Inhibition of Mitochondrial Hydrogen Sulfide Production Worsens Heart Contractility and Enhances Sensitivity of Mitochondrial Permeability Transition Pore to Calcium

Abstract

We examined the involvement of hydrogen sulfide (H2S) catalyzed by mitochondrial enzyme 3-mercaptopyruvate-sulfurtransferase (3-MST) in cardiac tolerance to calcium load and regulation of mitochondrial permeability transition pore (MPTP) opening. In isolated rat heart, it has been revealed that the enzyme inhibition by O-carboxymethyl hydroxylamine (O-CMH) (50 mg/kg, i.p., 30 min before the experiment start) results in worsening of all heart indices. In particular, the left ventricular developing pressure (LVDP), as well as myocardium contraction/relaxation rate (dP/dt) decreased by 50%. When modeling calcium load, CMH induced a rapid increase in LV end-diastolic pressure and developing of arhythmias. Further modeling of Ca2+ loads was accompanied by lower increment of LVDP and dP/dt comparing to that in control rats indicating low functional reserves and low Ca2+ efficacy in O-CMH-pretreated rats. Cardiac mitochondria in O-CMH group were more sensitive to Ca2+ showing maximum swelling at 10−5 moles/L in the incubation medium vs 10−4 moles/L in control group (p < 0.05). Preincubation of cardiac mitochondria with O-CMH in concentrations of 10−5, 10−4, and 10−3 moles/L evoked an increase in Ca2+ -induced swelling by 17.8, 20, and 44%, respectively. An inhibition of mitochondrial pathway of H2S synthesis increased heart mitochondria sensitivity to Ca2+, which resulted in swelling of mitochondrial membranes and low ability of myocardium to manage Ca2+ homeostasis under Ca2+ loads. Thus, it has been found that endogenous hydrogen sulfide of mitochondrial origin is involved in the regulation of MPTP opening, and also plays an important role in regulating the heart functioning.