EFFECT OF SELECTIVE ANGIOTENSIN-II RECEPTOR ANTAGONISM AND ANGIOTENSIN CONVERTING ENZYME-INHIBITION ON THE CORONARY VASCULATURE INVIVO - INTRAVASCULAR 2-DIMENSIONAL AND DOPPLER ULTRASOUND STUDIES

Background. Although angiotensin converting enzyme (ACE) inhibitors have been reported to increase coronary blood How, the effect of selective angiotensin II (AT1)-receptor antagonism on the coronary circulation has not been defined. Methods and Results. We examined the effects of the AT1-receptor antagonist Losartan (DuP 753, 0.2-3.2 mg/kg) on coronary arteries in vivo in 11 dogs, using a combination of intravascular two-dimensional and Doppler ultrasound. In six dogs, a 30-MHz, 4.3F ultrasound imaging catheter was placed in the midsegment of the circumflex coronary artery to measure cross-sectional area (CSA), and a 0.018-in. Doppler wire was placed alongside to measure coronary How velocity. At peak effect (1.6 mg/kg), Losartan increased mean coronary CSA from 7.9+/-0.5 to 9.5+/-0.8 mm 2 and average peak velocity (APV) from 32+/-10 to 56+/-18 cm/sec, resulting in an increase in coronary blood flow from 74+/-19 to 151+/-36 mL/min. The maximal effect of the ACE inhibitor enalaprilat (5 mg) was an increase in CSA from 7.7+/-0.7 to 8.4+/-0.8 mm2 and an increase in APV from 36+/-10 to 53+/-20 cm/sec, with an increase in coronary blood flow from 82+/-25 to 122+/-41 mL/min. Relative to maximal hyperemia with adenosine (6 mg i.c.), the magnitude of flow increase from baseline was 0.37 with the AT1-receptor antagonist and 0.19 with the ACE inhibitor (p<0.05). These effects were seen without changes in heart rate or systemic arterial pressure. In an additional five dogs, the ultrasound imaging catheter was introduced directly over a 0.014-in. Doppler wire, and the effects of indomethacin, propranolol, and N(omega)-nitro-L-arginine methylester ( L-NAME) on the vasodilator effect of Losartan (1.6 mg/kg) were examined. Indomethacin and propranolol had no effect on Losartan-induced vasodilation, suggesting that it was not mediated via prostaglandins or beta-adrenoceptors. However, Losartan-induced epicardial vasodilation was partially inhibited by L-NAME, suggesting an action partly dependent on endothelial release of nitric oxide. Conclusions. Thus, these acute studies in anesthetized dogs suggest that inhibition of AT1-receptors in the coronary circulation results in vasodilator responses greater in magnitude than ACE inhibition and partly endothelium dependent. The exact role for AT1-receptors in human coronary physiology and pathology remains to be defined.