Renal responses to AT1 blockade in angiotensin II-induced hypertensive rats.

Abstract

Previous studies have shown that uninephrectomized rats infused chronically with low doses of angiotensin II (Ang II) develop progressive hypertension that is prevented by coadministration of losartan in the drinking water. The present study was performed to contrast the effects of chronic and acute losartan treatment in reversing the Ang II-mediated actions on arterial pressure and renal function. Ang II was infused subcutaneously via osmotic minipumps (40 ng/min) for 13 days in two groups (N = 10 and N = 6); one group also received losartan in the drinking water (30 mg/kg.day) throughout this period. Untreated rats (N = 6) and rats (N = 6) receiving only losartan served as control groups. Ang II-infused rats had higher mean arterial pressures (153 +/- 7 versus 107 +/- 3 mm Hg) and lower GFR (0.7 +/- 0.04 versus 0.98 +/- 0.06 mL/min.g) than Ang II-infused rats receiving losartan chronically. The Ang II-infused rats responded to acute doses of losartan (10 mg/kg) with progressive reductions in arterial pressure and significant increases in cortical blood flow (34 +/- 12% increase), renal plasma flow, GFR, and sodium excretion; however, the increases in renal blood flow and GFR were not sustained as systemic arterial pressure decreased. Because Ang II-infused rats receiving losartan chronically still exhibited decreases in RBF in response to a bolus dose of Ang II, further studies evaluated the effects of acute losartan treatment in rats treated chronically with losartan. Although arterial pressure decreased only slightly, demonstrating adequate systemic vascular blockade, there were still substantial and sustained increases in renal plasma flow, cortical blood flow (20 +/- 4% increase), GFR, and sodium excretion. In summary, the modest responses to acute losartan in Ang II-infused rats indicate that chronic Ang II infusions lead to alterations in renal function that are only partially reversible by acute losartan treatment. In contrast, chronic treatment with losartan prevents the Ang II-induced decrease in GFR. The renal responses to acute losartan in the Ang II-infused rats treated chronically with losartan suggest that substantive intrarenal actions of Ang II can be maintained even when the systemic vascular AT1 receptors are effectively blocked.