Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Abstract

Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.

Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia

“…This is associated with 23‐ and 1.7‐fold increases in plasma low‐ and high‐density lipoprotein cholesterol, respectively, as we recently reported (de Beer et al . ). To correct for the significant difference in body weight, haemodynamic and metabolic variables were indexed to body weight.…”

“…and we have recently reported exercise responses in these animals (de Beer et al . ). Similar to our recent study, exercise‐induced systemic vasodilatation was reduced in FH compared to normal swine, indicated by lower SVCi at each exercise level (Fig.…”

“…The latter is consistent with our previous report of endothelial dysfunction and reduced NO bioavailability in the systemic circulation of FH swine (de Beer et al . ). Furthermore, pretreatment of arterioles with the selective ET B receptor antagonist BQ‐788 did not alter ET‐1 responses in arterioles from either group (data not shown) suggesting that ET A receptors are the primary mediators of ET‐mediated vasoconstriction in this vascular bed.…”

“…Thus, FH swine have reduced NO bioavailability, characteristic of systemic endothelial dysfunction, underlying attenuated exercise hyperaemia compared to normolipidaemic controls (de Beer et al . ).…”

Myosin phosphatase isoforms and related transcripts in the pig coronary circulation and effects of exercise and chronic occlusion

“…To the best of our knowledge PDE5 inhibitor drugs have not been tested for salutary effects on coronary blood flow in this model of chronic coronary occlusion. In other models, PDE5 inhibitors have been shown to increase coronary blood flow (de Beer et al, 2013; Houweling et al, 2012). In a pig model of myocardial infarction, PDE5 mRNA was reduced in coronary arterioles remote from the zone of infarction associated with attenuated coronary vasodilation to PDE5 inhibition, while the effect of exercise training was not investigated (Merkus et al, 2013).…”