Similar articles

Abstract: Objective: In addition to pH regulation, Na⁺/H⁺ exchanger (NIE) has been shown to facilitate cell growth and proliferation. However, the effects of long-term inhibition of Na⁺/H⁺ exchange on cardiac structural and functional remodeling post myocardial infarction (MI) are still controversial. The present study was therefore carried ont to further investigate the effects of long-term treatment with cariporide, a specific inhibitor of NHE-1, on cardiac remodeling after MI in rots; Methods: Male Wistar rots that underwent coronary ligation were randomly selected for cariporide treatment starting 6 h after induction of MI or no treatment. Treatment was continued up to 6 weeks post MI, after which, the arterial, venous and left ventricular catheters were chronically implanted. Twenty-four h later, after hemodynamic signals were recorded in conscious rats, they were sacrificed and hearts were taken out for morphological examinations; Results: Cariporide treatment decreased the heart weight and heart weight to body weight ratio (both P<0.05), decreased left ventricular end-diastohc pressure (P<0.001), improved myocardial contractility (dP/dt_max) (P<0.05) and tended to increase the survival of treated rots compared to that of untreated infarct rats; Conclusion: The results of the present study indicate that the long-term inhibition of NHE with cariporide can attenuate cardiac structural re-modeling and improve left ventricular dysfunction in infarcted rats, and suggest that Na⁺/H⁺ exchange inhibition could be an effective therapeutic strategy for myocardial infarction-induced heart failure.

[1] Cingolani, H.E., 1999. Na⁺/H⁺ exchange hyperactivity and myocardial hypertrophy: Are they linked phenomena? Carddovasc Res, 44:462-467.

[2] Duan, J., Karmazyn, M., 1992. Protective effects of amiloride on the ischemic repeffused rat heart. Relation to mitochonadrial function. Eur J Pharmacol, 210:149-157.

[3] Fliegel, L., 1999. Functional and cellular regulation of the myocardial Na⁺/H⁺ exchanger. J Thromb Thrombolysis, 8:9-14.

[4] Grace, A.A., Metcalfe, J.C., Weissberg, P.L. et al.,1996. Angioteusin II stimulates sodium dependent proton extrusion in perfused ferret heart. Am J Physiol, 270:C1687-C1694.

[5] Gumina, R.J., Mizumara, T., Beier, N. et al., 1998. A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmacol Exp Ther,286:175-1813.

[6] Hartmann, M., Decking, U.K., 1999. Blocking Na⁺-H⁺ exchange by cariporide reduces Na⁺-overload in ischemia and is cardioprotective. J Mol Cell Cardiol,31:1985-1995.

[7] Hasegawa, S., Nakano, M., Taniguehi, Y. et al., 1995. Effects of Na⁺/H⁺ exchange blocker amiloride on left ventricular remodeling after anterior myocardial infarction in rats. Cardiovasc Drugs Ther, 9:823-826.

[8] Hori, M., Nakatsubo, N., Kagiya, T. et al. 1990. The role of Na⁺/H⁺ exchange in norepinephrine-induced protein synthesis in neonatal cultured cardiomyocytes. Jpn Circ J, 54:535-539.

[9] Iwakura, K., Hori, M., Watanabe, Y. et al., 1990. Alpha 1-adrenoceptor stimulation increases intracellular pH and Ca²⁺ in cardiomyocytes through Na⁺/H⁺ and Na⁺/Ca²⁺ exchange. Eur J Pharmacol, 186:29-40.

[10] Junqueira, L.C., Bignolas, G., Brentani, R.R., 1979. Red sirius staining plus polarizing microscopy: a specific method for collagen detection in tissue sections. Histochem J, 79:445-447.

[11] Karmazyn, M., 1988. Amiloride enhances postiscbemic ventricular recovery: possible role of Na⁺/H⁺-exchange. Am J Physiol, 255:H608-H615.

[12] Klein, H.H., Pich, S., Bohle, R.M. et al., 1995. Myocardial protection by Na⁺/H⁺ exchange inhibition in ischemic, reporfused porcine hearts. Circulation, 92:912-917.

[13] Kramer, B.K., Smith, T.W., Kelly, R.A., 1991. Endothelin and increased contractility in adult rat ventricular myocytes. Role of intracellular alkalosis induced by activation of the protein kinase C-dependent Na⁺ - H⁺ exchanger. Circ Res, 68:269-279.

[14] Ladzdunski, M., Frelin, C., Vigne, P., 1985. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating intenal concentration of sodium and intemal pH. J Mol Cell Cardiol, 17:1029-1042.

[15] Ruzicka, M., Yuan, B., Leenen, F.H.H., 1999. Blockade of AT1 receptors and Na⁺/H⁺ exchanger and LV dysfunction after myocardial infarction in rots. Am J Physiol, 277:H610-H616.

[16] Scholz, W., Albus, U., Counillon, L. et al., 1995. Protective effects of HOE 642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischemia and reperfusion. Circ Res, 29:260-268.

[17] Sigurdsson, A., Swedberg, K., 1996. The role of neurohormonal activation in chronic heart failure and postmyocardial infarction. Am Heart J 132:229-234.

[18] Stauss, B., Itoi, K., Stauss, H., Unger, T., 1990. A novel inexpensive computer system to record and analyze hemodynamic data in conscious animals. Eur J Pharmacol, 183:863-864.

[19] Stromer, H., de Groot, M.C.H., Hon, M. et al., 2000. Na⁺/H⁺ exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca²⁺ overload and prolonged acidosis on reperfusion. Circulation,101:2749-2755.

[20] Wallert, M.A., Frohlich, O., 1992. Alpha 1-adrenergic stimulation of Na-H exchange in cardiac myocytes. Am J Physiol, 263:C1096-C1102.

[21] Xia, Q.G., Chung, O., Spitznagel, H. et al., 1999. Effects of a novel angioteusin AT1 receptor antagonist,HR720, on mrs with myocardial infarction. Eur J Pharmacol, 385:171-179.

[22] Yasutake, M., Ibuki C, Hearse D.J, Avkiran M., 1994. Na⁺/H⁺ exchange and repeffusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. Am J Physiol, 267:H2430-H2440.

[23] Yoshida, H., Kannazyn, M., 2000. Na⁺/H⁺ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium. Am J Physiol, 278:H300-H304.