Abstract 13752: Endothelium-Derived Hyperpolarizing Factor Contributes to Exercise-Induced Vasodilation in Hypercholesterolemia.
Background: Whether impaired endothelial function in hypercholesterolemia (HC) impacts on exercise-induced vasodilation, and whether the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to exercise vasodilation varies in comparison to healthy subjects is unknown. We hypothesized that there is a differential contribution of these two agonists to exercise-induced vasodilation.
Methods: In 26 healthy and 19 HC subjects, we measured forearm blood flow (FBF) using strain gauge plethysmography at rest, during handgrip exercise (performed at 15%, 30% and 45% of maximum grip strength) and after sodium nitroprusside (1.6 and 3.2 μg/min) infusion. Measurements were repeated after either NO blockade with L-NMMA, calcium-dependent potassium channel blockade with tetraethylammonium (TEA, inhibiting EDHF activity), and combined blockade.
Results: Exercise-induced vasodilation produced a stepwise increase in FBF in both groups (p<0.0001). At peak (45%) exercise, there was reduced vasodilation in HC subjects when compared with healthy (274% vs 438% increase in FBF from baseline, p=0.017). After TEA, vasodilation was significantly inhibited in both healthy (27%, p<0.0001) and HC (20%, p<0.0001) subjects. Addition of L-NMMA to TEA further reduced FBF in healthy (14%, p=0.012) but not in HC subjects, indicating a greater contribution of EDHF to the vasodilator response in HC. When L-NMMA was given first, FBF during exercise was attenuated equally in both the healthy (−19%, p<0.0001) and HC (−18%, p=0.0001) subjects. Addition of TEA to L-NMMA further reduced exercise-induced vasodilation by 9%, p=0.002 in the Healthy, and 18%, p=0.005 in HC subjects. Sodium nitroprusside-mediated dilation was similar in healthy and HC subjects, indicating preserved sensitivity of the smooth muscle cells to NO in HC.
Conclusions: This study demonstrates for the first time that compared to healthy subjects, exercise-induced vasodilation is A) impaired, and B) is predominantly mediated by EDHF in HC subjects. There is a decreased contribution of NO in HC subjects in whom EDHF activity is preserved. Whether enhancing EDHF activity therapeutically will improve physiologic function of the vasculature in HC needs to be further investigated.
- © 2010 by American Heart Association, Inc.