ENHANCED ENDOTHELIN-MEDIATED CORONARY VASOCONSTRICTION AND ATTENUATEDBASAL NITRIC-OXIDE ACTIVITY IN EXPERIMENTAL HYPERCHOLESTEROLEMIA

Background Experimental hypercholesterolemia is associated with corona ry vasomotor dysfunction. This study was designed to test the hypothes is that experimental hypercholesterolemia is characterized by altered coronary vasomotor responses to endothelin and inhibition of the endog enous NO pathway. Methods and Results Endothelin-l (ET-1) at 5 ng.kg(- 1). min(-1) or N-G-monomethyl-L-arginine (L-NMMA), a competitive inhib itor of nitric oxide synthase (NOS), at 50 mu g.kg(-1). min(-1) was in fused into the left anterior descending coronary artery in pigs before and after 10 weeks of cholesterol diet. There was a significant incre ase in serum cholesterol. At 10 weeks, ET-1 resulted in an accentuated decrease in coronary blood flow (CBF) and coronary artery diameter (C AD) compared with baseline (-88 +/- 6% versus -45 +/- 9%, P < .O5, 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 cor onary arteries were unchanged. The effect of L-NMMA on CBF, CAD, and C VR was attenuated at 10 weeks (-7 +/- 8% versus -48 +/- 4%, -2 +/- 3% versus -17 +/- 5%, and 16 +/- 10% versus 125 +/- 32%; each P < .05). I mmunohistochemistry staining for constitutive NOS revealed a decrease in immunoreactivity in the coronary arteries of hypercholesterolemic p igs. Conclusions The present study demonstrates an enhanced coronary v asoconstrictive response to pathophysiological doses of endothelin and an attenuated response to the inhibition of endogenous NO activity, s uggesting an alteration in coronary vascular reactivity in experimenta l hypercholesterolemia.