S10

P17

HYDROGEN SULFIDE AND NITRIC OXIDE INTERACTIONS IN INFLAMMATIONMatt Whiteman, University of Exeter, UK

Hydrogen sulfide (H2S) is a well known and pungent gas recently described as the third physi-ological gaseous mediator, together with NO and CO. In mammalian and human tissues H2S is synthesised enzymatically from the amino acids cysteine, homocysteine and cystathionine. In a relatively short period of time, H2S has attracted substantial interest as a potential target for pharmacological manipulation. Studies in animals and humans have shown that as with nitric oxide (NO), H2S is also involved in diverse physiological and pathophysiological pro-cesses such the regulation of blood pressure and inflammation. This commonality has led to the suggestion of NO-H2S cross-talk. However, as with NO, there is no consensus as to the precise role of H2S in inflammatory signalling since both pro- and anti-inflammatory effects are reported. Analogous with the NO field in the early days, unravelling the precise physiological function and pharmacological potential of H2S is limited by the lack of specific analytical and biochemical tools which has inevitably led to controversy in the literature. Commonly used inhibitors of endogenous H2S synthesis have been well known for several decades to interact with other metabolic pathways or even generate NO. Similarly, commonly used H2S donors release H2S far too quickly to be physiologically relevant but may have therapeutic applica-tions. In this presentation the complexities of the currently used pharmacological tools (e.g. donors and ‘specific’ inhibitors) and their application to studying the role of H2S in inflamma-tory signalling and the regulation of NO will be discussed.

doi:10.1016/j.freeradbiomed.2011.10.021

Matt Whiteman

P16

THE SEARCH FOR AN ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR − FROM NITRIC OXIDE TO HYDROGEN SULFIDE Rui Wang, Lakehead University, Canada

Endothelium-dependent vasorelaxation is mediated by both endothelium-derived relaxing factor (EDRF) and endothelium-derived hyperpolarizing factor (EDHF). While EDRF medi-ates the relaxation of large and conduit arteries, EDHF has a predominant relaxant effect on peripheral and resistance arteries. Without doubt nitric oxide (NO) is an EDRF, generated in endothelium via NO synthase. Recent studies have characterized hydrogen sulfide (H2S) as another EDRF, generated in endothelium and smooth muscle cells via cystathionine gamma-lyase (CSE). Both NO and H2S are gasotransmitters and both NOS and CSE are activated by calcium/calmodulin. However, the molecular targets of NO and H2S are quite different. NO mostly activates guanylyl cyclase/cGMP signaling pathway but H2S has KATP channels as its main target in smooth muscle cells. Deficiency in endothelium production of H2S leads to vulnerability of endothelium to hyperglycemia damage, delayed wound healing, suppressed endothelial proliferation and migration, abolished endothelium-dependent vasorelaxation, and age-dependent development of hypertension. Furthermore, the endothelium-dependent va-sorelaxation induced by H2S shares many common mechanistic traits with those of EDHF. It is more potent on resistance arteries than on conduit artery. H2S per se directly hyperpolarizes vascular smooth muscle cells via activation of KATP channels and indirectly hyperpolarizes smooth muscle cells via activation of small to medium-conductance KCa channels on endo-thelium. The likelihood that H2S is not only an EDRF but also an EDHF is both attractive and tangible. Supported by Natural Sciences and Engineering Research Council of Canada.

doi:10.1016/j.freeradbiomed.2011.10.020

Rui Wang