| Co-Investigator(Kenkyū-buntansha) |
YOSHIDA Junko KANAZAWA MEDICAL UNIVERSITY, Medical school, Lecturer, 医学部, 講師 (20064628)
ISHIBASHI Takaharu KANAZAWA MEDICAL UNIVERSITY, Medical school, Associate Professor, 医学部, 助教授 (60184561)
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| Research Abstract |
Endogenous adenosine is known to regulate the physiological cardiomyocyte function and to exert a protective action during ischemia and reperfusion. To explore the usefulness of adenosine analogue as a myocardial therapeutic agent, we first examined the electrophysiological effects of adenosine on guinea pig cardiomyocytes in the whole cell patch-clamp configuration. Adenosine shortened the action potential duration (APD) and hyperpolarized the resting membrane potential of atrial but not ventricular myocytes. When atrial cells were preincubated with pertussis toxin (LAP), adenosine did not shorten the APD, confirming that adenosine receptors. couple to the IAP-sensitive GTP-binding protein. Adenosine increased the outward membrane current at 0mV in the presence of nicardipine, an L-type Ca^<2+> channel blocker, which suggests that adenosine elicited the specific K^+-outward current. Adenosine A_1 receptor agonist, N^6-cyclohexyladenosine (CHA), but not A_2 or A_3 receptor agonist, rep
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roduced both the adenosine-induced shortening effect on APD and the increasing effect on the outward membrane current of atrial myocytes. These effects were completely abolished by A_1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). Glybenclamide, a KATP channel blocker, completely abolished the CHA-induced shortening effect on APR and also partially abolished the effect on the outward membrane current, which suggests that the effects of CHA are mediated by the activation of K_<ATP> channels on the plasma membrane. Further, the effect of CHA effect, on the outward membrane current was completely abolished by preincubating the cells with chelerythrine, a protein kinase C inhibitor, and was partially,inhibited by 5-hydroxydecanoic acid (5-HD), known as a specific inhibitor of mitochondrial K_<ATP> channels. These results suggest that the shortening of APD caused by adenosine A_1 receptor stimulation was conducted in part through an activation of K_<ATP> channels via protein kinase C and 5-HD-sensitive intracellular signaling pathways, which may be involved in the mechanisms by which adenosine exerts a protective action during ischemia and reperfusion. Less
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