title: Heat and α1-adrenergic responsiveness in human skeletal muscle feed arteries: the role of nitric oxide.
abstract: 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.
authors.affiliation: Geriatric Research, Education, and Clinical Center, George E Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA. stephen.ives@utah.edu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ives
authors.forename: Robert H I
authors.initials: RH
authors.lastname: Andtbacka
authors.forename: Sun Hyung
authors.initials: SH
authors.lastname: Kwon
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Shiu
authors.forename: Ting
authors.initials: T
authors.lastname: Ruan
authors.forename: R Dirk
authors.initials: RD
authors.lastname: Noyes
authors.forename: Quan-Jiang
authors.initials: QJ
authors.lastname: Zhang
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
authors.forename: Russell S
authors.initials: RS
authors.lastname: Richardson
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D009213:Myography; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D010766:Phosphorylation; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D004791:Enzyme Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III