Heat and α1-adrenergic responsiveness in human skeletal muscle feed arteries: the role of nitric oxide.

Increased local temperature exerts a sympatholytic effect on human skeletal muscle feed arteries. We hypothesized that this attenuated α(1)-adrenergic receptor responsiveness may be due to a temperature-induced increase in nitric oxide (NO) bioavailability, thereby reducing the impact of the α(1)-adrenergic receptor agonist phenylephrine (PE). Thirteen human skeletal muscle feed arteries were harvested, and wire myography was used to generate PE concentration-response curves at 37 °C and 39 °C, with and without the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA). A subset of arteries (n = 4) were exposed to 37 °C or 39 °C, and the protein content of endothelial NOS (eNOS) and α(1)-adrenergic receptors was determined by Western blot analysis. Additionally, cultured bovine endothelial cells were exposed to static or shear stress conditions at 37 °C and 39 °C and assayed for eNOS activation (phosphorylation at Ser(1177)), eNOS expression, and NO metabolites [nitrate + nitrite (NOx)]. Maximal PE-induced vasocontraction (PE(max)) was lower at 39 °C than at 37 °C [39 ± 10 vs. 84 ± 30% maximal response to 100 mM KCl (KCl(max))]. NO blockade restored vasocontraction at 39 °C to that achieved at 37 °C (80 ± 26% KCl(max)). Western blot analysis of the feed arteries revealed that heating increased eNOS protein, but not α(1)-adrenergic receptors. Heating of bovine endothelial cells resulted in greater shear stress-induced eNOS activation and NOx production. Together, these data reveal for the first time that, in human skeletal muscle feed arteries, NO blockade can restore the heat-attenuated α(1)-adrenergic receptor-mediated vasocontraction and implicate endothelium-derived NO bioavailability as a major contributor to heat-induced sympatholysis. Consequently, these findings highlight the important role of vasodilators in modulating the vascular response to vasoconstrictors.