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EXPERIMENTAL STUDY

Differential effects of angiotensin AT₁ and AT₂ receptors on the expression, translation and function of the Na⁺-H⁺ exchanger and Na⁺-HCO₃^– symporter in the rat heart after myocardial infarction

Steffen Sandmann, PhD^*, Minghuan Yu, MD^*, Elena Kaschina, MD^*, Annegret Blume, PhD^*, Elena Bouzinova, PhD, Christian Aalkjaer, MD and Thomas Unger, MD^*

^* Institute of Pharmacology, University of Kiel, Kiel, Germany
Institute of Physiology, University of Aarhus, Aarhus, Denmark

Manuscript received November 17, 2000; revised manuscript received February 16, 2001, accepted March 1, 2001.

Reprint requests and correspondence: Dr. Thomas Unger, Institute of Pharmacology, University of Kiel, Hospitalstr. 4, 24105 Kiel, Germany
th.unger{at}pharmakologie.uni-kiel.de

OBJECTIVES

This study investigated the role of angiotensin receptor subtype 1 (AT₁) and angiotensin receptor subtype 2 (AT₂) in the regulation of Na⁺-H⁺ exchanger (NHE) and Na⁺-HCO₃^– symporter (NBC) in the infarcted myocardium.

BACKGROUND

The cardiac renin-angiotensin system is activated after myocardial infarction (MI), and both angiotensin AT₁ and AT₂ receptors are upregulated in the myocardium.

METHODS

Na⁺-H⁺ exchanger isoform-1 and NBC-1 gene expression were determined by reverse transcription polymerase chain reaction and Northern blot analysis; 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 with placebo, the angiotensin-converting enzyme inhibitor ramipril (1 mg/kg/day), the AT₁ receptor antagonist valsartan (10 mg/kg/day) or the AT₂ receptor 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) expression and protein levels were increased twofold in the LV free wall after MI, whereas 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 upregulation of both transporters. Valsartan inhibited the upregulation of NHE-1 mRNA 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 protein but had no effect on NHE-1 upregulation. Ramipril and valsartan prevented post-MI increase in NHE-1 activity, whereas ramipril and PD 123319 decreased NBC-1 activity.

CONCLUSIONS

Angiotensin II via its AT₁ and AT₂ receptors differentially controls transcriptional and translational regulation as well as the activity of NHE-1 and NBC-1 in the ischemic myocardium and contributes to the control of pH regulation in cardiac tissue.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   Ang II = angiotensin II   AT1 = angiotensin receptor subtype 1   AT2 = angiotensin receptor subtype 2   BCECF-AM = acetoxymethylester of the fluorescence dye 2',7'-bis-(2-carboxyethyl)-5 (and -6)-carboxyfluorescein   ßi = cellular buffering power [ßi(mM) = (NH4+)i/pHi]   cDNA = complementary DNA   GAPDH = glyceraldehyde-3-phosphate dehydrogenase   IS = interventricular septum   JH = H+ efflux [JH = ßi(dpHi/dt)]   LV = left ventricle/ventricular   MI = myocardial infarction   mRNA = messenger RNA   NBC-1 = Na+-HCO3– symporter isoform-1   NCE = Na+-Ca2+ exchanger   NHE-1 = Na+-H+ exchanger isoform-1   PCR = polymerase chain reaction   pHi = intracellular pH   PSS = physiological saline solution   RT-PCR = reverse transcription polymerase chain reaction   RV = right ventricle/ventricular

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