Blunted exercise‐induced vasodilation in familial hypercholesterolemic swine does not involve enhanced ET‐1‐mediated vasoconstriction

Abstract

Hypercholesterolemia causes endothelial dysfunction and activation of the vascular endothelin‐1 (ET‐1) system. The procontractile effect of ET‐1 action on resistance vessels would therefore be expected to limit exercise‐induced vasodilation. To assess the role of hypercholesterolemia on ET‐1 activation and exercise‐induced vasodilation, we compared the effects of ET receptor blockade in instrumented Yucatan (Y) and familial hypercholesterolemic (FH) swine, at rest and during exercise. Exercise induced systemic vasodilation, measured as systemic vascular conductance index (SVCi = SVC/kg bodyweight), that was reduced in FH swine (36%) compared to Y swine (91%). Unexpectedly, the ETA/ETB receptor blocker tezosentan did not enhance exercise‐induced vasodilation in FH swine and the vasodilator effect of tezosentan at rest was reduced in FH swine (16%) versus Y swine (48%). Isolated skeletal muscle 2A arterioles from FH swine demonstrated enhanced sensitivity to ET‐1; however, plasma ET‐1 levels tended to be lower in conscious FH swine compared to Y swine (p=0.08). Thus, our data suggest that although the skeletal muscle vasculature of FH swine exhibits enhanced sensitivity to ET‐1, an ET‐1‐mediated enhancement of systemic vascular tone does not account for the reduced exercise‐induced dilation in FH swine, possibly as a result of reduced production/release of ET‐1 in FH swine. Supported by NIH‐HL52490.