Stimulation of mitochondrial hydrogen sulfide and glutathione production improves the Frank–Starling response of the rat heart via a nitric oxide–dependent pathway

Abstract

The Frank-Starling response of the heart is known to be mediated by NO signaling, which is regulated by GSH and H2S. We hypothesized that stimulation of endogenous H2S or GSH synthesis improve Frank-Starling response . Wistar male rats were injected with propargylglycine (PAG, 11.3mg/kg-1, 40min,n=12), an inhibitor of H2S producing enzyme (cystationine-γ-lyase) and L-cysteine (121mg/kg-1, 30min,n=20), a precursor of H2S and GSH. Pretreatment with PAG or L-cysteine separately slightly improved P-V dependence of the isolated rat heart, but combination of PAG and L-cysteine (n=12) improved heart contractile activity. H2S content, cNOS activity, nitrate reductase activity and nitrite content increased by 2, 3.83, 2.5 and 1.3 times in cardiac mitochondria as well as GSH and GSSG levels increased by 2.24 and 1.86 times in heart homogenates of PAG+L-cysteine group comparing to control (all P<0.05). Inhibition of glutathione with DL-buthionine-sulfoximine (22.2mg/kg-1, 40min, n=6) drastically decreased Frank-Starling response of the heart and prevented PAG+L-cysteine induced increase of GSH and GSSG levels (BSO+PAG+L-cysteine,n=9). Inhibitor of NOS, N-nitro-L-arginine-methylester hydrochloride (40min, 27mg/kg-1), abolished positive inotropy induced by PAG+L-cysteine pretreatment (L-NAME+PAG+L-cysteine,n=7). Thus, PAG+L-cysteine administration improves Frank-Starling response with up-regulation of mitochondrial H2S, glutathione and NO synthesis that might be promising approach in treatment of myocardial dysfunction.