Effect of 3‐mercaptopyruvate sulfurtransferase (3‐MST) inhibitors on contractile responses in porcine coronary artery

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Background and Purpose Hydrogen sulphide (H 2 S) is synthesised endogenously through cystathionine β‐synthase (CBS), cystathionine γ‐lyase (CSE) and 3‐mercaptopyruvate sulfurtransferase (3‐MST). Although exogenous H 2 S is known to produce vasodilatation, the vascular effect of H 2 S produced through 3‐MST is unknown. In this study, we demonstrate the effect of a novel inhibitor of 3‐MST, namely DPHE, and determined the effect of this compound on contractile responses in porcine coronary artery. Experimental Approach Synthesis of H 2 S through 3‐MST and CBS/CSE was determined in rat liver cytosol. Effects of 3‐MST inhibitors DPHE, 3‐PAB, or I3MT‐3, or CBS/CSE inhibitors AOAA and propargylglycine (PPG) on contractile responses in porcine coronary arteries were determined using isolated tissue baths. Key Results DPHE inhibited the production of H 2 S from 3‐mercaptopyruvate (IC 50 ~ 8 μM). The 3‐MST inhibitors DPHE, I3MT‐3 and 3‐PAB all inhibited contractions to U46619 in porcine coronary artery segments through an endothelium‐independent mechanism. DPHE and I3MT‐3 reduced the U46619 contractions in the absence of extracellular calcium and inhibited the contraction to the L‐type calcium channel opener BAY K8644. The combination of AOAA (100 μM) and PPG (10 μM) had no effect on the U46619 contractions. The inhibitory effect of the 3‐MST inhibitors does not appear to involve Rho kinase, ERK‐MAP kinase or the mitochondrial electron transport chain. Conclusions and Implications Inhibition of 3‐MST in coronary arteries leads to an inhibition of both calcium‐dependent and calcium‐independent contractions, whereas CBS/CSE inhibitors had no effect on receptor‐mediated contractions. These data suggest that 3‐MST, not CBS/CSE, regulates vascular tone in porcine coronary artery.

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