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.
Yong
Qian Chen
QC
Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Pan
Ting-Ting
TT
Hu
Li-Fang
LF
Bian
Jin-Song
JS
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D006862:Hydrogen Sulfide