Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis

Abstract

Background —The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT 1 ) receptor inhibition improves endothelial dysfunction. Methods and Results —In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9±2%, P =0.02) reduction in FVRI and inhibited angiotensin II–mediated vasoconstriction in both patient groups ( P <0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44±5% to 58±4% reduction in FVRI with infusion at a rate of 150 μg/min, P <0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT 1 receptor inhibition ( P =0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4±0.9% to 3.2±0.8%, P =0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6±1.7 to 26.7±2.4 μmol/L ( P =0.008). Conclusions —The results of the present study indicate that inhibition of the AT 1 receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.