Biomedical Sciences ETDs

Publication Date

5-1-2012

Abstract

Myogenic tone is an important regulator of blood flow and may contribute to peripheral vascular resistance and blood pressure. Myogenic tone is a luminal pressure-induced constriction of the vasculature that is mediated by a vascular smooth muscle cell (VSMC) plasma membrane potential (Em) depolarization and Ca2+ influx. Ca2+ sparks, which are ryanodine receptor (RyR) mediated Ca2+ release events, oppose myogenic tone by activating large-conductance Ca2+-activated K+ channels (BKCa) to hyperpolarize VSMC Em. The gaseous signaling molecules (gasotransmitters) NO and CO activate Ca2+ sparks to cause vasodilation. H2S, a third gasotransmitter produced by cystationine γ-lyase (CSE) in the vasculature, activates several K+ channels to promote VSMC Em hyperpolarization. We therefore sought to determine whether H2S inhibits the development of myogenic tone. We hypothesized that H2S opposes myogenic tone through the activation of Ca2+ sparks and subsequent BKCa channel activation. We observed that in small mesenteric arteries CSE-produced H2S reduced myogenic tone. We also found that RyR-mediated Ca2+ sparks and BKCa channel activity opposed tone in these arteries. We also observed that exogenous and endogenous H2S activates sparks and hyperpolarizes VSMC Em. Futhermore, exogenous H2S-mediated vasodilation, spark activation, and VSMC Em hyperpolarization required active endothelial BKCa channels and cytochrome P450 2C. Therefore, H2S seems to be an important regulator of myogenic tone in the mesenteric circulation. The mechanism by which H2S causes vasodilation in this bed is an unexpectedly complex pathway, with activation of endothelial BKCa channels and cytochrome P450 with subsequent activation of VSMC Ca2+ sparks. The effects of H2S here described may be an important mechanism by which this signaling molecule alters hemodynamic parameters in vivo.

Keywords

Vascular Physiology, Hydrogen Sulfide, Myogenic Tone, Calcium Sparks

Sponsors

American Heart Association, National Institutes of Health

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Kanagy, Nancy

First Committee Member (Chair)

Walker, Ben

Second Committee Member

Resta, Tom

Third Committee Member

Gonzalez Bosc, Laura

Fourth Committee Member

Shuttleworth, Bill

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