (PRA) in the male Sprague–Dawley rat. Loop of Henle chloride reabsorption (measured by recollection micropuncture) and PRA were determined before and after acute infusion of CPMD (N = 8) or vehicle (N = 8). Although delivery to the loop was not significantly changed, CPMD increased (P < 0.05) absolute loop chloride reabsorption from 1798 pEq/min ± 200 SE to 2453 pEq/min ± 206 SE. PRA was decreased (P < 0.01) from 9.2 ng/ml/hr ± 1.0 SE to 5.6 ng/ml/hr ± 0.8 SE following CPMD infusion. Comparable vehicle infusion did not alter loop chloride reabsorption or PRA. Arterial pressure, and whole kidney and single nephron glomerular filtration rates were unchanged following infusion of CPMD or vehicle. These results demonstrate that an increase in loop chloride reabsorption is associated with a decrease in renin release. This observation is consistent with the hypothesis that renin release is inversely related to the magnitude of chloride transport in the thick ascending limb of the loop of Henle.

We have previously reported that 1) selective dietary sodium loading (without chloride) does not produce hypertension in rats of the Dahl salt-sensitive strain (DS) and 2) selective chloride loading (without sodium) lowers plasma renin activity in the intact Sprague-Dawley rat maintained on a low NaCl diet. The present study examined the effect of selective dietary chloride loading on two models of hypertension: the DS and the renin-dependent one-kidney, one clip Sprague-Dawley rat. The DS were pair-fed (n = 7/group) a "normal" NaCl, a high NaCl (4%), or a "normal" sodium-high chloride diet for 11 weeks. From Week 7 until the end of the experiment, the high NaCl-fed animals had higher (p less than or equal to 0.05) blood pressures than animals fed either the normal NaCl or normal sodium-high chloride diet, which were not different from each other. Thus, in the DS, hypertension depends on high dietary intakes of both sodium and chloride. In one-kidney, one clip hypertensive rats, selective chloride loading failed to lower plasma renin activity (9 +/- 1 vs 7 +/- 1 ng angiotensin I/ml/hr) or to prevent hypertension (160 +/- 10 vs 166 +/- 9 mm Hg). Thus, selective dietary chloride loading (without sodium) does not alter blood pressure in either salt-sensitive or renin-dependent hypertension.

Arginine vasopressin (AVP) is known to produce increases in total peripheral resistance (TPR) and mean arterial pressure (MAP) and decreases in heart rate (HR), cardiac output (CO), and plasma renin activity (PRA). Some recent observations with AVP and synthetic analogues have suggested that under certain conditions, AVP can induce cardiovascular and reninsecretory responses in the opposite directions. To characterize the receptors mediating these responses, the effects of AVP, oxytocin, and synthetic neurohypophyseal analogues with specific antidiuretic, vasoconstrictor, or oxytocic activities were studied in conscious dogs. AVP and 2-phenylalanine-8-ornithine-oxytocin (Phe2Orn8OT, a selective vasoconstrictor agonist) produced similar responses when infused at 10 ng X kg-1 X min-1. That is, TPR and MAP increased, and CO, HR, and PRA decreased. Pretreatment with a selective vasoconstrictor antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid) 2-(O-methyl)tyrosine]AVP, abbreviated d(CH2)5Tyr(Me)-AVP (10 micrograms/kg), blocked the actions of Phe2Orn8OT. However, in the presence of d(CH2)5Tyr(Me)AVP, AVP actually decreased TPR and increased CO, HR, and PRA. An analogue with selective antidiuretic activity, 4-valine-8-D-AVP (VDAVP, 10 ng X kg-1 X min-1), produced the same effects as the combination of vasopressin plus d(CH2)5Tyr(Me)AVP. Neither the effects of VDAVP nor of AVP plus antagonist were blocked by propranolol (1 mg/kg). These data indicate that vasopressin, by its antidiuretic activity, produces cardiovascular effects that are opposite to many of those produced by its vasoconstrictor action and that these effects are not dependent on mediation by beta-adrenoceptors.

The effect of extracellular volume expansion on transcapillary Starling forces, capillary uptake, and the reabsorption coefficient in the peritubule microcirculation of the dog kidney was examined. Micropuncture techniques were used to obtain measurement before and after 4% body wt expansion with isotonic saline. Extracellular volume expansion significantly changed all Starling pressures and capillary uptake. Efferent arteriolar oncotic pressure, interstitial oncotic pressure, and capillary uptake decreased (33.1 +/- 3.3 to 22.1 +/- 4.1 mmHg; 5.2 +/- 0.4 to 4.0 +/- 0.3 mmHg; and 44.9 +/- 9.2 to 28.7 +/- 8.6 nl/min, respectively), whereas capillary hydrostatic pressure and interstitial hydrostatic pressure increased (11.3 +/- 1.2 to 13.7 +/- 1.4 and 5.9 +/- 1.0 to 10.4 +/- 1.2 mmHg, respectively). The calculated reabsorption coefficient was 2.40 during hydropenia and 2.36 nl . min-1 . mmHg-1 following volume expansion. The results show that extracellular volume expansion significantly depresses capillary uptake in the dog and suggest that the decreased uptake can be accounted for totally by changes in transcapillary pressures and a constant reabsorption coefficient.

The kidney has several characteristics which make renal pressures and fluid dynamics unique when compared to other organs. Renal blood flow is roughly 100 times that of skeletal muscle. The renal circulation consists of two distinct capillary beds in series: a high pressure system in the glomerulus that favors filtration and a low pressure system in the peritubule network that favors reabsorption. The hydrostatic pressure in the glomerular capillary is 4-6 times higher than the hydrostatic pressure in the peritubule capillary so that approximately 25% of the plasma is filtered. The bulk of the filtrate is subsequently reabsorbed by the peritubule capillary network. Micropuncture techniques have been used to obtain quantitative measurements of the pressures and fluid dynamics of the peritubule microcirculation. The net force for uptake of all the fluid reabsorbed by a single proximal tubule up to the point of micropuncture is 21 mm Hg acting over a capillary bed with a permeability surface area product of 2 nl/min per mm Hg. In contrast to subcutaneous tissue and muscle, the renal interstitial fluid pressure is positive. The consequence of a positive interstitial fluid pressure is that normal lymph flow is relatively high and changes in interstitial fluid pressure have relatively little effects on lymph flow.

A possible effect of decreased plasma ionized calcium concentration on renal phosphate handling was investigated in dogs with control of parathyroid hormone. Intrarenal artery infusion of either EDTA or sodium citrate decreased ionized calcium concentration 25 per cent in renal vein blood but had no significant effect on fractional phosphate excretion. Similarly, intravenous infusion of chelators had no significant effect on fractional phosphate excretion. It is concluded that acute decreases in ionized calcium have no significant effect on the renal handling of phosphate.

We previously have shown that chronic sodium chloride (NaCl) loading protects against HgCl2-induced acute renal failure (ARF) in dogs. To determine whether NaCl loading protects against an ischemic model of ARF, unilateral oliguric renal failure was produced by the infusion of norepinephrine (NE) into the renal artery of both saline-expanded (SE) and water-drinking (WD) dogs (n = 7). The renal renin content (30 U/g kidney) of SE dogs was suppressed (P less than 0.001) compared to that of WD dogs (132 +/- 18). Forty-eight hours after infusion of NE (1.5 microgram/kg per min X 100 min), inulin clearances from the infused kidney of SE (6 ml/min +/- 2) and WD dogs (7 +/- 2) did not differ; in both groups, respective clearances from the noninfused kidney (43 ml/min +/- 3) and (36 +/- 5) also did not differ from each other. The present fall in renal blood flow to the infused kidney 48 hours after NE in SE (44%) and WD dogs (38%) did not differ. Because of failure to demonstrate protection, a lower dose of NE (0.75 microgram/kg per min X 40 min) was infused into SE and WD animals (n = 6). Forty-eight hours after low dose NE, inulin clearances of the infused kidney of SE (17 ml/min +/- 5) and WD dogs (17 +/- 4) did not differ. Respective clearances in the noninfused kidney of SE (46 ml/min +/- 6) and WD dogs (35 +/- 4) did not differ. Therefore, despite suppression of renal renin content, NaCl loading failed to protect against this ischemic model of ARF. In conclusion, unlike HgCl2-induced ARF, it is unlikely that the renin angiotensin system contributes to the pathogenesis of this ischemic model of ARF.

To evaluate the contribution of plasma volume expansion per se on acute inhibition of renin release by sodium chloride infusion, renin responses to comparable plasma volume expansion with intravenous infusions of sodium chloride, sodium bicarbonate, or albumin were studied in separate groups of sodium chloride-depleted rats. In addition, urinary prostaglandin E2 (PGE2) excretion rate was compared in the saline- and sodium bicarbonate-infused animals to evaluate the relationship between acute changes in renin release and intrarenal PGE2 synthesis. All three groups were plasma volume-expanded by approximately 55%. Plasma renin activity (PRA) decreased in response to saline (12.3 k 1.0 to 6.7 f 0.7 ng AI/ml/hr; P < 0.01) whereas PRA did not change with sodium bicarbonate (1 1.3 f 1.4 to 10.2 f 1.5) or albumin (9.9 f 0.7 to 8.2 k I.O). The rate of PGE2 excretion was not changed by either saline (72.2 k 13.1 to 72.3 f 18.7 pg/min) or sodium bicarbonate infusion (70.7 f 8.8 to 64.9 f 7.0). These results support the hypothesis that acute suppression of PRA by infusion of saline is not dependent upon volume expansion per se. In confirmation of earlier observations, inhibition of renin release by sodium chloride was related to chloride. Finally, the results suggest that the renal tubular mechanism for inhibition of renin release by sodium chloride is not related to overall changes in renal PGE2 synthesis in the rat. 0 1986 Society for Experimental Biology and Medicine.

The purpose of this study was to determine if alterations of calcium and calcium regulating hormones precede the onset of NaCl induced hypertension in the Dahl salt sensitive (S) rat. After a 5 day balance study, serum ionized calcium, PTH, and 1,25 dihydroxy vitamin D concentrations were measured in Dahl-S and salt resistant (R) rats that had been maintained on a "normal" (1%) or high (7%) NaCl intake. Blood pressure was higher in Dahl-S than R (P less than .01), but was not affected by 5 days of high NaCl. On both NaCl intakes, urine calcium excretion was increased, serum calcium was decreased, and serum PTH and 1,25 dihydroxy vitamin D were increased in Dahl-S compared to Dahl-R (P less than .01). On the high NaCl intake, fecal calcium was greater in Dahl-S than in Dahl-R, and net 5 day calcium balance was less positive in Dahl-S (P less than .05). In contrast to NaCl, a high dietary intake of sodium with anions other than chloride (NaAA) fails to produce hypertension in the Dahl-S rat. NaAA loading resulted in decreased urine calcium excretion (P less than .01), and after 5 days of the high NaAA diet, serum calcium and PTH did not differ in Dahl-S and Dahl-R. Thus, alterations of calcium, PTH, and vitamin D precede NaCl-induced hypertension in Dahl-S. These alterations may contribute to the development of hypertension in this animal model.

A marked increase in preglomerular resistance mediated through the renin-angiotensin system has been proposed as the mechanism for the sustained decrease in glomerular filtration rate seen following release of 24-hour ureteral obstruction. The importance of the renin-angiotensin system in mediating this response was evaluated by determining whole kidney and single nephron function following release of 24-hour ureteral obstruction in rats with normal renal renin content and in rats depleted of renal renin by desoxycorticosterone acetate acetate (DOCA) and saline treatment. The DOCA and saline treatment was effective in reducing renal renin content to less than 10% of the normal values. However, when compared to nonobstructed kidneys, both whole kidney filtration rate and single nephron filtration rate were similarly and significantly reduced in both groups following release of 24-hour ureteral obstruction. Single nephron stopflow techniques were used to determine the net hydrostatic force for filtration. The net hydrostatic force for filtration in control nonobstructed nephrons averaged 37.8 +/- 1.1 mm. Hg, but was significantly decreased to 22.5 +/- 2.2 mm. Hg in the normal renin obstructed kidney and to 18.8 +/- 1.0 mm. Hg in the renin-depleted obstructed kidney. It is concluded that the marked depression in glomerular filtration rate seen following release of 24-hour ureteral obstruction is due to increased afferent arteriole resistance and that the renin-angiotensin system is apparently not important in mediating the response.

The effect of increased peritubule capillary oncotic pressure on sodium reabsorption by the proximal tubule of the dog was investistigated after extracellular volume expansion (ECVE) with Ringer's solution or during continued hydropenia. Control measurements were made after ECVE or during hydropenia and again during renal arterial infusion with hyperoncotic albumin solution. Absolute reabsorption by the proximal tubule was calculated from fractional reabsorption and single nephron filtration rates as determined by micropuncture. Direct measurements of efferent arteriole protein were used to determine efferent arteriolar oncotic pressure. Albumin infused into the renal artery after ECVE significantly increased efferent oncotic pressure by 17.6 plus or minus 5.3 mm Hg. Fractional and absolute reabsorption by the proximal tubule increased from 20 plus or minus 6 to 37 plus or minus 5% and from 22 plus or minus 6 to 36 plus or minus 7 nl/min, respectively. During hydropenia, the albumin infusion significantly increased efferent oncotic pressure by 15.0 plus or minus 4.4 mm Hg. However, in contrast to the effect seen during ECVE, neither fractional nor absolute reabsorption was changed, delta equals 0.3 plus or minus 1.5% and 3 plus or minus 5 nl/min, respectively. Single nephron filtration rates were not significantly different between the groups and were unchanged by the albumin infusion. Peritubule capillary hydrostatic pressures, measured with a null-servo device, were not changed by the albumin infusion in either group. Renal interstitial hydrostatic pressure, measured from chronically implanted polyethylene capsules, was decreased significantly from 7.2 plus or minus 0.9 to 3.4 plus or minus 0.6 mm Hg in the hydropenic group and from 0.6 plus or minus 0.6 to 4.8 plus or minus 0.7 mm Hg in the Ringer's expanded group. In the hydropenic group, the increase in efferent oncotic pressure was nearly compensated for by changes in interstitial forces so that the calculated net force for capillary uptake was almost unchanged, 17.8 mm Hg before vs. 21.4 mm Hg during the albumin infusion. The increased efferent oncotic pressure in the Ringer's expanded group was not compensated, so that the calculated net force for uptake was increased, 11.9 mm Hg before to 22.2 mm Hg during the albumin infusion. Thus, while the increase in efferent oncotic pressure during albumin infusion was not significantly different between the groups, absolute and fractional reabsorptions were increased only in the animals in which the extracellular volume was expanded. The results suggest that ECVE alters the effect of increased peritubule oncotic pressure on sodium reabsorption by the proximal tubule.

Selective dietary sodium loading (without chloride) fails to produce hypertension in the Dahl salt-sensitive rat. This study attempted to evaluate the effect of selective sodium loading on blood pressure in another NaCl-dependent model of hypertension--deoxycorticosterone acetate (DOCA)-salt hypertension. Three groups of uninephrectomized rats were studied for 32 days on one of the following regimens: (1) high NaCl diet plus DOCA, (2) high dietary sodium intake without chloride plus DOCA, and (3) high NaCl diet without DOCA. Both indirect and direct arterial pressure were higher (p less than 0.01) in the DOCA-NaCl group than in the other two groups. In the two DOCA-treated groups, net sodium and potassium balance and total carcass sodium and potassium content did not differ. In the DOCA-NaCl group, higher blood pressures were associated with a more positive chloride balance and total carcass chloride content (p less than 0.01), an expanded extracellular fluid volume (p less than 0.05), and increased renal vascular resistance (p less than 0.01). Higher renal vascular resistance in DOCA-NaCl animals suggests that chloride contributes to NaCl-induced vasoconstriction.

Effects of extracellular fluid volume contraction and expansion on the bicarbonaturia of parathyroid hormone. To evaluate the effect of extracellular fluid volume alterations on the bicarbonaturia of parathyroid hormone, thyroparathyroidectomized dogs were made alkalotic and volume-contracted or expanded through hemodialysis. Clearance studies were performed before and after infusion of purified bovine parathyroid extract (PTE). Glomerular filtration rate and blood bicarbonate concentrations were kept constant throughout the experiments. A significant increase in fractional bicarbonate excretion was observed following PTE infusion in both the volume-contracted (8.67 ± 3.25 to 14.70 ± 3.63%, P < 0.010) and the volume-expanded state (22.80 ± 3.04 to 37.26 ± 3.38%, P < 0.050). It is concluded that PTE decreases reabsorption of bicarbonate independent of the volume state of the animal.

Plasma volume expansion alters renal tubular sodium chloride transport and renal nerve activity. The purpose of this study was to determine the mechanism(s) for inhibition of renin secretion by acute volume expansion with albumin in the anesthetized dog. In dogs with a single intact kidney, albumin infusion decreased renin release by 86% and significantly increased renal blood flow, glomerular filtration rate, and sodium excretion. Albumin volume expansion inhibited renin secretion to a lesser extent in dogs with denervated filtering kidneys and in dogs with innervated nonfiltering kidneys. In dogs with denervated nonfiltering kidneys, albumin infusion did not change renin secretion. Comparable volume expansion was produced in all groups. Thus, inhibition of renin release by acute plasma volume expansion is dependent on both a renal tubular mechanism and the integrity of the renal nerves. Partial inhibition of renin release was observed with interruption of either one of the mechanisms, whereas interruption of both mechanisms totally abolished the effect of acute plasma volume expansion on renin secretion.