GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries

Abstract

Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.

Role of Hydrogen Sulfide and Polysulfides in the Regulation of Lipolysis in the Adipose Tissue: Possible Implications for the Pathogenesis of Metabolic Syndrome

“…The effect of obesity on the adipose tissue H 2 S system is controversial. Both increases [18] and decreases [26,30,37,38] in the expression of CBS, CSE, MST and adipose tissue H 2 S production have been observed, depending on type of diet, the duration of highcalorie feeding, the animal species and adipose tissue depots. Increased H 2 S excretion in the exhaled air of obese children [39] and increased plasma H 2 S in morbidly obese adults [40] have been reported.…”

“…According to some studies [28], NaHS is more susceptible to oxidation than Na 2 S, and its solution could contain other more oxidized reactive sulfur species with potentially different effects. Although GYY4137 is considered a more physiologically relevant H 2 S donor, as it releases gasotransmitters slowly and for a prolonged time [29,30], it has also some limitations. In particular, both GYY4137 and the products of its decomposition may have some H 2 S-independent effects [31,32].…”

Hydrogen Sulfide-Induced Vasodilation: The Involvement of Vascular Potassium Channels

“…XE991 also inhibited H₂S-induced vasodilatation of porcine coronary arteries ( Hedegaard et al, 2014 ) and murine aortas ( Köhn et al, 2012 ). GYY4137-induced relaxation was also inhibited by K V7 blocker ( Abramavicius et al, 2021 ). The mechanism may be related to persulfidation of K V7 channels by CBS-derived H 2 S ( Vellecco et al, 2020 ).…”

“…Exogenous H 2 S dilated mesenteric arteries of intermittent hypoxia rats, requires BK channels ( Jackson-Weaver et al, 2011 ). Blockers of BK channel also inhibited GYY4137 induced relaxations in rat mesenteric arteries ( Abramavicius et al, 2021 ).…”

“…NaHS produced vasorelaxation in different vessel beds, including aorta ( Köhn et al, 2012 ), coronary artery ( Hedegaard et al, 2014 ), carotid artery ( Centeno et al, 2019 ), and mesenteric small artery ( White et al, 2013 ). GYY4137, a slow-releasing H 2 S donor, induced concentration-dependent relaxation in rat mesenteric arteries ( Abramavicius et al, 2021 ) and bovine posterior ciliary artery ( Chitnis et al, 2013 ). N-phenylthiourea (PTU) and N, N′-diphenylthiourea (DPTU) compounds, showing long-lasting H 2 S donation, promoted vasodilation in rat aortic rings ( Citi et al, 2020 ).…”