Renal vascular reactivity in mice: AngII-Induced vasoconstriction in AT(1A) receptor null mice

The present study describes methodology and its application to evaluate ren al reactivity in acute studies on anesthetized mice. Renal blood flow (RBF) was measured using an ultrasonic transit-time flowmeter and a non-cannulat ing V-shaped probe. An intrarenal artery injection technique established fe asibility and reproducibility of studies of renal vascular reactivity to an giotensin II (AngII) in adult wild-type mice. The study also examined wheth er AngII would affect RBF in mice lacking AT(1A) receptors due to gene targ eting. Mean arterial pressure averaged 83 and 62 mmHg, respectively, in mic e with and without AT(1A) receptors. The RBF was similar in both groups, av eraging 7 ml/min per g kidney wt. AngII injection (10-mu l bolus) into the renal artery produced transient, dose-dependent, selective reductions in RB F in AT(1A) knockout mice as well as wild-type mice. The response was consi derably greater in mice with AT(1A) receptors: 10% for 0.1 ng, 30% for 1 ng , and 45% for 5 ng AngII in control animals versus respective decreases of 6, 15, and 17% in knockout mice. In other studies, angiotensin-converting e nzyme (captopril) or renin (CP-71362-14) was inhibited. During inhibition o f AngII, formation, renal vascular reactivity to AngII increased twofold in both groups. Coadministration of the AT(1) receptor antagonist losartan (1 to 1000 ng) elicited dose-dependent inhibition of AngII effects, with near maximum blockage of 80 to 90% in both groups of mice. The putative AT(2) r eceptor antagonist PD 123319 inhibited 30 to 40% of AngII-induced vasoconst riction, whereas CGP 42112 had no effect in either group. In conclusion, An gII can elicit renal vasoconstriction, albeit attenuated, in AT(1A) knockou t mice. The weaker RBF effects are most likely due to the absence of the AT (1A) receptor. Inhibition of the response by AT(1) receptor antagonist sugg ests mediation by the AT(1B) receptor in these animals. The residual constr ictor effect observed during AT(1) receptor blockade and sensitive to PD 12 3319 appears to be mediated by a non-AT(1) receptor.