White, Benjamin J. O.
(2012)
The vascular effects of hydrogen sulphide.
PhD thesis, University of Nottingham.
Abstract
In recent years it has become apparent that hydrogen sulphide (H2S) is an important biological mediator. In the vasculature, it produces complex responses: contraction in some blood vessels, relaxation in others, via multiple mechanisms. This thesis examined the relationship between H2S and oxygen in determining vascular responsiveness, and was conducted using porcine splenic and mesenteric arteries. Studies were also conducted using porcine splenic veins, since few studies have examined venous function. Additionally, studies were extended to the resistance vasculature by determining responses to a H2S donor in small arteries isolated from the rat mesentery.
Porcine vessels were set up in an isometric tension recording system and rat small mesenteric arteries were set up in a pressure myograph. Vessels were pre-contracted and responses to the H2S donor, NaHS, were generated in the presence and absence of putative inhibitors, under either 95% O2:5% CO2, 95% air:5% CO2 or 95% N2:5% CO2 gassing conditions.
Generally, in both porcine arteries and veins, when gassing with higher oxygen levels (95% O2:5% CO2 or 95% Air:5% CO2), NaHS induced contractile responses, whereas gassing with a lower oxygen level (95% N2:5% CO2), NaHS induced vasorelaxation. At higher O2 levels, removal of the endothelium or, the nitric oxide (NO) synthase inhibitor L-NAME, significantly attenuated contractile response in all porcine vessels. This suggests an interaction between endothelium-derived NO and NaHS, whereby the removal of the vasorelaxatory influence of NO resulted in contraction. In porcine arteries, relaxation at lower O2 levels was attenuated by glibenclamide, suggesting that NaHS activated KATP channels to cause relaxation. In porcine veins, removal of the endothelium or, L-NAME, abolished NaHS-induced relaxation, showing this relaxation occurred via the release of endothelium-derived NO. In rat mesenteric small arteries responses to NaHS did not change with different O2 levels and NaHS-induced vasodilatation that was abolished by desensitization of sensory nerves with capsaicin or the presence of BIBN 4096. These observations suggest NaHS-induced vasodilatation is mediated via release of CGRP from sensory nerves.
Thus, responses to NaHS in large conduit arteries and veins, are sensitive to the prevailing level of O2 the tissue is exposed to. At more physiological levels of O2 the predominant response is a vasorelaxation, mediated by either, activation of KATP channels in arteries or, the release of NO in veins. In small arteries, the predominant response is a vasodilator response, involving the release of neuropeptides from sensory nerves. The predominance of a vasorelaxant/vasodilator response is consistent with the observation that mice which lack the capacity to generate endogenous H2S are hypertensive.
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