Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin I

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 G(s), agonist, had no effect on exchanger activity. Likewise, the G(i) 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 G(q)-linked agonists on exchanger activity. Phenylephrine, an alpha(1)-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC(50) of 21 mu M. 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 tn 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 G(q) 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. (C) 1996 Academic Press Limited