Role of NO and EETs and of Endothelium-Independent Smooth Muscle Tone Relaxation in the Regulation of AWV

Arterial wall viscosity (AWV) is a physiological phenomenon that takes part in the control of cardiac energy dissipation along the arterial tree. The energy stored within the conduit artery wall during systole is proportional to the stress strain product and corresponds to the elastic extension work developed to support the cushioning function. This energy depends on the elastic properties of the arterial wall and the operating conditions that determine the rate and magnitude of pulse diameter. This stored elastic energy (W E ) is restored during the unloading phase as the arterial wall recoil and thus provides a continuous driving force to flow during diastole. However, in contrast to a pure elastic material that fully restores this energy leading to a stable pressure–diameter relationship during the loading and unloading phase, viscoelastic conduit arteries exhibit during the latter period a shifted relationship toward the diameter axis, the diameter being larger at any given stress. This shift determines through the cardiac cycle, the hysteresis loop of the pressure–diameter relationship, whose area has an energy dimension and corresponds to the energy dissipated as heat during each cardiac beat. Thereby, AWV can be expressed as an absolute value of energy dissipated in viscous work (W V ) or as a percentage of the W E within the arterial wall (W V /W E ; Figure 1). This critical relationship between stored and dissipated energies characterizes the damping properties of the arterial wall and could be maintained around an optimal value in chronic state. Furthermore, most comparisons between in vivo and ex vivo experiments demonstrate a lower absolute and relative value of viscosity in vivo when evaluated in the same operational conditions. This suggests an excess of damping in vitro and in turn an active and highly regulated process to maintain a low rate of energy dissipation in vivo. However, the determinants of AWV remain controversial. Thus, AWV depends on the passive viscous properties of the wall components, and particularly the Abstract—Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase (N-monomethyl-larginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure–diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress. Nmonomethyl-l-arginine paradoxically reduced relative viscosity (34.9±8.9%–28.9±8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5±15.5%–32.0±13.6%) but increased by tetraethylammonium (31.7±6.6%– 35.7±8.0%). This increase was more marked with N-monomethyl-l-arginine+fluconazole (31.1±10.7%–43.3±13.2%) and N-monomethyl-l-arginine+tetraethylammonium (29.5±2.3%–41.5±11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4±2.9%–28.7±2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation. Clinical Trial Registration—URL: https://eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53. (Hypertension. 2018;71:143-150. DOI: 10.1161/HYPERTENSIONAHA.117.09870.) • Online Data Supplement