Regulation of sarcolemmal Na+/H+ exchanger activity by angiotensin II in adult rat ventricular myocytes opposing actions via AT(1) versus AT(2) receptors

Increased sarcolemmal Na+/H+ exchanger activity has been implicated as a me diator of the cardiac actions of angiotensin II. We studied the receptor su btypes and signaling pathways involved in the regulation of sarcolemmal Na/H+ exchanger activity by angiotensin II in adult rat ventricular myocytes. Cells were loaded with the pH-sensitive fluoroprobe carboxy-seminaphthorho dafluor-1, and acid efflux rates estimated during recovery from intracellul ar acidosis were used to quantify exchanger activity. Sarcolemmal Na+/H+ ex changer activity was not affected by angiotensin II alone but was increased by angiotensin II plus PD123319 (AT(2) antagonist), In contrast, angiotens in II plus losartan (AT(1) antagonist) or CGP42112A (AT(2) agonist) did not affect exchanger activity. The increase in Na+/H+ exchanger activity induc ed by angiotensin II plus PD123319 was blocked by losartan, PD98059 (extrac ellular signal-regulated kinase inhibitor), GF109203X (protein kinase C inh ibitor), and tyrphostin AG1478 (epidermal growth factor receptor kinase inh ibitor). Extracellular signal-regulated kinase phosphorylation and activity , measured by immunoblot analysis and an immune-complex kinase assay, respe ctively, were increased significantly by angiotensin II plus PD123319; thes e increases were blocked by losartan and PD98059. The increase in extracell ular signal-regulated kinase phosphorylation induced by angiotensin II plus PD123319 was blocked also by GF109203X and tyrphostin AG1478. These data s how that AT(1) stimulation increases sarcolemmal Na+/H+ exchanger activity in adult rat ventricular myocytes and that this response requires extracell ular signal-regulated kinase activation through a protein kinase C- and epi dermal growth factor receptor-mediated mechanism. The positive effect of AT (1) stimulation on Na+/H+ exchanger activity is counteracted by simultaneou s AT(2) stimulation through a mechanism that does not involve direct inhibi tion of the exchanger or attenuation of extracellular signal-regulated kina se activation.