Negative regulation of beta-adrenergic function by hydrogen sulphide in the rat hearts.

Beta-adrenoceptor is over-stimulated during myocardial ischemia, in which hydrogen sulphide (H2S) concentration was found to be lowered. The present study attempted to investigate if H2S modulates beta-adrenoceptor function and the underlying mechanism. We examined the effect of NaHS (a H2S donor) on myocyte contraction and electrically-induced (EI) intracellular calcium ([Ca2+](i)) transients upon beta-adrenergic stimulation in rat ventricular myocytes with a video edge tracker method and a spectrofluorometric method using fura-2/AM as a calcium indicator, respectively. We found that isoproterenol (ISO, 10(-9)-10(-6) M), a beta-adrenoceptor agonist, concentration-dependently increased the twitch amplitude of ventricular myocytes, which was attenuated by NaHS (10(-5)-10(-3) M) in a dose-dependent manner. The amplitudes and maximal velocities (+/-dl/dt) of myocyte twitch and EI-[Ca2+](i) transient amplitudes were enhanced by ISO, forskolin (an adenylyl cyclase activator), 8-bromoadenosine-3',5'-cyclic monophosphate (an activator of protein kinase A) and Bay K-8644 (a selective L-type Ca2+ channel agonist). Administration of NaHS (100 microM) only significantly attenuated the effects of ISO and forskolin. Moreover, NaHS reversed ISO-induced cAMP elevation and forskolin-stimulated adenylyl cyclase activity. In addition, stimulation of beta-adrenoceptor by ISO significantly decreased endogenous H2S production in rat ventricular myocytes. In conclusion, H2S may negatively modulate beta-adrenoceptor function via inhibiting adenylyl cyclase activity. Impairment of this negative modulation during ischemia may induce cardiac arrhythmias. Our study may provide a novel mechanism for ischemia-induced cardiac injury.