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—Activation of the sarcolemmal Na+ -H+ exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of α1 -adrenoceptor (AR) stimulation. Although such regulation of sarcolemmal NHE activity has been shown to be selectively mediated through the α1A -AR subtype, distal signaling mechanisms remain poorly defined. We investigated the roles of various kinase pathways in α1A -AR–mediated stimulation of sarcolemmal NHE activity in adult rat ventricular myocytes. As an index of NHE activity,trans -sarcolemmal acid efflux rate (J H ) was determined through microepifluorescence in single cells, during recovery from intracellular acidosis in bicarbonate-free conditions. Extracellular signal-regulated kinase (ERK), p38-mitogen-activated protein kinase (MAPK), and p90rsk activities were indexed on the basis of analysis of their phosphorylation status. In control cells, there was no change inJ H in response to vehicle. Phenylephrine and A61603, an α1A -AR subtype–selective agonist, increasedJ H , as well as cellular ERK and p90rsk activities. Neither agonist affected p38 activity, which was increased with sorbitol. The MAPK kinase inhibitor PD98059 abolished phenylephrine- and A61603-induced increases inJ H and cellular ERK and p90rsk activities. In contrast, the PKC inhibitor GF109203X abolished phenylephrine- and A61603-induced increases inJ H but failed to prevent the increases in ERK and p90rsk activities. Our findings suggest that α1A -AR–mediated stimulation of sarcolemmal NHE activity in rat ventricular myocytes requires activation of the ERK (but not the p38) pathway of the MAPK cascade and that the ERK-mediated effect may occur via p90rsk . Activation of PKC is also required for α1A -AR–mediated NHE stimulation, but such regulation occurs through an ERK-independent pathway.

circulation research

Roles of Mitogen-Activated Protein Kinases and Protein Kinase C in α 1A -Adrenoceptor–Mediated Stimulation of the Sarcolemmal Na + -H + Exchanger