Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1.
The Na+/Ca2+ exchanger plays an important role in the maintenance of calcium homeostasis in the heart. Therefore, factors which regulate the exchanger have a significant impact on cardiac function. Previously, we showed that the non-hydrolysable GTP analog, 5'guanylyl imidodiphosphate [Gpp(NH)p], stimulates Na+/Ca2+ exchange activity, implying the involvement of a G protein in exchanger regulation. In this study, we examined the effect of G protein agonists on Na+/Ca2+ exchanger activity. Isoproterenol, a Gs agonist, had no effect on exchanger activity. Likewise, the Gi agonist, carbachol, did not influence Na+/Ca2+ exchanger activity. Since these G proteins couple to the adenylate cyclase system, it would appear that cAMP-linked events do not regulate the Na+/Ca2+ exchanger. We next examined the influence of Gq-linked agonists on exchanger activity. Phenylephrine, an alpha 1-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC50 of 21 microM. Moreover, the Na+/Ca2+ exchanger activity was enhanced by angiotensin II and endothelin 1, which caused maximal stimulation of exchanger activity up to 125% and 211%, respectively. The selective protein kinase C inhibitor chelerythrine significantly attenuated the ability of phenylephrine and angiotensin II to stimulate the Na+/Ca2+ exchanger. In addition, the protein kinase C activator, phorbol 12-myristate 13-acetate, stimulated exchanger activity by 32%, raising the possibility that all three Gq agonists mediate their actions in part through the promotion of phospholipase C activity and the subsequent activation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is discussed.
Ballard
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C
Department of Pharmacology, University of South Alabama, Mobile 36688, USA.
Schaffer
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S
D000470:Alkaloids; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger
D000470:Alkaloids; D053119:Benzophenanthridines; D002352:Carrier Proteins; D016232:Endothelins; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D019831:Sodium-Calcium Exchanger; D000804:Angiotensin II; D010656:Phenylephrine; D006165:Guanylyl Imidodiphosphate; D002217:Carbachol; C016299:chelerythrine; D011493:Protein Kinase C; D007545:Isoproterenol; D002118:Calcium