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 Gsagonist, had no effect on exchanger activity. Likewise, the Giagonist, 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, anα1-adrenergic agonist, increased Na+/Ca2 +exchanger activity up to 111 % with an EC50of 21μ . 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 Gqagonists 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.