title: Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults.
abstract: Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1mol/L) and sodium sulfide (10-5-101mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (allP<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg;P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg;P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
authors.forename: Jody L
authors.initials: JL
authors.lastname: Greaney
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Kutz
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
authors.forename: Sean W
authors.initials: SW
authors.lastname: Shank
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jandu
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.).
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.affiliation: From the Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park (J.L.G., J.L.K., S.W.S., L.M.A.); Department of Exercise Science, Shenandoah University, Winchester, VA (J.L.K.); and Departments of Anesthesia and Critical Care Medicine and Bioengineering, Johns Hopkins University School of Medicine, Baltimore, MD (S.J., L.S.). lma191@psu.edu.
authors.forename: Lacy M
authors.initials: LM
authors.lastname: Alexander
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology*; D008875:Middle Aged; D012867:Skin / Q000098:blood supply; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000109:Acetylcholine; D006862:Hydrogen Sulfide
keywords: 3-mercaptopyruvate sulfurtransferase; cystathionine γ-lyase; endothelial dysfunction; endothelium-dependent dilation; microdialysis; nitric oxide