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 c alcium 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 imidodiphos phate [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 activi ty. Isoproterenol, a G(s), agonist, had no effect on exchanger activit y. Likewise, the G(i) agonist, carbachol, did not influence Na+/Ca2+ e xchanger activity. Since these G proteins couple to the adenylate cycl ase system, it would appear that cAMP-linked events do not regulate th e Na+/Ca2+ exchanger. We next examined the influence of G(q)-linked ag onists on exchanger activity. Phenylephrine, an alpha(1)-adrenergic ag onist, 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 pr otein kinase C inhibitor chelerythrine significantly attenuated the ab ility of phenylephrine and angiotensin II tn stimulate the Na+/Ca2+ ex changer. In addition, the protein kinase C activator, phorbol, 12-myri state 13-acetate, stimulated exchanger activity by 32%, raising the po ssibility that all three G(q) agonists mediate their actions in part t hrough the promotion of phospholipase C activity and the subsequent ac tivation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is dis cussed. (C) 1996 Academic Press Limited