REGIONAL HEMODYNAMIC-EFFECTS OF THE AT(1) RECEPTOR ANTAGONIST CV-11974 IN CONSCIOUS RENAL HYPERTENSIVE RATS

Angiotensin II subtype 1 (AT(1)) receptor antagonists reduce mean arte rial pressure in various experimental models of hypertension, includin g two-kidney, one clip (2K1C) renal hypertension. However, the regiona l hemodynamic mechanisms underlying the hypotensive effect of AT(1) re ceptor antagonists in 2K1C rats under dynamic conditions have not been documented. Therefore, in the present study we determined the hemodyn amic profile of the AT(1) receptor antagonist CV-11974 in conscious 2K 1C rats and sham-operated control rats. Approximately 4 weeks after cl ipping, rats underwent a further two-stage operation for implantation of Doppler flow probes on the contralateral (left) renal artery, super ior mesenteric artery, and distal aorta as well as for the implantatio n of intravascular catheters. At least 24 hours after the last operati on continuous recordings were made of mean arterial pressure; heart ra te; and renal, mesenteric, and hindquarters flows and conductances (Do ppler shift/mean arterial pressure) in response to three doses of CV-1 1974 (0.01, 0.1, and 1.0 mg/kg IV). CV-11974 caused a small hypotensiv e effect (decrease of approximately 15 mmH,a) in the sham group, but r egional flows and vascular conductances did not change. By contrast, i n 2K1C rats CV-11974 caused dose-dependent hypotension that was maxima l (-19+/-6, -41+/-4, and -51+/-8 mm Hg, respectively) after 6 hours. T hese changes were associated with generalized vasodilatation (increase d conductance) in all three vascular beds, although there were subtle differences with the different CV-11974 doses. The lowest dose of this compound tested (0.01 mg/kg, n=7) caused transient vasodilatation, an d the intermediate dose (0.1 mg/kg, n=8) caused maximal vasodilatation in the mesenteric and hindquarters circulations (approximately 50% in crease in conductances). A 10-fold higher dose of CV-11974 (1.0 mg/kg, n=7) produced sustained, hyperemic renal vasodilatation (approximatel y 30% and 70% increases in renal flow and conductance, respectively) i n addition to mesenteric and hindquarters vasodilatation. Thus, CV-119 74-induced hypotension was accompanied by widespread vasodilatation, a lthough this was dose dependent only in the renal vascular bed. This s tudy illustrates that AT(1) receptor blockade causes vasodilatation in both renal and nonrenal circulations in 2K1C hypertension, contrastin g with the relatively selective renal vasodilatation observed previous ly in spontaneously hypertensive rats. In addition, it was demonstrate d that the maximal hypotension caused by CV-11974 occurred much later than the blockade of the cardiovascular effects of angiotensin II. Thi s temporal disparity may imply that in addition to inhibition of tonic vasoconstriction maintained by circulating and/or tissue renin angiot ensin systems, other mechanisms may also be involved in the antihypert ensive effect of CV-11974.