Reduced pH and contractility in failing rat cardiomyocytes

Abstract

To determine whether reduced cardiomyocyte contractility in heart failure is associated with reduced intracellular pH (pH(i)). Involvement of the Na(+)/H(+) exchanger and the H(+)/K(+) ATPase were investigated with specific blockers. Myocardial infarction and subsequent heart failure in Sprague-Dawley rats were induced by chronic occlusion of the left coronary artery. 6 weeks post-ligation, contractility (cell shortening) and pH(i) (BCECF fluorescence) were recorded in freshly dissociated cardiomyocytes during 2-10 Hz electrical stimulation, with or without either Na(+)/H(+) exchanger or H(+)/K(+) ATPase inhibition. Elevated end-diastolic and reduced peak systolic pressures confirmed heart failure. Increased heart weights (20-30%; P < or = 0.01) and cardiomyocyte lengths and widths (22-25%; P < or = 0.01) confirmed substantial cardiac hypertrophy. In myocytes isolated from sham operated rats, a positive staircase response occurred with stimulation rates from 2 to 7 Hz; further increases in stimulation rate up to 10 Hz reduced contractility. In contrast, pH(i) fell progressively over the entire stimulation range. In failing myocytes, pH(i) was consistently 0.07 pH units lower and contractility 40% lower (P < or = 0.01) than sham control values; the shape of the contractility staircase remained similar to controls. At all stimulation frequencies, Na(+)/H(+) exchanger inhibition reduced pH(i) by 0.05 pH units (P < or = 0.01) and contractility by 22% (P < or = 0.05) in cardiomyocytes from the heart failure group. A significantly smaller decrease of pH(i) and reduction in contractility was observed after inhibition of Na(+)/H(+) exchanger (10 micro m HOE694) in sham myocytes. H(+)/K(+) ATPase inhibition (100 micro m SCH28080) had no effect on pH(i). Reduced pH(i) is accompanied by reduced cardiomyocyte contractility in isolated myocytes from post-MI heart failure. The data suggest compensatory Na(+)/H(+) exchanger activation in heart failure, whereas H(+)/K(+) ATPase does not appear to contribute significantly to pH(i) maintenance.