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The renin-angiotensin system, endothelin (ET), and vasoconstrictor prostaglandins have been reported in separate studies to mediate the renal vasoconstrictor effect of cyclosporin A (CsA). However, direct comparison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable agonist-inhibiting doses of receptor antagonists for angiotensin II (ANG II), DuP-753 at 2.5 mg/kg, for ETA, BQ-123 at 0.5 mg/kg, and for thromboxane A2 (TxA2), SQ-29,548 at 1.6 mg.kg-1.h-1, or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared in anesthetized Sprague-Dawley rats. All three receptor antagonists significantly limited the CsA-induced increase in renal vascular resistance; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Because all three receptor antagonists demonstrated at least some attenuation of CsA-induced renal vasoconstriction, the potential role of acute CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonists were determined to exclude the possibilities that there was a general increased agonist sensitivity and that detection of a single or primary constrictor mediator was obscured by "crossover" receptor antagonist effects. CsA significantly reduced renal blood flow (39%) in the presence of the NOS inhibitor, N omega-nitro-L-arginine methyl ester, and there was negligible indication that receptor antagonists had nonspecific effects. It is concluded that CsA-induced renal vasoconstriction is complex and involves activation of multiple constrictor agonists independently or sequentially.

Influence of arachidonate cyclooxygenase (COX) products on endothelin (ET)-evoked renal vasoconstriction was assessed. In microperfused rat afferent (AA) and efferent arterioles (EA), indomethacin had no effects on the maximal contraction of both AA and EA by ET, but reduced the duration of ET-induced constriction in both arterioles. ET infusion to rats in vivo resulted in a selective increase in efferent but not afferent arteriolar resistance, leading to a dramatic increase in transcapillary hydraulic pressure difference. Glomerular filtration rate (GFR), which fell progressively during infusion of ET alone, was markedly preserved by COX inhibition, but not during selective thromboxane A2 antagonism. In isolated glomeruli, release of prostaglandin (PG) F2 alpha in response to 10(-6) mol/l ET exceeded that the PGE2 by a ratio of 3.2. Collectively, these data provide strong evidence that locally released COX products, possibly PGF2 alpha, play a key role in sustaining ET-induced renal arteriolar constriction. COX inhibition leads to acute vasorelaxation of AA despite continued ET administration, without affecting EA constriction in vivo, thereby resulting in a dramatic reversal of the effects of ET on GFR.

Studies in intact renovascular models have shown that calcium entry blockers inhibit angiotensin (ANG II)-induced vasoconstriction in afferent (AA) but not efferent arterioles (EA), suggesting that increases in smooth muscle cell cytosolic calcium, the initiating intracellular message, result from entry through potential-operated channels in AA, but from organelle storage mobilization or entry through nonpotential-operated channels in EA. The present study examined the effects of diltiazem (10(-5) M) on the constrictor responses to KCl (50 mM) and half-maximal constricting concentrations (EC50) of ANG II and the effects of low-calcium bathing medium on EC50 ANG II responses in isolated rat AA and EA. KCl caused slightly greater decreases in lumen diameter in AA than in EA (P < 0.05) that were completely inhibited by diltiazem in both. Vasoconstriction to ANG II was significantly inhibited by diltiazem (29 +/- 12 vs. 67 +/- 31%; P < 0.02) in AA. However, constrictor response to ANG II in EA was unchanged by diltiazem (42 +/- 32 vs. 41 +/- 31%). Constriction to ANG II of AA in low-calcium medium was significantly attenuated (8 +/- 13 vs. 54 +/- 12%; P < 0.01); however, EA constrictor response was not affected (43 +/- 22 vs. 51 +/- 19%). These data indicate that EC50 ANG II-induced AA constriction requires calcium entry primarily through potential-operated channels. While potential-operated calcium entry channels can be functionally expressed in EA, intracellular calcium mobilization is the primary mechanism for ANG II-induced constriction.

The specific intrarenal sites and mechanism of endothelin (ET) vascular action are controversial. In this study afferent (AA) and efferent arterioles (EA) were isolated from the kidneys of normal Sprague-Dawley rats. Their respective concentration-dependent changes in lumen diameter in response to ET-1 were compared with those of angiotensin II (ANG II) and norepinephrine (NE). In a second series of experiments, the duration of vasoconstriction to comparable transient submaximal ET-1, ANG II, and NE concentrations in AA and EA was examined. The role of angiotensin II in mediating endothelin vasoconstriction also was examined with the converting-enzyme inhibitor captopril (CAP) and the competitive inhibitor [Sar1,Ala8]ANG II (SAR). The half-maximal constriction concentration (EC50) of ET-1 was less in EA than AA (P < 0.01). EC50 of ET-1 in AA was similar to that of ANG II, but was less than that of NE (P < 0.001). In EA the EC50 of ET-1 was also similar to that of ANG II, but much less than that of NE (P < 0.001). In both AA and EA the duration of ET-1 constriction was at least twice that of ANG II and more than fivefold that of NE. Neither CAP (10(-6) M) nor SAR (10(-7) M) changed the vasoconstrictor response to submaximal concentrations of ET-1 in AA or EA. It is concluded that ET-1 is a potent and prolonged constrictor agonist with a small, but significantly greater, concentration-dependent effect in EA than AA. The constrictor effect of ET-1 does not require ANG II activity.

The effects of atriopeptin III (AP III) on in vitro prepared afferent (AA) and efferent arterioles (EA) from rat kidneys were tested in a system in which lumen diameter could be measured. AP III (10(-13)-10(-7) M) had no effect on lumen diameter of AA that were not preconstricted. When AA were preconstricted with either angiotensin II (ANG II) or norepinephrine (NE), however, AP III increased lumen diameter in a concentration-dependent manner to the preconstriction baseline value. Maximal vasodilation occurred at 10(-10) M AP III. Unlike AA, EA constricted by 50% to 10(-10) M AP III further constricted EA that were pretreated with ANG II or NE. Dilation in ANG II-preconstricted AA to AP III was not inhibited by indomethacin. Constriction of EA to AP III was not altered by [Sar1-Ala8] ANG II, enalapril, OKY 046, or phentolamine. Results indicate that in isolated renal arterioles AP III dilates preconstricted AA but constricts EA that have either not been pretreated or have been preconstricted with other agonists. The effect of AP III on preconstricted AA does not require vasodilator prostaglandin mediation. The constrictor effect of AP III on EA is not dependent on angiotensin, thromboxane, or alpha-adrenergic mediation.

Differential sensitivity of the pre- and postglomerular arterial vessels to vasoconstrictor activity of angiotensin II (ANG II) and norepinephrine (NE) is controversial. To avoid the complex extravascular neurohumoral variables that may have accounted for different results in the intact rat kidney, an isolated arteriole technique was used to examine the dose responses of ANG II and NE on afferent (AA) and efferent arterioles (EA) from Sprague-Dawley rats. EA were more sensitive than AA to ANG II (EC50 = 3.2 +/- 1.8 x 10(-11) and 1.0 +/- 1.6 x 10(-9) M, respectively, P less than 0.001), whereas EC50 of both AA and EA to NE were similar (3.4 +/- 2.3 x 10(-8) and 1.4 +/- 2.6 x 10(-8) M, respectively). The dose-response curves of AA to ANG II were not different when perfused at different luminal pressures (90 and 30 mmHg). In contrast, EA were more sensitive to ANG II at 30 than at 90 mmHg (3.0 +/- 1.2 x 10(-11) and 5.0 +/- 1.8 x 10(-10) M, respectively, P less than 0.005). The EC50 of EA to NE was unaffected by similar changes in luminal pressures. The mean dose-response curves of AA to ANG II were the same with and without the addition of 10(-5) M indomethacin; however, in arterioles displaying a focal constriction pattern to ANG II the response became uniform. It is concluded that, in the isolated rat glomerular arterioles, EA are more sensitive to ANG II than AA, but both vessels respond similarly to NE. The decreased ANG II sensitivity in AA is not related to the higher in vivo pressure, and the attenuated response in AA does not appear to be mediated primarily through ANG II-stimulated vasodilator prostanoid activity. EA sensitivity to ANG II appears to be inversely related to lumen pressure.

Controversy has existed over apparent dissimilarities in the autoregulatory capacities of the rat and dog. A protocol was designed to evaluate both the effects of the anesthetic agents. Nembutal (used most commonly in dogs) and Inactin (most frequently employed in rats) and the species peculiarities of these two mammals on autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). With Nembutal autoregulation of RBF was present in both experimental animals. Inactin impaired RBF autoregulation similarly in both species. With impaired RBF autoregulation similarly in both species. With either anesthetic GFR was autoregulated well in both rat and dog. Comparison of the two species revealed a greater RBF per gram kidney weight and a higher renal perfusion pressure (RPP) at which autoregulation of both hemodynamic parameters was lost in the rat. It is concluded from these studies that 1) the frequent use of Inactin in the rat in large part accounts for the observed lack of autoregulation of RBF in this animal and 2) renal hemodynamic responses are qualitatively similar in rat and dog when the same anesthetic agents are used.

Munich-Wistar rats underwent thyroidectomy (TX) with reimplantation of the parathyroid glands. Systemic hemodynamic and micropuncture studies were performed at 1 and 3 wk post-TX, and the results were compared with levothyroxine replaced controls (TXT4). Cardiac output (CO) in TX rats fell progressively and was 40% of that in TXT4 at 3 wk. Renal blood flow declined in parallel with CO. Systemic blood pressure did not fall in TX rats because of a 50% increase in systemic vascular resistance by 3 wk post-TX. Glomerular dynamics were not significantly different between TX and TXT4 rats at 1 wk; however, by 3 wk single-nephron glomerular filtration rate (SNGFR) had fallen to 16.5 +/- 1.1 vs. 34.1 +/- 3.4 nl/min in TXT4 controls (P less than 0.001). In 3-wk TX rats, glomerular plasma flow (QA) was 50.9 +/- 3.7 vs. 108.0 +/- 8.7 nl/min in TXT4 rats (P less than 0.001), net hydraulic ultrafiltration pressure (delta P) was 33 +/- 2 vs. 37 +/- 1 mmHg in TXT4 rats (P less than 0.01), and the ultrafiltration coefficient (Kf) was 0.025 +/- 0.003 vs. 0.084 +/- 0.008 nl X s-1 X mmHg-1 in TXT4 controls (P less than 0.001). Although the changes in systemic and glomerular hemodynamics were progressive over 3 wk, proximal tubular reabsorption fell maximally within 1 wk. Similar patterns of alterations in glomerular dynamics are known physiological consequences of angiotensin II (ANG II).(ABSTRACT TRUNCATED AT 250 WORDS)

The responsiveness of the renal vascular system was investigated in uninephrectomized Sprague-Dawley rats in which acute renal failure had been induced by norepinephrine. The animals were studied at 1' and 3 wk after norepinephrine infusion. Uninephrectomized littermates served as controls. Compared with controls, there was an absence of renal blood flow autoregulation in 1-wk acute renal failure that returned in part by 3 wk. In 1-wk rats there was a marked increase, rather than decrease, in renovascular resistance as renal perfusion pressure was decreased. The renal vasculature was significantly less responsive in 1-wk rats than in control or 3-wk animals when acetylcholine, angiotensin II, or norepinephrine was infused into the renal artery at minimal vasoactive doses (all P less than 0.01). Paradoxically, renal vasoconstriction in response to renal nerve stimulation was greater in 1-wk than in 3-wk and control rats (P less than 0.01) and was not inhibited by renal artery infusion of phenoxybenzamine. Renal denervation significantly improved renal blood flow autoregulation in 1-wk animals (P less than 0.001) and completely abolished the increase in renovascular resistance as renal perfusion pressure was lowered. No effects of renal denervation on renal blood flow autoregulation were seen in control and 3-wk rats. It is concluded that renovascular responses to neurohumoral stimuli are aberrant in acute renal failure. The loss of renal blood flow autoregulation is related to an increased renovascular resistance that is due to increased activity of non-alpha-adrenergic mechanisms of the autonomic nervous system.