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 arterial pressure in various experimental models of hypertension, including two-kidney, one clip (2K1C) renal hypertension. However, the regional hemodynamic mechanisms underlying the hypotensive effect of AT(1) receptor antagonists in 2K1C rats under dynamic conditions have not been documented. Therefore, in the present study we determined the hemodynamic profile of the AT(1) receptor antagonist CV-11974 in conscious 2K1C rats and sham-operated control rats. Approximately 4 weeks after clipping, rats underwent a further two-stage operation for implantation of Doppler flow probes on the contralateral (left) renal artery, superior mesenteric artery, and distal aorta as well as for the implantation of intravascular catheters. At least 24 hours after the last operation continuous recordings were made of mean arterial pressure; heart rate; and renal, mesenteric, and hindquarters flows and conductances (Doppler shift/mean arterial pressure) in response to three doses of CV-11974 (0.01, 0.1, and 1.0 mg/kg IV). CV-11974 caused a small hypotensive effect (decrease of approximately 15 mmH,a) in the sham group, but regional flows and vascular conductances did not change. By contrast, in 2K1C rats CV-11974 caused dose-dependent hypotension that was maximal (-19+/-6, -41+/-4, and -51+/-8 mm Hg, respectively) after 6 hours. These changes were associated with generalized vasodilatation (increased 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, and the intermediate dose (0.1 mg/kg, n=8) caused maximal vasodilatation in the mesenteric and hindquarters circulations (approximately 50% increase in conductances). A 10-fold higher dose of CV-11974 (1.0 mg/kg, n=7) produced sustained, hyperemic renal vasodilatation (approximately 30% and 70% increases in renal flow and conductance, respectively) in addition to mesenteric and hindquarters vasodilatation. Thus, CV-11974-induced hypotension was accompanied by widespread vasodilatation, although this was dose dependent only in the renal vascular bed. This study illustrates that AT(1) receptor blockade causes vasodilatation in both renal and nonrenal circulations in 2K1C hypertension, contrasting with the relatively selective renal vasodilatation observed previously in spontaneously hypertensive rats. In addition, it was demonstrated that the maximal hypotension caused by CV-11974 occurred much later than the blockade of the cardiovascular effects of angiotensin II. This temporal disparity may imply that in addition to inhibition of tonic vasoconstriction maintained by circulating and/or tissue renin angiotensin systems, other mechanisms may also be involved in the antihypertensive effect of CV-11974.