British journal of pharmacology · 2025
Effect of 3-mercaptopyruvate sulfurtransferase (3-MST) inhibitors on contractile responses in porcine coronary artery.
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Almaheize Maha, Alharthi Sahar, Hemp Patricia, Mattos Jennifer, van Leer Marcus, Garle Michael, Alexander Stephen, Roberts Richard
Аннотация
BACKGROUND AND PURPOSE: Hydrogen sulphide (H2S) is synthesised endogenously through cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although exogenous H2S is known to produce vasodilatation, the vascular effect of H2S 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 H2S 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 H2S from 3-mercaptopyruvate (IC50 ~ 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.
EXPERIMENTAL APPROACH: Synthesis of H2S 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 H2S from 3-mercaptopyruvate (IC50 ~ 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.