Crucial Role of NO and Endothelium-Derived Hyperpolarizing Factor in Human Sustained Conduit Artery Flow-Mediated Dilatation

Abstract

Abstract-Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear.Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44°C), during the local infusion of saline and inhibitors of NO synthase (N G -monomethyl-L-arginine [L-NMMA]: 8 to 20 mol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 mol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 mol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter-wall shear stress relationship was constructed. During heating, compared with saline, the diameter-shear stress relationship was shifted downward by L-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of L-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62Ϯ0.03 mm), was decreased under our experimental conditions by L-NMMA (Ϫ39Ϯ4%), tetraethylammonium chloride (Ϫ14Ϯ4%), fluconazole (Ϫ18Ϯ6%), and to a greater extent, by the combinations of L-NMMA with tetraethylammonium (Ϫ64Ϯ4%) or with fluconazole (Ϫ71Ϯ3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways. Key Words: conduit arteries Ⅲ endothelium Ⅲ flow-mediated dilatation Ⅲ nitric oxide Ⅲ endothelium-derived hyperpolarizing factor Ⅲ cytochrome P450 C onduit artery flow-mediated dilatation (FMD) is a fundamental mechanism that regulates vascular conductance at rest and during exercise, as well as maintaining wall shear stress within physiological values. Vasodilatation is related to the integrity of the endothelium that releases vasodilatating factors in response to the increase in shear stress. 1 In humans, we 2 and others 3,4 have demonstrated previously the major contribution of NO to peripheral conduit artery FMD in response to reactive hyperemia after a brief period of distal ischemia. This test is currently used in clinical experiments as an index of endothelial function and NO availability. 5,6 However, recent data suggest that, during more sustained hyperemia, conduit artery FMD may occur independently of NO release. [7][8][9] In fact, the local inhibition of NO synthesis by N G -monomethyl-L-arginine (L-NMMA) in healthy subjects did not affect radial artery FMD induced by hand skin heating...

There^|^rsquo;s More to Flow-Mediated Dilation Than Nitric Oxide

“…The vasodilatory response to local hand warming is decreased to a greater extent when TEA is combined with L-NMMA than when either of these inhibitors are infused independently. This supports the suggestion that there is cross-talk between EDHF and NO [130][131][132] .…”

“…Although investigation into the role of EDHF in human conduit arteries has been limited, it has been demonstrated that EDHF inhibition with tetraethylammonium (TEA, nonselective K ＋ channel inhibitor) decreases basal radial artery tone as well as the vasodilatory response to sustained increases in shear stress through local hand warming 130,131) . The vasodilatory response to local hand warming is decreased to a greater extent when TEA is combined with L-NMMA than when either of these inhibitors are infused independently.…”

Flow-Mediated Vasodilation in End-Stage Renal Disease

“…The FMD decline observed in ESRD-CVD Ϫ patients at higher SS could be interpreted as resulting from the time-limited NO-mediated response not compensated by synergic factors (prostacyclin and endothelium-derived hyperpolarizing factor, EDHF). Indeed, during more sustained hyperemia (like with the hand-warming protocol), EDHF plays an important role and can compensate for the lower NO response (18,20).…”

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

“…Strong evidence indicates that endothelium-derived NO and other relaxing factors can be released from the endothelium in response to increased shear stress mediating flow-induced vasodilatation. 2,3 Endothelium-derived NO also has a role in the arterial remodeling of large conduit arteries in response to a chronic increase in blood flow. 47,48 In small resistance-sized arteries, the situation is less clear.…”

“…1 Both flow-mediated dilatation and flow-mediated remodeling are endothelium-dependent processes. 2,3 Structural remodeling of the arterial wall in response to hemodynamic changes can occur under both physiological and pathological conditions, for example, in the uterine vascular bed during pregnancy and in hypertension, respectively. [4][5][6] Because in established hypertension cardiac output is within the normal range, the increased blood pressure is mainly due to increased vascular resistance.…”