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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

View larger version (46K): [in a new window]   Figure 1 (A) Representative experiments showing upregulation of Na+-H+ exchanger isoform-1 (NHE-1) messenger RNA (mRNA) in the myocardium of sham-operated and placebo-treated animals with myocardial infarction (MI) one day and seven days after MI. Total RNA obtained from the left ventricular (LV) free wall was amplified by reverse transcription polymerase chain reaction (upper line) and analyzed by Northern blot (lower line). (B) Relative changes in mRNA expression were determined by densitometric analysis and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals. *p < 0.05 compared with sham operation. Data represent mean ± SEM, n = 6.

View larger version (47K): [in a new window]   Figure 2 (A) Representative experiments showing upregulation of Na+-HCO3– symporter isoform-1 (NBC-1) messenger RNA (mRNA) in the myocardium of sham-operated and placebo-treated animals with myocardial infarction (MI) one day and seven days after MI. Total RNA obtained from the left ventricular (LV) free wall was amplified by reverse transcription polymerase chain reaction (upper line) and analyzed by Northern blot (lower line). (B) Relative changes in mRNA expression were determined by densitometric analysis and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals. *p < 0.05 compared with sham operation. Data represent mean ± SEM, n = 6.

View larger version (37K): [in a new window]   Figure 3 Effects of chronic treatment with the angiotensin-converting enzyme inhibitor ramipril (1 mg/kg/day), the AT1 receptor antagonist valsartan (10 mg/kg/day) and the AT2 receptor antagonist PD 123319 (30 mg/kg/day) on messenger RNA (mRNA) expression of Na+-H+ exchanger isoform-1 (NHE-1) (A) and Na+-HCO3– symporter isoform-1 (NBC-1) (B) in the left ventricular free wall one day and seven days after myocardial infarction (MI) compared with sham-operated and placebo-treated animals with MI. *p < 0.05 compared with sham operation; #p < 0.05 compared with placebo MI. Data represent mean ± SEM, n = 6.

View larger version (46K): [in a new window]   Figure 4 Effects of chronic treatment with the angiotensin-converter enzyme inhibitor ramipril (1 mg/kg/day), the AT1 receptor antagonist valsartan (10 mg/kg/day) and the AT2 receptor antagonist PD 123319 (30 mg/kg/day) on protein levels of Na+-H+ exchanger isoform-1 (NHE-1) (A) and Na+-HCO3– symporter isoform-1 (NBC-1) (B) in the left ventricular free wall one day and seven days after myocardial infarction (MI) compared with sham-operated and placebo-treated animals with MI. *p < 0.05 compared with sham operation; #p < 0.05 compared with placebo MI. Data represent mean ± SEM, n = 6. PD = PD 123319; Pl = placebo; Ra = ramipril; Sh = sham-operated; Va = valsartan.

View larger version (31K): [in a new window]   Figure 5 Representative original traces showing recovery from intracellular acidosis after stepwise washout of 30 mM NH4Cl of endocardial tissue preparations from infarcted rat hearts. Effects of chronic treatment with the angiotensin-converting enzyme inhibitor ramipril, the AT1 receptor antagonist valsartan and the AT2 receptor antagonist PD 123319 on puffering power (ßi) and proton efflux (JH) seven days after myocardial infarction (MI) compared with sham-operated and placebo-treated animals with MI. ami = amiloride; PSS = physiological saline solution.

View larger version (24K): [in a new window]   Figure 6 Effects of chronic treatment with the angiotensin-converting enzyme inhibitor ramipril (1 mg/kg/day), the AT1 receptor antagonist valsartan (10 mg/kg/day) and the AT2 receptor antagonist PD 123319 (30 mg/kg/day) on Na+-dependent HCO3–-independent net H+ influx (NHE activity; A) and Na+ and HCO3–-dependent net H+ influx (NBC activity; B) in endocardial tissue preparations seven days after myocardial infarction compared with sham-operated and placebo-treated animals with myocardial infarction. *p < 0.05 compared with sham operation; #p < 0.05 compared with placebo-treated myocardial infarction. Data represent mean ± SEM, n = 10 to 12.

View larger version (29K): [in a new window]   Figure 7 Possible contribution of angiotensin receptor subtype 1 (AT1) and angiotensin receptor subtype 2 (AT2) in the regulation of intracellular pH after myocardial infarction (MI). NBC-1 = Na+-HCO3– symporter isoform-1; NHE-1 = Na+-H+ exchanger isoform-1.