Abstract 259: The Contribution of Endothelial Derived Hyperpolarizing Factor and Nitric Oxide to Vasodilator tone in Hypercholesterolemia
Vasodilator tone in humans is modulated by a variety of endothelium-derived factors including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). EDHF contributes to vasodilation by stimulating calcium dependent potassium channels (K+ca) that can be inhibited by tetraethylammonium (TEA). The role of EDHF to resting and bradykinin (BK)-mediated vasodilation in hypercholesterolemia (HC) is unknown. We hypothesized that the contribution of EDHF in HC will be different from healthy subjects. METHODS In 16 healthy and 16 HC subjects, we measured forearm blood flow (FBF) using strain gauge plethysmography at rest and after endothelium-dependent and -independent vasodilation with intra-brachial artery infusion of bradykinin (BK, 100, 200, 400ng/min) and sodium nitroprusside (SNP, 1.6 and 3.2 μg/min), respectively. Measurements were repeated after NO blockade with L-NMMA (8 μmol/min) and combined NO and K+ca blockade using TEA. In separate experiments, TEA infusions preceded combined blockade with L-NMMA and TEA. Responses were compared using a linear mixed model. RESULTS L-NMMA reduced resting FBF by 23%, p=0.003 in healthy subjects and by 19% in HC (p=0.001). After addition of TEA, FBF was unchanged in healthy subjects (p=0.6), but was further reduced in the HC by 21%, p=0.006, indicating an important contribution of EDHF to resting vasodilator tone in HC. BK infusions produced similar progressive vasodilation in both healthy and HC. L-NMMA significantly inhibited BK-mediated forearm vasodilation in both groups (p<0.001) with a 20%(healthy) and 34%(HC) reduction in FBF at peak BK. Addition of TEA to L-NMMA further reduced BK-mediated vasodilation (p<0.001) by 28% in healthy and 25% in HC subjects at the peak BK dose (p=ns healthy vs HC). When TEA was administered before L-NMMA, BK-mediated vasodilation was equally (29%) and significantly inhibited in both healthy and HC subjects (p<0.01). SNP-mediated vasodilation was unchanged after L-NMMA and TEA. CONCLUSION Tonic basal activity of EDHF contributes to resting vasodilator tone by activating K+ca channels in HC but not in healthy subjects. This study demonstrates for the first time that both NO and EDHF equally contribute to BK-mediated vasodilation in both health and HC.