Effects of candesartan on angiotensin II-induced renal vasoconstriction inrats and mice

This study determined the inhibitory effect of the angiotensin II (AngII) t ype 1 (AT(1)) receptor blocker candesartan on renal vascular reactivity in vivo. Reactivity to AngII before and during candesartan administration was assessed by measuring (by electromagnetic or ultrasonic flowmetry) renal bl ood flow responses to AngII in rats and mice. AngII produced greater renal vasoconstriction in 7-wk-old, spontaneously hypertensive rats than in Wista r-Kyoto rats. After indomethacin treatment, AngII (2 ng) produced 40% reduc tions in renal blood flow in both rat strains, without affecting systemic a rterial pressure. Coadministration of candesartan blocked AngII effects in a dose-dependent manner, with similar levels of inhibition in spontaneously hypertensive rats and Wistar-Kyoto rats; maximal inhibition was 80%. In ra ts that had been pretreated (for 30 min) with intravenous candesartan, AngI I-induced renal vasoconstriction was inhibited dose dependently up to 98%. To evaluate receptor subtype mediation, responses were compared in mice wit h or without the AT(1A) receptor (deleted by gene targeting). Intrarenal An gII (1 ng) caused a 32% reduction of renal blood flow in wild-type mice and an 8% reduction of renal blood flow in AT(1A) receptor-knockout mice. Ten nanograms of AngII were required to elicit 20% renal vasoconstriction in th ese mutant mice. Concurrent injection of candesartan caused dose-dependent inhibition of AngII up to 80%. The candesartan IC50 values for percentage c hanges in renal blood flow did not differ in the two groups of mice. These studies establish that candesartan is an effective, highly selective, AT(1) receptor blocker, inhibiting renal vasoconstriction in rodents in a concen tration- and time-dependent manner. Candesartan effectively blocks AT(1A) a nd AT(1B) receptors in renal resistance vessels of rodents, with similar ef ficacies in rats and mice.