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.
Highlights
Hydrogen sulfide (H2S) is considered an essential signaling molecule in the cardiovascular and nervous systems (Szabó, 2007; Wallace et al, 2018) and a variety of pathophysiological changes including cancer, glycometabolic disorders, diabetes, sepsis, and human malignt hyperthermia are associated with altered endogenous levels of H2S (Szabó, 2007; Szabo and Papapetropoulos, 2017; Vellecco et al, 2020)
We found that GYY4137 induced concentrationdependent relaxations while there was no change in vascular tone by adding the GYY4137H (Figures1B,C), suggesting that release of sulfides is pivotal for GYY4137 relaxation
In the presence of an inhibitor of nitric oxide (NO) synthase, L-NAME (10–4 M), the concentration-response curves for Na2S were unaltered (Figure 5B), while L-NAME rightward shifted concentration-response curves for GYY4137 (Figure 5C). These results suggest that in rat small mesenteric arteries, endotheliumderived NO is of importance for some of the effects of GYY4137 on vascular tone, while there were no significant differences for Na2S
Summary
Hydrogen sulfide (H2S) is considered an essential signaling molecule in the cardiovascular and nervous systems (Szabó, 2007; Wallace et al, 2018) and a variety of pathophysiological changes including cancer, glycometabolic disorders, diabetes, sepsis, and human malignt hyperthermia are associated with altered endogenous levels of H2S (Szabó, 2007; Szabo and Papapetropoulos, 2017; Vellecco et al, 2020). Several mechanisms mediate vasodilatation induced by addition of exogenous H2S salts, including lowering of smooth muscle cells calcium by activation of K channels (Skovgaard et al., 2011; Hedegaard et al, 2016), enhancement of nitric oxide (NO). The opening of potassium channels leads to hyperpolarization and smooth muscle relaxation. Different types of K channels are involved in H2S vasodilatation, including in large arteries ATP-sensitive K channels (KATP) (Zhao and Wang, 2002; Kubo et al, 2007; Webb et al, 2008; Martelli et al, 2013a), voltage-gated K channels (KV7, KCNQ) (Martelli et al, 2013a; Hedegaard et al, 2014), and 4-. H2S vasodilatation involves KATP channels (Tang et al, 2005), large-conductance calcium-dependent potassium channels (BKCa) (Jackson-Weaver et al, 2011; Jackson-Weaver et al, 2013), and KV7 channels (Schleifenbaum et al, 2010; Hedegaard et al, 2016), and potassium channel-independent vasodilatation (Hedegaard et al., 2016)
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