Arterial Stiffness Is Regulated by Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor During Changes in Blood Flow in Humans

Abstract

Cytochrome-derived epoxyeicosatrienoic acids may be important endothelium-derived hyperpolarizing factors, opening calcium-activated potassium channels, but their involvement in the regulation of arterial stiffness during changes in blood flow in humans is unknown. In healthy volunteers, we measured arterial pressure, radial artery diameter, wall thickness, and flow (NIUS02) during hand skin heating in the presence of saline or inhibitors of NO synthase (N(G)-monomethyl-L-arginine), calcium-activated potassium channels (tetraethylammonium), and cytochrome epoxygenases (fluconazole). Arterial compliance and elastic modulus were calculated and fitted as functions of midwall stress to suppress the confounding influence of geometric changes. Under saline infusion, heating induced an upward shift of the compliance-midwall stress curve and a downward shift of the modulus-midwall stress curve demonstrating a decrease in arterial tone and stiffness when blood flow increases. These shifts were reduced by N(G)-monomethyl-L-arginine and abolished by the combinations of N(G)-monomethyl-L-arginine+tetraethylammonium and N(G)-monomethyl arginine+fluconazole. In parallel, in isolated mice coronary arteries, fluconazole and tetraethylammonium reduced the relaxations to acetylcholine. However, fluconazole did not affect the relaxations to the openers of calcium-activated potassium channels of small- and intermediate-conductance NS309 and of large-conductance NS1619 excluding a direct effect on these channels. Moreover, tetraethylammonium reduced the relaxations to NS1619 but not to NS309, suggesting that the endothelium-derived hyperpolarizing factor involved mainly acts on large-conductance calcium-activated potassium channels. These results show in humans that, during flow variations, arterial stiffness is regulated by the endothelium through the release of both NO and cytochrome-related endothelium-derived hyperpolarizing factor.

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

“…In the large conduit arteries, L-type Ca 2+ channels are important determinants of their mechanical properties and compliance, which are such that blood pressure and flow are propagated between the heart and arterioles and that thereby pulsatile flow is transformed into steady flow due to the "windkessel" effect (Westerhof et al, 2009). For example, CaBs increase vascular compliance of large elastic vessels and may be of importance for the pathogenesis and prognosis of cardiovascular complications such as atherosclerosis, left ventricular hypertrophy and heart failure (Bellien et al, 2010;Belz, 1995;Essalihi et al, 2007;Safar et al, 1989;Slama et al, 1995;Vayssettes-Courchay et al, 2011). Further evidence for a role of L-type Ca 2+ channels in atherosclerosis was obtained in carotid and femoral VSMCs, where the L-type Ca 2+ channel gene expression differs between atherosclerotic versus non-atherosclerotic regions (Tiwari et al, 2006).…”

Early stage detection of conduit artery endothelial dysfunction in patients with type 1 diabetes

“…13,14 Furthermore, heating can also provide, by the calculation of mechanical parameters, significant insights into the effects of type 1 diabetes regarding the adaptation of the arterial elastic properties during physiological blood flow variations. 16,17 This is particularly important since this adaptation mainly contributes to maintaining an appropriate arterial conductance and ventricular vascular coupling, in particular during exercise. 16,17 Therefore, in present study we were prompted to evaluate whether hand skin heating may facilitate the early detection of conduit artery endothelial dysfunction in type 1 diabetic patients, as compared with post-ischaemic hyperaemia.…”

“…16,17 This is particularly important since this adaptation mainly contributes to maintaining an appropriate arterial conductance and ventricular vascular coupling, in particular during exercise. 16,17 Therefore, in present study we were prompted to evaluate whether hand skin heating may facilitate the early detection of conduit artery endothelial dysfunction in type 1 diabetic patients, as compared with post-ischaemic hyperaemia.…”

Korean Red Ginseng Improves Vascular Stiffness in Patients with Coronary Artery Disease

“…Importantly, atherosclerosis decreases vascular elasticity and increases vascular stiffness, thereby increasing PWV [24]. PWV is also affected by endothelial function and is regulated by endothelium-derived NO and hyperpolarizing factor [25,26]. KRG has probable anti-oxidative properties; it is known to promote NO production and to protect endothelial cells from oxidative stress [2,15,27,28].…”