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Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1
Na+/H+ exchange (NHE) represents a major mechanism for intracellular pH regulation, particularly in the ischemic myocardium. NHE has also been shown to be important in the regulation of cell proliferation and growth. We examined whether inhibition of NHE results in an attenuation of early postinfarction myocyte remodeling responses in the rat. Male Sprague-Dawley rats were randomized to receive either a control diet or an identical diet supplemented with the NHE inhibitor cariporide. After 1 wk, animals were anesthetized, subjected to ligation of the left main coronary artery, and maintained for an additional week, after which time they were anesthetized and intraventricular pressures were obtained. Hearts were removed, and myocytes were isolated to obtain cell dimensions and determine the response to isoproterenol. Body, heart, and lung weights were obtained. Coronary artery ligation in control animals resulted in a significant elevation in left ventricular end-diastolic pressure, as well as increased heart weight- and lung weight-to-body weight ratios, both of which were abrogated by cariporide. Cell length and area significantly increased by 14 and 19.2%, respectively, whereas cell width increased by 4.1% (P > 0.05). These cells exhibited a significant hyporesponsiveness to the positive inotropic responses to isoproterenol at the lower drug concentrations (3 and 10 nM). A <1% dimensional change occurred in myocytes from cariporide-fed animals, and the hyporesponse to isoproterenol was reversed. Cariporide had no effect on infarct size or blood pressure. These studies suggest that the early adaptive hypertrophic response of surviving myocytes is dependent on NHE activity. As such, it is attractive to suggest that NHE inhibition could be an effective therapeutic strategy for prevention of postinfarction remodeling, independent of infarct size or afterload reduction.
sodium-hydrogen exchange; myocyte remodeling; heart failure; cariporide
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