Renal oxygenases: differential contribution to vasoconstriction induced by ET-1 and ANG II

1997 ◽  
Vol 273 (1) ◽  
pp. R293-R300 ◽  
Author(s):  
A. Oyekan ◽  
M. Balazy ◽  
J. C. McGiff
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Individual Contribution ◽  
Isolated Perfused Kidney ◽  
Renal Vasoconstriction ◽  
Vasoconstrictor Response ◽  
The Individual ◽  
Cytochrome P 450 ◽  
Differential Contribution

In the rat isolated perfused kidney, 5,8,11,14-eicosatetraynoic acid, an inhibitor of all pathways of arachidonic acid (AA) metabolism, diminished endothelin-1 (ET-1)- and angiotensin II (ANG II)-induced renal vasoconstriction by approximately 60-70%. We then examined the individual contribution of each oxygenase, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CYP) to the vasoconstrictor effects of ET-1 and ANG II. Inhibition of COX with indomethacin reduced by 30-40% the vasoconstrictor responses to ET-1 and ANG II. Inhibition of 12-LOX with baicalein and 5- and 12-LOX with 5,8,11-eicosatriynoic acid attenuated ANG II-induced renal vasoconstriction by approximately 40-60% but did not affect responses to ET-1. In contrast, 12,12-dibromododec-11-enoic acid (DBDD), an inhibitor of the CYP omega/omega 1-hydroxylase pathway, diminished ET-1-induced renal vasoconstriction by 30-40%, an effect reproduced by depletion of CYP enzymes with CoCl2. Neither DBDD nor CoCl2 affected renal vasoconstriction elicited by ANG II. ET-1 increased efflux of 19- and 20-hydroxyeicosatetraenoic acid, an effect reduced by DBDD. Thus products of the COX and CYP pathways contribute to the renal vasoconstrictor response to ET-1, whereas COX- and LOX-derived eicosanoids contribute to the response to ANG II, accounting for > or = 80% of the vasoactivity of the peptides.

Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca2+-dependent phospholipase A2

2005 ◽  
Vol 288 (5) ◽  
pp. H2306-H2316 ◽  
Author(s):  
Fang Li ◽  
Kafait U. Malik
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Interfering Rna ◽  
Relationship Of ◽  
The Relationship ◽  
Cytochrome P 450 ◽  
Hydroxyeicosatetraenoic Acids

Angiotensin II (ANG II) promotes vascular smooth muscle cell (VSMC) growth, stimulates Ca2+-calmodulin (CaM)-dependent kinase II (CaMKII), and activates cytosolic Ca2+-dependent phospholipase A2 (cPLA2), which releases arachidonic acid (AA). ANG II also generates H2O2 and activates Akt, which have been implicated in ANG II actions in VSMC. This study was conducted to investigate the relationship of these signaling molecules to Akt activation in rat aortic VSMC. ANG II increased Akt activity, as measured by its phosphorylation at serine-473. ANG II (200 nM)-induced Akt phosphorylation was decreased by extracellular Ca2+ depletion and calcium chelator EGTA and inhibitors of CaM [ N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide] and CaMKII {(2-[ N-(2-hydroxyethyl)]- N-(4-me-thoxybenzenesulfonyl)]amino- N-(4-chlorocinnamyl)- N-methylbenzyl-amine)}. cPLA2 inhibitor pyrrolidine-1, antisense oligonucleotide, and retroviral small interfering RNA also attenuated ANG II-induced Akt phosphorylation. AA increased Akt phosphorylation, and AA metabolism inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) blocked ANG II- and AA-induced Akt phosphorylation (199.03 ± 27.91% with ANG II and 110.18 ± 22.40% with ETYA + ANG II; 405.00 ± 86.22% with AA and 153.97 ± 63.26% with ETYA + AA). Inhibitors of lipoxygenase (cinnamyl-3,4-dihydroxy-α-cyanocinnamate) and cytochrome P-450 (ketoconazole and 17-octadecynoic acid), but not cyclooxygenase (indomethacin), attenuated ANG II- and AA-induced Akt phosphorylation. Furthermore, 5( S)-, 12( S)-, 15( S)-, and 20-hydroxyeicosatetraenoic acids and 5,6-, 11,12-, and 14,15-epoxyeicosatrienoic acids increased Akt phosphorylation. Catalase inhibited ANG II-increased H2O2 production but not Akt phosphorylation. Oleic acid, which also increased H2O2 production, did not cause Akt phosphorylation. These data suggest that ANG II-induced Akt activation in VSMC is mediated by AA metabolites, most likely generated via lipoxygenase and cytochrome P-450 consequent to AA released by CaMKII-activated cPLA2 and independent of H2O2 production.

Afferent arteriolar responses to ANG II involve activation of PLA2 and modulation by lipoxygenase and P-450 pathways

1997 ◽  
Vol 273 (2) ◽  
pp. F274-F282 ◽  
Author(s):  
J. D. Imig ◽  
P. C. Deichmann
Keyword(s):  
Arachidonic Acid ◽  
Vessel Diameter ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Pathway ◽  
Vasoconstrictor Response ◽  
Vasoconstrictor Effect ◽  
Cytochrome P 450

Activation of angiotensin receptors activates phospholipase A2 (PLA2) in various tissues, resulting in the release of arachidonic acid and formation of vasoactive metabolites. The present study examined the role of the lipoxygenase and cytochrome P-450 pathways by evaluating the effects of PLA2, cyclooxygenase, lipoxygenase, and epoxygenase inhibition on the afferent arteriolar responses to angiotensin II (ANG II) and norepinephrine in the vitro perfused rat juxtamedullary nephron preparation. ANG II (0.01-100 nM) resulted in a dose-dependent afferent arteriolar vasoconstriction ranging from 3 +/- 1 to 32 +/- 2% (n = 47). Norepinephrine at 0.01, 0.1, and 1.0 microM also decreased afferent arteriolar diameter by 5 +/- 1, 17 +/- 1, and 34 +/- 2%, respectively (n = 43). In the presence of arachidonyl trifluoromethyl ketone (AACOCF3, 20 microM), a PLA2 inhibitor, afferent arteriolar vasoconstriction to ANG II (100 nM) was attenuated, and the diameter decreased by 23 +/- 4% (n = 7). The cyclooxygenase inhibitor, indomethacin (10 microM), and the cyclooxygenase-2 inhibitor, NS-398 (10 microM), did not affect the afferent arteriolar response to ANG II. The lipoxygenase inhibitor biacalein (1 microM) attenuated the afferent arteriolar response to ANG II, and vessel diameter decreased by 11 +/- 5% (n = 6) in response to 100 nM ANG II. On the other hand, miconazole (1 microM), a selective epoxygenase inhibitor, enhanced the afferent arteriolar vasoconstriction to 100 nM ANG II. 17-Octadecynoic acid (17-ODYA, 1 microM), an inhibitor of hydroxylase and epoxygenase metabolism of arachidonic acid, also increased the responsiveness of the afferent arteriole. PLA2, lipoxygenase, or cytochrome P-450 inhibition had no effect on the afferent arteriolar vasoconstriction to norepinephrine. The afferent arteriolar vasoconstrictor response to norepinephrine (0.1 microM) was enhanced by indomethacin or NS-398, and diameter decreased by 25 +/- 3% and 28 +/- 4%, respectively. Results of this study suggest that metabolites of the cyclooxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of norepinephrine. Furthermore, these data suggest that activation of PLA2 is involved in part of the afferent arteriolar response to ANG II and that metabolites of the lipoxygenase pathway augment and metabolites of the epoxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of ANG II.

Interactions between adenosine and angiotensin II in controlling glomerular filtration

1985 ◽  
Vol 248 (3) ◽  
pp. F340-F346 ◽  
Author(s):  
J. E. Hall ◽  
J. P. Granger ◽  
R. L. Hester
Keyword(s):  
Renal Failure ◽  
Angiotensin Ii ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Renal Vasoconstriction ◽  
Ischemic Renal Failure ◽  
Constrictor Response

This study examined interactions between adenosine (Ado) and angiotensin II (ANG II) in controlling renal blood flow (RBF) and glomerular filtration rate (GFR). In six normal dogs, intrarenal Ado infusion (1.0 mumol/min) transiently decreased RBF, but during sustained Ado infusion RBF increased to 122 +/- 7% of control, although GFR remained at 75 +/- 6% of control. Blockade of ANG II formation with the converting enzyme inhibitor SQ 14225 (n = 6) almost abolished the transient decrease in RBF but did not prevent the sustained fall in GFR caused by Ado. When circulating ANG II was held constant by intravenous infusion of SQ 14225 and 20 ng . kg-1 . min-1 of ANG II (n = 6), Ado transiently decreased RBF but the return of RBF was much slower than in normal dogs and RBF did not increase above control. Maintenance of constant circulating ANG II did not prevent Ado-mediated decreases in GFR. These observations suggest that Ado-mediated reductions in GFR do not depend entirely on ANG II and may be due to dilation of efferent arterioles by Ado. However, the transient renal vasoconstriction caused by Ado depends on ANG II, and data from this study suggest that part of the waning constrictor response to Ado is due to suppression of renin secretion and endogenous ANG II formation. In circumstances where high ANG II levels are maintained (i.e., ischemic renal failure), Ado may be capable of causing sustained renal vasoconstriction.

scholarly journals Role of Intramitochondrial Arachidonic Acid and Acyl-CoA Synthetase 4 in Angiotensin II-Regulated Aldosterone Synthesis in NCI-H295R Adrenocortical Cell Line

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3284-3294 ◽  
Author(s):  
Pablo G. Mele ◽  
Alejandra Duarte ◽  
Cristina Paz ◽  
Alessandro Capponi ◽  
Ernesto J. Podestá
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Regulatory Protein ◽  
Steroidogenic Acute Regulatory Protein ◽  
Ang Ii ◽  
Steroid Production ◽  
Glomerulosa Cells ◽  
Steroidogenic Acute Regulatory ◽  
Export System

Although the role of arachidonic acid (AA) in angiotensin II (ANG II)- and potassium-stimulated steroid production in zona glomerulosa cells is well documented, the mechanism responsible for AA release is not fully described. In this study we evaluated the mechanism involved in the release of intramitochondrial AA and its role in the regulation of aldosterone synthesis by ANG II in glomerulosa cells. We show that ANG II and potassium induce the expression of acyl-coenzyme A (CoA) thioesterase 2 and acyl-CoA synthetase 4, two enzymes involved in intramitochondrial AA generation/export system well characterized in other steroidogenic systems. We demonstrate that mitochondrial ATP is required for AA generation/export system, steroid production, and steroidogenic acute regulatory protein induction. We also demonstrate the role of protein tyrosine phosphatases regulating acyl-CoA synthetase 4 and steroidogenic acute regulatory protein induction, and hence ANG II-stimulated aldosterone synthesis.

Afferent arteriolar response to arachidonic acid: involvement of metabolic pathways

1996 ◽  
Vol 271 (1) ◽  
pp. F87-F93 ◽  
Author(s):  
J. D. Imig ◽  
L. G. Navar
Keyword(s):  
Arachidonic Acid ◽  
Cyclooxygenase Inhibition ◽  
Lipoxygenase Inhibition ◽  
Vasoconstrictor Response ◽  
Afferent Arterioles ◽  
Renal Microvasculature ◽  
Differential Responses ◽  
Enzymatic Pathways ◽  
Cytochrome P 450

Arachidonic acid (AA) metabolites have been implicated in the control of renal hemodynamics, but the nature of the metabolites produced by renal cells when AA is released has remained uncertain. Experiments were performed using the in vitro perfused juxtamedullary nephron preparation to examine the effects of perfusion and superfusion of AA on the renal microvasculature. Extraluminal exposure of the vessels by superfusion with solutions containing 0.1, 1.0, and 10 microM AA decreased afferent arteriolar diameter by 8 +/- 2, 16 +/- 3, and 20 +/- 3%, respectively. The same doses of AA added to the perfusate produced a similar afferent arteriolar vasoconstriction. Inhibition of the major enzymatic pathways unmasked differential responses of AA that were dependent on the direction from which the vasculature was exposed to AA. 17-Octadecynoic acid (1 microM), an inhibitor of the cytochrome P-450 pathway, eliminated the vasoconstrictor response to superfused AA but had little effect on the response to perfused AA. Lipoxygenase inhibition with baicalein (0.5 microM) did not alter the afferent arteriolar vasoconstriction during superfusion with AA but did attenuate the vasoconstrictor response to perfused AA by 34%. Cyclooxygenase inhibition with 10 microM indomethacin reduced the afferent arteriolar response to superfusion with 10 microM AA by 46%, but the responses to perfusion with AA were reversed, leading to the unmasking of a 17% afferent arteriolar dilation. The AA-induced vasorelaxation observed during cyclooxygenase inhibition was prevented by the subsequent addition of a P-450 inhibitor. Additionally, after endothelial removal with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), the vasodilatory response reverted to a vasoconstriction. The results of this study demonstrate that in the rat, AA metabolites exert predominant actions on afferent arterioles, but differential responses are mediated via different enzymatic pathways depending on the origin of AA. Increased AA availability of intraluminal origin leads to production of cyclooxygenase-derived vasoconstrictor metabolites and also to endothelial-derived cytochrome P-450 vasodilatory metabolites. In contrast, increased AA availability of interstitial origin leads to production of vasoconstrictor cytochrome P-450 metabolites.

Angiotensin II-induced relaxation of fowl aorta

1988 ◽  
Vol 255 (4) ◽  
pp. R591-R599 ◽  
Author(s):  
K. Yamaguchi ◽  
H. Nishimura
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Arachidonic Acid Metabolism ◽  
Isometric Tension ◽  
Eicosatetraenoic Acid ◽  
Ang Ii ◽  
Acid Metabolites ◽  
Relaxation Responses ◽  
Underlying Mechanisms ◽  
Dose Dependent

Angiotensin II (ANG II) decreases blood pressure of fowl. To characterize the vasodilating action of ANG II and its underlying mechanisms, we examined the effect of [Asp1, Val5]ANG II (fowl ANG II) on isometric tension of fowl aortic rings. [Val5]ANG II (10(-8) to 10(-5) M) produced rapid, reversible, dose-dependent relaxation of aortas precontracted with phenylephrine. [Sar1,Ile8]ANG II blocked ANG II-induced relaxation; propranolol, atropine, methysergid, pyrilamine, and cimetidine did not. Endothelium removal abolished relaxation responses to ANG II and acetylcholine but not to isoproterenol or sodium nitroprusside. Inhibitors of phospholipase or arachidonic acid metabolism (quinacrine, indomethacin, 5,8,11,14-eicosatetraenoic acid, hydroquinone, metyrapone, SKF 525A) and a calcium channel blocker (verapamil) did not inhibit ANG II-induced relaxation, whereas indomethacin nearly completely blocked arachidonic acid-induced dilation of aortas with or without endothelia. Guanosine 3',5'-cyclic monophosphate (cGMP) levels in the aorta increased 15 s after ANG II application. Aortic relaxation was caused by 8-bromo-cGMP with or without intact endothelium. These results suggest that ANG II-induced relaxation of fowl aortas involves 1) an endothelium-dependent mechanism and 2) cGMP but not arachidonic acid metabolites.

Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D

1997 ◽  
Vol 136 (2) ◽  
pp. 207-212 ◽  
Author(s):  
Junji Shinoda ◽  
Osamu Kozawa ◽  
Atsushi Suzuki ◽  
Yasuko Watanabe-Tomita ◽  
Yutaka Oiso ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Phospholipase D ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Ang Ii ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle

Abstract In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholinehydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/l and 0·1 μmol/l. d,l-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1α, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells. European Journal of Endocrinology 136 207–212

Angiotensin-induced defects in renal oxygenation: role of oxidative stress

2005 ◽  
Vol 288 (1) ◽  
pp. H22-H28 ◽  
Author(s):  
William J. Welch ◽  
Jonathan Blau ◽  
Hui Xie ◽  
Tina Chabrashvili ◽  
Christopher S. Wilcox
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Glass Electrode ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Mrna And Protein Expression ◽  
Renal Vascular ◽  
Induced Defects ◽  
Renal Oxygen

We tested the hypothesis that superoxide anion (O2−·) generated in the kidney by prolonged angiotensin II (ANG II) reduces renal cortical Po2 and the use of O2 for tubular sodium transport (TNa:QO2). Groups ( n = 8–11) of rats received angiotensin II (ANG II, 200 ng·kg−1·min−1 sc) or vehicle for 2 wk with concurrent infusions of a permeant nitroxide SOD mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, 200 nmol·kg−1·min−1) or vehicle. Rats were studied under anesthesia with measurements of renal oxygen usage and Po2 in the cortex and tubules with a glass electrode. Compared with vehicle, ANG II increased mean arterial pressure (107 ± 4 vs. 146 ± 6 mmHg; P < 0.001), renal vascular resistance (42 ± 3 vs. 65 ± 7 mmHg·ml−1·min−1·100 g−1; P < 0.001), renal cortical NADPH oxidase activity (2.3 ± 0.2 vs. 3.6 ± 0.4 nmol O2−··min−1·mg−1 protein; P < 0.05), mRNA and protein expression for p22 phox (2.1- and 1.8-fold respectively; P < 0.05) and reduced the mRNA for extracellular (EC)-SOD (−1.8 fold; P < 0.05). ANG II reduced the Po2 in the proximal tubule (39 ± 1 vs. 34 ± 2 mmHg; P < 0.05) and throughout the cortex and reduced the TNa:QO2 (17 ± 1 vs. 9 ± 2 μmol/μmol; P < 0.001). Tempol blunted or prevented all these effects of ANG II. The effects of prolonged ANG II to cause hypertension, renal vasoconstriction, renal cortical hypoxia, and reduced efficiency of O2 usage for Na+ transport, activation of NADPH oxidase, increased expression of p22 phox, and reduced expression of EC-SOD can be ascribed to O2−· generation because they are prevented by an SOD mimetic.

Effects of chloride channel blockers on rat renal vascular responses to angiotensin II and norepinephrine

2004 ◽  
Vol 286 (2) ◽  
pp. F323-F330 ◽  
Author(s):  
Joen Steendahl ◽  
Niels-Henrik Holstein-Rathlou ◽  
Charlotte Mehlin Sorensen ◽  
Max Salomonsson
Keyword(s):  
Angiotensin Ii ◽  
Niflumic Acid ◽  
Channel Blockers ◽  
Ang Ii ◽  
Renal Vasculature ◽  
Renal Vasoconstriction ◽  
Electromagnetic Flowmetry ◽  
Control Response ◽  
Renal Vascular

The aim of the present study was to investigate the role of Ca2+-activated Cl- channels in the renal vasoconstriction elicited by angiotensin II (ANG II) and norepinephrine (NE). Renal blood flow (RBF) was measured in vivo using electromagnetic flowmetry. Ratiometric photometry of fura 2 fluorescence was used to estimate intracellular free Ca2+ concentration ([Ca2+]i) in isolated preglomerular vessels from rat kidneys. Renal arterial injection of ANG II (2-4 ng) and NE (20-40 ng) produced a transient decrease in RBF. Administration of ANG II (10-7 M) and NE (5 × 10-6 M) to the isolated preglomerular vessels caused a prompt increase in [Ca2+]i. Renal preinfusion of DIDS (0.6 and 1.25 μmol/min) attenuated the ANG II-induced vasoconstriction to ∼35% of the control response, whereas the effects of NE were unaltered. Niflumic acid (0.14 and 0.28 μmol/min) and 2-[(2-cyclopentenyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1 H-inden-5-yl)oxy]acetic acid (IAA-94; 0.045 and 0.09 μmol/min) did not affect the vasoconstrictive responses of these compounds. Pretreatment with niflumic acid (50 μM) or IAA-94 (30 μM) for 2 min decreased baseline [Ca2+]i but did not change the magnitude of the [Ca2+]i response to ANG II and NE in the isolated vessels. The present results do not support the hypothesis that Ca2+-activated Cl- channels play a crucial role in the hemodynamic effects of ANG II and NE in rat renal vasculature.

Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat

2007 ◽  
Vol 293 (4) ◽  
pp. H2537-H2542 ◽  
Author(s):  
David W. Stepp ◽  
Erika I. Boesen ◽  
Jennifer C. Sullivan ◽  
James D. Mintz ◽  
Clark D. Hair ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Zucker Rats ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Insulin Resistant

Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease.

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