Chronic kinin receptor blockade attenuates the antihypertensive effect of ramipril

Abstract

The contribution of endogenous kinins to the chronic antihypertensive effect of angiotensin converting enzyme inhibitors was investigated in two-kidney, one clip hypertensive Wistar rats, using the new bradykinin B2-receptor antagonist HOE 140 (D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]-bradykinin). In a first protocol, rats were pretreated orally with the angiotensin converting enzyme inhibitor ramipril (1 mg/kg per day), for 4 weeks. Acute blockade of bradykinin receptors by intravenous injections of HOE 140 at doses of 8.4 and 100 μg/kg, which inhibited the depressor responses to exogenous bradykinin, did not affect the antihypertensive effect of ramipril in these animals. Bradykinin receptors were then blocked chronically by subcutaneous infusion of HOE 140 (500 μg/kg per day) via osmotic minipumps for 6 weeks, while ramipril treatment was continued. HOE 140 partially reversed the antihypertensive effect of ramipril from 115.3±4.6 to 123.8±3.3 mm Hg (mean arterial blood pressure) after 3 weeks and to 121.3±2.9 mm Hg after 6 weeks. In contrast, in controls (ramipril plus subcutaneous vehicle infusion) mean arterial blood pressure decreased further from 112.0±6.0 to 1103±4.9 mm Hg after 3 weeks and to 103.7±5.0 mm Hg after 6 weeks (p<0.05 and p<0.01, HOE 140 versus controls). Plasma catecholamines were not significantly different between the two groups at the end of the experiment, indicating that the partial reversal of the antihypertensive effect was not due to a bradykinin-like agonistic effect on catecholamine release. In a second protocol, HOE 140 (500 μg/kg per day s.c.) was coadministered with ramipril (1 mg/kg per day p.o.) in two-kidney, one clip hypertensive Wistar rats for 6 weeks. Again, HOE 140 attenuated the antihypertensive effects of ramipril (mean arterial blood pressure 131.8±2.6 versus 115.7±4.5 mm Hg after 3 weeks and 124.4±4.2 versus 105.4±4.8 mm Hg after 6 weeks; p<0.05, HOE 140 versus controls). Our results demonstrate that potentiation of endogenous bradykinin contributes to the chronic antihypertensive action of an angiotensin converting enzyme inhibitor in renovascular hypertension.