Differential effects of angiotensin AT(1) and AT(2) receptors on the expression, translation and function of the Na+-H+ exchanger and Na+-HCO3- symporter in the rat heart after myocardial infarction

OBJECTIVES This study investigated the role of angiotensin receptor subtype 1 (AT(1)) and angiotensin receptor subtype 2 (AT(2)) in the regulation of Na+-H+ exchanger (NHE) and Na+-HCO3- symporter (NBC) in the infarcted myoca rdium. BACKGROUND The cardiac renin-angiotensin system is activated after myocardi al infarction (MI), and both angiotensin AT(1) and AT(2) receptors are upre gulated in the myocardium. METHODS Na+-H+ exchanger isoform-1 and NBC-1 gene expression were determine d by reverse transcription polymerase chain reaction and Northern blot anal ysis; protein levels by Western blot analysis; and activity by measurement of H+ transport in left ventricular (LV) free wall, interventricular septum (IS) and right ventricle (RV) after induction of MI. Rats were treated wit h placebo, the angiotensin-converting enzyme inhibitor ramipril (1 mg/kg/da y), the AT(1) receptor antagonist valsartan (10 mg/kg/day) or the AT(2) rec eptor antagonist PD 123319 (30 mg/kg/day). Treatment was started seven days before surgery. RESULTS Na+-H+ exchanger isoform-1 and NBC-1 messenger RNA (mRNA) expressio n and protein levels were increased twofold in the LV free wall after MI, w hereas no changes were observed in the IS and RV. Na+-dependent H+ flux was increased in the LV free wall. Ramipril inhibited mRNA and protein upregul ation of both transporters. Valsartan inhibited the upregulation of NHE-1 m RNA and protein but had no effect on NBC-1 mRNA expression and translation. In contrast, PD 123319 abolished the upregulation of NBC-1 mRNA and protei n but had no effect on NHE-1 upregulation. Ramipril and valsartan prevented post-MI increase in NHE-1 activity, whereas ramipril and PD 123319 decreas ed NBC-1 activity. CONCLUSIONS Angiotensin II via its AT(1) and AT(2) receptors differentially controls transcriptional and translational regulation as well as the activ ity of NHE-1 and NBC-1 in the ischemic: myocardium and contributes to the c ontrol of pH regulation in cardiac tissue. (J Am Coll Cardiol 2001;37:2154- 65) (C) 2001 by the American College of Cardioloy.