EFFECTS OF ACUTE AT(1) RECEPTOR BLOCKADE BY CANDESARTAN ON ARTERIAL-PRESSURE AND RENAL-FUNCTION IN RATS

Experiments were performed on normal anesthetized rats to determine th e effects of candesartan, a novel AT(1) receptor antagonist, on the ar terial pressure and renal hemodynamic responses to bolus doses of angi otensin II (ANG II) and on renal hemodynamics and sodium excretion. Co ntrol arterial pressure responses to bolus ANG II doses of 10, 50, 100 and 1,000 ng were 26 +/- 6, 54 +/- 7, 57 +/- 7, and 79 +/- 7 mmHg; th e decreases in cortical renal blood flow (CRBF), measured with laser-D oppler flowmetry, were 47 +/- 9, 64 +/- 8, 71 +/- 6, and 82 +/- 6%. Th e vasoconstrictor responses to ANG II up to 1,000 ng were completely b locked by candesartan doses of 1 and 0.1 mg/kg, whereas treatment with 0.01 mg/kg candesartan attenuated the arterial pressure and CRBF resp onses. The higher doses of candesartan (1 and 0.1 mg/kg) elicited rapi d decreases in arterial pressure, leading to associated decreases in s odium excretion. Renal blood flow (RBF), glomerular filtration rate (G FR), and urine flow also decreased following treatment with candesarta n at 1 mg/kg. In contrast, when candesartan was given at 0.01 mg/kg, w hich did not decrease arterial pressure significantly, there were sign ificant increases in GFR (16 +/- 4), RBF (9 +/- 2), urine flow (11 +/- 2), sodium excretion (35 +/- 7), and fractional sodium excretion (39 +/- 8%). The inability to overcome blockade, even with very high ANG I I doses, indicates that candesartan is a potent noncompetitive blocker of ANG II presser and renal vasoconstrictor effects. The lower candes artan dose that did not cause significant hypotension elicited substan tial increases in RBF, GFR, and sodium excretion, revealing the direct renal vasodilator and natriuretic effects of AT(1) receptor blockade.