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.
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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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