Effects of candesartan on angiotensin II-induced renal vasoconstriction in rats and mice.
This study determined the inhibitory effect of the angiotensin II (AngII) type I (AT1) 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 blood flow responses to AngII in rats and mice. AngII produced greater renal vasoconstriction in 7-wk-old, spontaneously hypertensive rats than in Wistar-Kyoto rats. After indomethacin treatment, AngII (2 ng) produced 40% reductions in renal blood flow in both rat strains, without affecting systemic arterial 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 rats that had been pretreated (for 30 min) with intravenous candesartan, AngII-induced renal vasoconstriction was inhibited dose dependently up to 98%. To evaluate receptor subtype mediation, responses were compared in mice with or without the AT1A receptor (deleted by gene targeting). Intrarenal AngII (1 ng) caused a 32% reduction of renal blood flow in wild-type mice and an 8% reduction of renal blood flow in AT1A receptor-knockout mice. Ten nanograms of AngII were required to elicit 20% renal vasoconstriction in these mutant mice. Concurrent injection of candesartan caused dose-dependent inhibition of AngII up to 80%. The candesartan IC50 values for percentage changes in renal blood flow did not differ in the two groups of mice. These studies establish that candesartan is an effective, highly selective, AT1 receptor blocker, inhibiting renal vasoconstriction in rodents in a concentration- and time-dependent manner. Candesartan effectively blocks AT1A and AT1B receptors in renal resistance vessels of rodents, with similar efficacies in rats and mice.
Ruan
X
X
University of North Carolina at Chapel Hill, 27599-7545, USA.
Purdy
K E
KE
Oliverio
M I
MI
Coffman
T M
TM
Arendshorst
W J
WJ
D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D012039:Regional Blood Flow / Q000187:drug effects; D012077:Renal Artery; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan