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 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 α₁-adrenergic agonist, increased Na⁺/Ca²⁺ exchanger activity up to 111% with an EC₅₀ of 21 μM. 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 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.