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Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%-50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT.

Background and Purpose: Diabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.Experimental Approach: Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) in the kidney of these and lean ZSF1 rats along with their blood pressure.Key Result: Obese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.Conclusion and Implications: Overall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment. [ABSTRACT FROM AUTHOR]

The introduction of calcineurin inhibitors (CNI) into clinical practice in the late 1970s transformed organ transplantation and led to significant improvement in acute rejection episodes. However, despite their significant clinical utility, the use of these agents is hampered by the development of hypertension and nephrotoxicity, which ultimately lead to end-stage kidney disease and overt cardiovascular outcomes. There are currently no effective agents to treat or prevent these complications. Importantly, CNI-free immunosuppressive regimens lack the overall efficacy of CNI-based treatments and put patients at risk of allograft rejection. Cytochrome P-450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have potent vasodilator and antihypertensive properties in addition to many cytoprotective effects, but their effects on CNI-induced nephrotoxicity have not been explored. Here, we show that PVPA, a novel, orally active analog of 14,15-EET, effectively prevents the development of hypertension and ameliorates kidney injury in cyclosporine-treated rats. PVPA treatment reduced proteinuria and renal dysfunction induced by cyclosporine. PVPA inhibited inflammatory cell infiltration into the kidney and decreased renal fibrosis. PVPA also reduced tubular epithelial cell apoptosis, attenuated the generation of reactive oxygen species, and modulated the unfolded protein response that is associated with endoplasmic reticulum stress. Consistent with the in vivo data, PVPA attenuated cyclosporine-induced apoptosis of NRK- 52E cells in vitro. These data indicate that the cytochrome P-450/EET system offers a novel therapeutic strategy to treat or prevent CNIinduced nephrotoxicity. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), the predominant protein in plasma HDL, have long been the focus of intense studies in the field of atherosclerosis and cardiovascular disease. ApoA-I, in large part, is responsible for HDL assembly and its main atheroprotective function, that of shuttling excess cholesterol from peripheral tissues to the liver for excretion (reverse cholesterol transport). Recently, a protective role for HDL in cancer was suggested from several large clinical studies where an inverse relationship between plasma HDL-cholesterol (HDL-C) levels and risk of developing cancer was noted. This notion has now been tested and found to be supported in mouse tumor studies, where increasing levels of apoA-I/HDL were discovered to protect against tumor development and provision of human apoA-I was therapeutic against established tumors. This mini-review discusses the emerging role of apoA-I in tumor biology and its potential as cancer therapeutic. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin-angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studieswe used single ß-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R, and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here, we further explore this region for the potential to modulate ligand specificity. In this study, (1) a library of 47 peptides derived from the C-terminal tetrapeptide sequence (-IHPF) of Ang II was synthesized and assessed for ACE2 binding, (2) the terminal group requirements for high affinity ACE2 binding were explored by and Nand C-terminal modification, (3) high affinity ACE2 binding chimeric AngII analogswere then synthesized and assessed, (4) the structure of the full-length Ang II analogs were assessed by circular dichroism, and (5) the Ang II analogs were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity. [ABSTRACT FROM AUTHOR]

Cocoa powder has twice more antioxidants than red wine and three times more than green tea. Ten percent of its weight is made up of flavonoids. Cocoa has antioxidant and anti-inflammatory effects by downregulating cyclooxigenase-2 receptors expression in the endothelium and enhancing nitric oxide bioavailability. There are evidences that while polyphenols ingestion have cardioprotective effects in the adult, it may have deleterious effect on the fetus if ingested by the mother on the third trimester of pregnancy, causing intrauterine fetal ductus arteriosus (DA) constriction. Polyphenols present in many foods and their anti-inflammatory and antinociceptive activities have been shown to be as or more powerful than those of indomethacin. These effects are dependent on the inhibition of modulation of the arachidonic acid and the synthesis of prostaglandins, especially E-2, which is responsible for fetal DA patency. So, we hypothesized that this same mechanism is responsible for the harmful effect of polyphenol-rich foods, such as cocoa, upon the fetal DA after maternal intake of such substances in the third trimester of pregnancy, thereby rising the perspective of a note of caution for pregnant women diet. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathways in response to stress stimuli. EETs evoke a plethora of pathways limiting impairments of cellular structures, reducing cell death, and promoting anti-inflammatory reactions in various cell types. Considering EETs are capable of producing various biological protective effects, we hypothesized that EETs would protect rat neonatal cardiomyocytes (NCM) against LPS-induced cytotoxicity. In this study, we used a dualacting, synthetic analog of EETs, UA-8 [13-(3-propylureido)tridec-8-enoic acid], possessing both EET-mimetic and soluble epoxide hydrolase selective inhibitory properties and 14,15- EET as a model of canonical EET molecules. We found that both UA-8 and 14,15-EET significantly improved cell viability and mitochondrial function of cardiomyocytes exposed to LPS. Furthermore, treatment with UA-8 or 14,15-EET resulted in significant attenuation of LPS-triggered pro-inflammatory response, caspase-3 activation and reduction in the total antioxidant capacity in cardiomyocytes. Importantly, EET-mediated effects were significantly reduced by pharmacological inhibition of peroxisome proliferator-activated receptors ? (PPAR?) suggesting that PPAR? signaling was required for EETs exerted protective effects. Data presented in the current study demonstrate that activation of PPAR? signaling plays a crucial role in EET-mediated protection against LPS-cytotoxicity in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1α in such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion. Administration of 14,15-EET (2.5 mg/kg) or EET-B (2.5 mg/kg) 5 min before reperfusion reduced infarct size expressed as a percentage of the area at risk from 64.3 ± 1.3% in control to 42.6 ± 1.9% and 46.0 ± 1.6%, respectively, and their coadministration did not provide any stronger effect. The 14,15-EET antagonist 14,15-epoxyeicosa-5( Z)-enoic acid (2.5 mg/kg) inhibited the infarct size-limiting effect of EET-B (62.5 ± 1.1%). Similarly, the HIF-1α inhibitors 2-methoxyestradiol (2.5 mg/kg) and acriflavine (2 mg/kg) completely abolished the cardioprotective effect of EET-B. In a separate set of experiments, the immunoreactivity of HIF-1α and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and nonischemic septa. At the end of ischemia, the HIF-1α immunogenic signal markedly increased in the ischemic area compared with the septum (10.31 ± 0.78% vs. 0.34 ± 0.08%). After 20 min and 2 h of reperfusion, HIF-1α immunoreactivity decreased to 2.40 ± 0.48% and 1.85 ± 0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1α immunoreactivity (7.80 ± 0.69% and 6.44 ± 1.37%, respectively) and significantly reduced PHD3 immunogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1α and downregulation of its degrading enzyme PHD3. NEW & NOTEWORTHY The present study shows that EET-B is an effective agonistic 14,15-epoxyeicosatrienoic acid analog, and its administration before reperfusion markedly reduced myocardial infarction in rats. Most importantly, we demonstrate that increased hypoxia-inducible factor-1α levels play a role in cardioprotection mediated by EET-B in reperfusion likely by mechanisms including downregulation of the hypoxia-inducible factor -1α-degrading enzyme prolyl hydroxylase domain protein 3.

Chronic kidney disease is a known complication of hematopoietic stem cell transplant (HSCT) and can be caused by irradiation at the time of the HSCT. In our rat model there is a 6- to 8-wk latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension. The current study tested the hypothesis that decreased endothelial-derived factors contribute to impaired afferent arteriolar function in rats exposed to total body irradiation (TBI). WAG/RijCmcr rats underwent 11 Gy TBI, and afferent arteriolar responses to acetylcholine were determined at 1, 3, and 6 wk. Blood pressure and blood urea nitrogen were not different between control and irradiated rats. Afferent arteriolar diameters were not altered in irradiated rats. Impaired endothelial-dependent responses to acetylcholine were evident at 3 and 6 wk following TBI. Nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) contribution to acetylcholine dilator responses were evaluated. NOS inhibition with N(G)-nitro-l-arginine methyl ester (l-NAME) reduced acetylcholine responses by 50% in controls and 90% in 3-wk TBI rats. COX inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of l-NAME. EPOX inhibition with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide significantly decreased acetylcholine responses (35%) in controls but did not significantly alter acetylcholine responses (4%) in TBI rats. Biochemical analysis revealed decreased urinary EPOX metabolites but no change in COX, NOS, or reactive oxygen species at 3 wk TBI. Taken together, these results indicate that afferent arteriolar endothelial dysfunction involves a decrease in EPOX metabolites that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis., Competing Interests: Drs. Imig and Falck have a patent application that covers the composition of matter for EET-A. There are no other conflicts of interest, financial or otherwise, are declared by the authors., (© 2016 Authors; published by Portland Press Limited.)

Cerebral arterial myogenic and autoregulatory responses are impaired in Fawn Hooded hypertensive (FHH) rats. Cerebral autoregulatory responses are restored in the congenic rat strain in which a segment of chromosome 1 from the Brown Norway (BN) rat was transferred into the FHH genetic background (FHH.1BN). The impact of this region on cerebral arterial dilator responses remains unknown. Aminopeptidase is a gene that was transferred into the FHH genetic background to generate the FHH.1BN rats and is responsible for degradation of the vasodilator bradykinin. Thus, we hypothesized that FHH rats will have increased aminopeptidase P levels with impaired cerebral arterial responses to bradykinin compared to BN and FHH.1BN rats. We demonstrated higher cerebral arterial expression of aminopeptidase P in FHH compared to BN rats. Accordingly, we demonstrated markedly impaired cerebral arterial dilation to bradykinin in FHH compared to BN rats. Interestingly, aminopeptidase P expression was lower in FHH.1BN compared to FHH rats. Decreased aminopeptidase P levels in FHH.1BN rats were associated with increased cerebral arterial bradykinin-induced dilator responses. Aminopeptidase P inhibition by apstatin improved cerebral arterial bradykinin dilator responses in FHH rats to a level similar to FHH.1BN rats. Unlike bradykinin, cerebral arterial responses to acetylcholine were similar between FHH and FHH.1BN groups. These findings indicate decreased bradykinin bioavailability contributes to impaired cerebral arterial dilation in FHH rats. Overall, these data indicate an important role of aminopeptidase P in the impaired cerebral arterial function in FHH rat.

Epoxyeicosatrienoic acids (EETs) contribute to haemodynamics, electrolyte homoeostasis and blood pressure regulation, leading to the concept that EETs can be therapeutically targeted for hypertension. In the present study, multiple structural EET analogues were synthesized based on the EET pharmacophore and vasodilator structure-activity studies. Four EET analogues with 91-119% vasodilatory activity in the isolated bovine coronary artery (EC50: 0.18-1.6 μM) were identified and studied for blood-pressure-lowering in hypertension. Two EET analogues in which the COOH group at carbon 1 of the EET pharmacophore was replaced with either an aspartic acid (EET-A) or a heterocyclic surrogate (EET-X) were administered for 14 days [10 mg/kg per day intraperitoneally (i.p.)]. Both EET-A and EET-X lowered blood pressure in spontaneously hypertensive rats (SHRs) and in angiotensin II (AngII) hypertension. On day 14, the mean arterial pressures in EET analogue-treated AngII-hypertensive and SHRs were 30-50 mmHg (EET-A) and 15-20 mmHg (EET-X) lower than those in vehicle-treated controls. These EET analogues (10 mg/kg per day) were further tested in AngII hypertension by administering orally in drinking water for 14 days and EET-A lowered blood pressure. Additional experiments demonstrated that EET-A inhibits epithelial sodium channel (ENaC) activity in cultured cortical collecting duct cells and reduced renal expression of ENaC subunits in AngII hypertension. In conclusion, we have characterized EET-A as an orally active antihypertensive EET analogue that protects vascular endothelial function and has ENaC inhibitory activity in AngII hypertension.

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats., Methods: ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol., Results: ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats., Conclusions: Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Angiotensin II type 1 receptor blockers (ARBs) are widely used in treating hypertension. In the present study, we tested the hypothesis that a novel ARB, azilsartan medoxomil (AZL-M) will prevent renal and cardiovascular injury in the spontaneously hypertensive obese rat (SHROB), a model of cardiometabolic syndrome., Methods: Male SHROB were treated with vehicle or AZL-M orally for 56 days. Vehicle treated normotensive Wistar-Kyoto (WKY) rats served as controls. The effects of AZL-M on kidney injury, vascular endothelial and heart functions, lipid profile, and glucose tolerance were assessed., Results: AZL-M demonstrated anti-hypertensive effects along with markedly improved vascular endothelial function in SHROB. In these rats, AZL-M demonstrates strong kidney protective effects with lower albuminuria and nephrinuria along with reduced tubular cast formation and glomerular injury. AZL-M treatment also improved left ventricular heart function, attenuated development of left ventricular hypertrophy, and reduced cardiac fibrosis in SHROB., Conclusion: Overall, these findings demonstrate kidney and heart protective effects of AZL-M in SHROB, and these effects were associated with its ability to lower blood pressure and improve endothelial function.

Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor γ (PPARγ) agonists. We hypothesized that the PPARγ agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four-weeks and compared with spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Blood pressure increased in SHROB (164 ± 7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the K(ATP) channel opener pinacidil was attenuated in SHROB (E(Max) = 77 ± 7%), compared with WKY (E(Max) = 115 ± 19) and SHR (E(Max) = 93 ± 12%). Vasodilation to pinacidil was improved by rosiglitazone (E(Max) = 92 ± 14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90 ± 20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37 ± 9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome.

The present study explored the hypothesis that a prolonged 8 weeks exposure to a high fructose intake suppresses adrenergic and angiotensin II (Ang II)-mediated vasoconstriction and is associated with a higher contribution of α1D-adrenoceptors. A total of thirty-two Sprague-Dawley rats received either 20 % fructose solution (FFR) or tap water (control, C) to drink ad libitum for 8 weeks. Metabolic and haemodynamic parameters were assessed weekly. The renal cortical vasoconstrictor responses to noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined in the presence and absence of BMY7378 (α1D-adrenoceptor antagonist). FFR had increased blood pressure, plasma levels of glucose, TAG and insulin. FFR expressed reduced renal vascular responses to adrenergic agonists and Ang II (NA: 50 %, PE: 50 %, ME, 65 %, Ang II: 54 %). Furthermore in the C group, the magnitude of the renal cortical vasoconstriction to all agonists was blunted in the presence of the low or high dose of BMY7378 (NA: 30 and 31 %, PE: 23 and 33 %, ME: 19 and 44 %, Ang II: 53 and 77 %), respectively, while in the FFR, vasoconstriction was enhanced to adrenergic agonists and reduced to Ang II (NA: 8 and 83 %, PE: 55 %, ME, 2 and 177 %, Ang II: 61 and 31 %). Chronic high fructose intake blunts vascular sensitivity to adrenergic agonists and Ang II. Moreover, blocking of the α1D-adrenoceptor subtype results in enhancement of renal vasoconstriction to adrenergic agonists, suggesting an inhibitory action of α1D-adrenoceptors in the FFR. α1D-Adrenoceptors buffer the AT1-receptor response in the renal vasculature of normal rats and fructose feeding suppressed this interaction.

Purpose: Fructose feeding induces a moderate increase in blood pressure, insulin resistance, and hyperinsulinemia. This study investigated the role of α(1B)-adrenoceptor subtype in the control of renal hemodynamic responses to exogenously administered angiotensin II (Ang II) and a set of adrenergic agonists in a model of high fructose-fed rats., Methods: Sprague-Dawley rats were fed for 8 weeks with 20% fructose in drinking water (FFR). The renal cortical vasoconstriction to noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II in the presence and absence of chloroethylclonidine (CEC) (α(1B)-adrenoceptor antagonist) was determined. Data, mean ± SEM or SD were subjected to ANOVA with significance at p < .05., Results: FFR showed significant increase in the systolic blood pressure, plasma glucose, and insulin levels when compared to control. FFR expressed reduced renal cortical vascular sensitivity to NA, PE, ME, and Ang II. Furthermore, renal cortical vasoconstriction response to NA, PE, ME, and Ang II was blunted in the presence of CEC in control. While in FFR, renal cortical vasoconstriction to NA, PE, and ME was enhanced by CEC. Renal cortical vasoconstriction to Ang II in FFR was reduced in the presence of CEC., Conclusions: In the presence of a hyperinsulinemic state resulting from chronic and high fructose feeding, an attenuated AT(1) and α(1)-adrenoceptors response to Ang II and adrenergic stimuli respectively, is expected. In addition, α(1B)-adrenoceptor is the functional subtype that mediates renal cortical vasoconstriction in control rat, while high fructose feeding did influence the functionality of α(1B)-adrenoceptor in mediating the renal cortical hemodynamic changes.

Background: It is well established that renal sympathetic nerves are primarily involved in renal sodium and water regulation. However, the relationship between renal sympathetic nerve activity (RSNA) and renal potassium handling is not extensively known. The present study was performed to investigate the role of the renal sympathetic nervous system in the regulation of tubular potassium reabsorption and secretion., Methods: Male Sprague Dawley (SD) rats (each group, n=6) were fasted overnight, anesthetized with pentobarbital sodium (60 mg/kg intraperitoneal), denervated by application of phenol to the left renal artery and maintained on an intravenous infusion of saline for 2 hours. During this period, 6 urine and plasma samples were collected at 20-minute intervals to study kidney function parameters., Results: In denervated rats, there were significantly higher (all p<0.05 vs. innervated control) urine flow rate (UFR), glomerular filtration rate (GFR), absolute sodium excretion (U(Na)V), fractional sodium excretion (FE(N)a), absolute potassium excretion (U(K)V), fractional potassium excretion (FE(K)) and urinary sodium to urinary potassium ratio (U(Na)/U(K)). No appreciable differences were seen in the mean arterial pressure (MAP) and plasma sodium (P(Na)) between denervated and innervated SD rats. However, plasma potassium (P(K)) levels were significantly lower (p<0.05) in denervated rats as compared with innervated counterparts., Conclusions: There is a possible involvement of renal nerves in the regulation of renal potassium handling. This effect is largely attributable to a direct action of renal sympathetic nerves on the renal tubular segments.

The role of renal sympathetic nerves in the pathogenesis of ischemic acute renal failure (ARF) and the immediate changes in the renal excretory functions following renal ischemia were investigated. Two groups of male Sprague Dawley (SD) rats were anesthetized (pentobarbitone sodium, 60 mg kg(-1) i.p.) and subjected to unilateral renal ischemia by clamping the left renal artery for 30 min followed by reperfusion. In group 1, the renal nerves were electrically stimulated and the responses in the renal blood flow (RBF) and renal vascular resistance (RVR) were recorded, while group 2 was used to study the early changes in the renal functions following renal ischemia. In post-ischemic animals, basal RBF and the renal vasoconstrictor reperfusion to renal nerve stimulation (RNS) were significantly lower (all p < 0.05 vs. control). Mean arterial pressure (MAP), basal RVR, urine flow rate (UFR), absolute and fractional excretions of sodium (U(Na)V and FE(Na)), and potassium (U(K)V and FE(K)) were higher in ARF rats (all p < 0.05 vs. control). Post-ischemic animals showed markedly lower glomerular filtration rate (GFR) (p < 0.05 vs. control). No appreciable differences were observed in urinary sodium to potassium ratio (U(Na)/U(K)) during the early reperfusion phase of renal ischemia (p > 0.05 vs. control). The data suggest an immediate involvement of renal sympathetic nerve action in the pathogenesis of ischemic ARF primarily through altered renal hemodynamics. Diuresis, natriuresis, and kaliuresis due to impaired renal tubular functions are typical responses to renal ischemia and of comparable magnitudes.

Background & Objectives: Regulation of renal function and haemodynamics are under a direct control from the renal sympathetic nerves and renal denervation produces overt diuresis and natriuresis in several mammalian species. However, the inter-related series of changes in renal function and haemodynamics following acute renal denervation (ARD) is not fully understood. Thus, we aimed to investigate and relate the changes in renal function and haemodynamics following acute unilateral renal denervation in anaesthetized Sprague Dawley (SD) rats., Methods: Male SD rats were fasted overnight, anaesthetized with sodium pentobarbitone (60 mg/kg ip), denervated by application of phenol to the left renal artery and maintained on an intravenous (iv) infusion of isotonic saline for 2 h. Throughout this period, six urine and plasma samples were taken at 20-min intervals to study kidney function parameters. In a different set of experiments, renal nerve stimulation (RNS) was carried out to characterize the changes in renal vasoconstrictor responses following ARD., Results: Denervated animals showed significantly (P<0.05 vs. control innervated rats) higher urine flow rate (UFR), absolute sodium excretion (UNaV), fractional sodium excretion (FENa) and glomerular filtration rate (GFR). The renal vasoconstrictor responses to RNS were significantly (P<0.05) lower in denervated rats as compared to the innervated counterparts. However, no appreciable differences were seen in the mean arterial pressure (MAP), plasma sodium (PNa), basal renal blood flow (RBF) and basal renal vascular resistance (RVR) in both innervated and denervated SD rats., Interpretation & Conclusions: Natriuresis, diuresis, enhanced GFR and impaired vasoconstriction in response to RNS are typical and instant responses to ARD in SD rats. Renal sympathetic nerves serve more important role in salt and water conservation than in dynamic autoregulation of RBF under normal sympathetic tone; yet, their effects on renal haemodynamics become more evident in the presence of augmented renal sympathetic nerve activity (RSNA).