A physiological role for hydrogen sulfide in the human cutaneous circulation

Open Access
Author:
Kutz, Jessica Leigh
Graduate Program:
Kinesiology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 17, 2015
Committee Members:
  • Lacy Marie Alexander, Dissertation Advisor
  • William Lawrence Kenney Jr., Committee Chair
  • Timothy R Mc Connell, Committee Member
  • Martin John Sliwinski, Committee Member
Keywords:
  • hydrogen sulfide
  • skin blood flow
  • hypertension
  • nitric oxide
Abstract:
Hydrogen sulfide (H2S), once considered a malodorous and toxic gas, is now recognized as a third endogenous gaso-transmitter, in addition to nitric oxide (NO) and carbon monoxide. H2S has significant vasoactive properties and plays a role in the modulation of vascular function. The purpose of this series of studies was to examine the vasodilatory role of H2S in the cutaneous circulation of healthy young adults and subsequently determine alterations in H2S-dependent vasodilation that occur with hypertension. In the first series of studies we hypothesized that (1) the H2S generating enzymes, cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MPST), would be expressed in the cutaneous circulation, and (2) that H2S-donors would elicit dose-dependent increases in cutaneous vasodilation through potassium ATP channels. We further hypothesized that both NO and by-products of cyclooxygenase (COX) metabolism would contribute, at least in part, to exogenous H2S-induced cutaneous vasodilation. The novel findings from the first series of studies were (1) CSE and 3-MPST were expressed in the human cutaneous microvasculature, (2) H2S donors elicited vasodilation in a dose-dependent manner in the cutaneous circulation of healthy young adults, (3) exogenous H2S-induced cutaneous vasodilation was mediated, in part, by calcium-dependent potassium channels, and (4) NO and COX inhibition attenuated exogenous H2S-induced cutaneous vasodilation. The results of these studies confirm the presence of H2S-generating enzymes in the cutaneous circulation as well as vasodilator responsiveness to a H2S donor. Additionally, H2S-mediated vasodilation occurred through downstream potassium channels and via interaction with the NO and COX vasodilatory pathways. H2S production and function are altered in the presence of hypertension in animal models. In the second series of studies, we hypothesized that endothelium-dependent (ACh, acetylcholine) vasodilation would be blunted in pre/stage 1 hypertensive adults compared to normotensive controls, due to blunted NO- and H2S-dependent vasodilation. Additionally, we hypothesized that the end-organ responsiveness to exogenous H2S would be preserved in pre/stage 1 hypertensive adults but that vasodilatory interaction with NOS and COX signaling pathways would be diminished compared to normotensive age matched controls. Our data demonstrated blunted vasodilation to a cholinergic stimulus in pre/stage 1 hypertensives, in part, due to a diminished H2S-dependent vasodilation. Additionally, our data demonstrated preserved end-organ responsiveness to exogenous H2S in pre/stage 1 hypertensive adults, despite a loss of vasodilatory interaction with NOS and COX vasodilatory pathways. Finally, we used reactive hyperemia to non-invasively assess microvascular function in pre/stage 1 hypertensive adults and normotensive age-matched controls. We sought to determine the role of H2S to the overall total hyperemic response (THR). Inhibition of endogenous H2S production blunted the THR in pre/stage 1 hypertensive adults, but not in normotensive adults; however this blunted response was not significantly different from the control site. Additionally, we found that NO does not mediate the reactive hyperemic response in normotensive or pre/stage 1 hypertensive adults. Also, the THR was related to both the H2S- and NO-dependent ACh-mediated vasodilation. These data support the use of cutaneous reactive hyperemia to assess generalized microvascular function; however, we were unable to detect statically significant differences in vascular function in a group of pre/stage 1 hypertensive adults. In summary, these data suggest that H2S contributes to vasodilation in the cutaneous microcirculation in humans. H2S donors caused robust vasodilation through calcium-dependent potassium channels and interaction with NOS and COX vasodilatory pathways. Pre/stage 1 hypertensive adults had diminished H2S-dependent vasodilation in response to a cholinergic stimulus; however, end-organ sensitivity to exogenous H2S was preserved despite a lack of vasodilatory interaction with NOS and COX pathway. Finally, H2S may modulate a portion of the reactive hyperemic response in pre/stage 1 hypertensive adults due to a loss of redundant signaling mechanisms.