© 1999 American Heart Association, Inc.
Cellular Biology |
Regulation of Sarcolemmal Na+/H+ Exchanger Activity by Angiotensin II in Adult Rat Ventricular Myocytes
Opposing Actions via AT1 Versus AT2 Receptors
From the Centre for Cardiovascular Biology and Medicine, King’s College London, UK.
Correspondence to Dr Metin Avkiran, Cardiovascular Research, The Rayne Institute, St Thomas’ Hospital, Lambeth Palace Rd, London SE1 7EH, UK. E-mail metin.avkiran{at}kcl.ac.uk
Abstract—Increased sarcolemmal Na+/H+ exchanger activity has been implicated as a mediator of the cardiac actions of angiotensin II. We studied the receptor subtypes 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-seminaphthorhodafluor-1, and acid efflux rates estimated during recovery from intracellular acidosis were used to quantify exchanger activity. Sarcolemmal Na+/H+ exchanger activity was not affected by angiotensin II alone but was increased by angiotensin II plus PD123319 (AT2 antagonist). In contrast, angiotensin II plus losartan (AT1 antagonist) or CGP42112A (AT2 agonist) did not affect exchanger activity. The increase in Na+/H+ exchanger activity induced by angiotensin II plus PD123319 was blocked by losartan, PD98059 (extracellular signal–regulated kinase inhibitor), GF109203X (protein kinase C inhibitor), and tyrphostin AG1478 (epidermal growth factor receptor kinase inhibitor). Extracellular signal–regulated kinase phosphorylation and activity, measured by immunoblot analysis and an immune-complex kinase assay, respectively, were increased significantly by angiotensin II plus PD123319; these increases were blocked by losartan and PD98059. The increase in extracellular signal–regulated kinase phosphorylation induced by angiotensin II plus PD123319 was blocked also by GF109203X and tyrphostin AG1478. These data show that AT1 stimulation increases sarcolemmal Na+/H+ exchanger activity in adult rat ventricular myocytes and that this response requires extracellular signal-regulated kinase activation through a protein kinase C– and epidermal growth factor receptor–mediated mechanism. The positive effect of AT1 stimulation on Na+/H+ exchanger activity is counteracted by simultaneous AT2 stimulation through a mechanism that does not involve direct inhibition of the exchanger or attenuation of extracellular signal–regulated kinase activation.
Key Words: angiotensin • myocyte • Na+/H+ exchanger • signal transduction • extracellular signal–regulated kinase
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