Enhanced Endothelin-Mediated Coronary Vasoconstriction and Attenuated Basal Nitric Oxide Activity in Experimental Hypercholesterolemia

Abstract

Background Experimental hypercholesterolemia is associated with coronary vasomotor dysfunction. This study was designed to test the hypothesis that experimental hypercholesterolemia is characterized by altered coronary vasomotor responses to endothelin and inhibition of the endogenous NO pathway. Methods and Results Endothelin-1 (ET-1) at 5 ng · kg ⁻¹ · min ⁻¹ or N ^G -monomethyl- l -arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase (NOS), at 50 μg · kg ⁻¹ · min ⁻¹ was infused into the left anterior descending coronary artery in pigs before and after 10 weeks of cholesterol diet. There was a significant increase in serum cholesterol. At 10 weeks, ET-1 resulted in an accentuated decrease in coronary blood flow (CBF) and coronary artery diameter (CAD) compared with baseline (−88±6% versus −45±9%, P <.05, and −77±14% versus −18±8%, P <.05, respectively) and an increase in coronary vascular resistance (CVR) (242±18% versus 110±17%, P <.05); ET receptor density and binding affinity in epicardial coronary arteries were unchanged. The effect of L-NMMA on CBF, CAD, and CVR was attenuated at 10 weeks (−7±8% versus −48±4%, −2±3% versus −17±5%, and 16±10% versus 125±32%; each P <.05). Immunohistochemistry staining for constitutive NOS revealed a decrease in immunoreactivity in the coronary arteries of hypercholesterolemic pigs. Conclusions The present study demonstrates an enhanced coronary vasoconstrictive response to pathophysiological doses of endothelin and an attenuated response to the inhibition of endogenous NO activity, suggesting an alteration in coronary vascular reactivity in experimental hypercholesterolemia.