Depressed phosphatidic acid-induced contractile activity of failing cardiomyocytes

Abstract

The effects of phosphatidic acid (PA), a known inotropic agent, on Ca 2+ transients and contractile activity of cardiomyocytes in congestive heart failure (CHF) due to myocardial infarction were examined. In control cells, PA induced a significant increase (25%) in active cell shortening and Ca 2+ transients. The phospholipase C (PLC) inhibitor, 2-nitro-4-carboxyphenyl N, N-diphenylcarbonate, blocked the positive inotropic action induced by PA, indicating that PA induces an increase in contractile activity and Ca 2+ transients through stimulation of PLC. Conversely, in failing cardiomyocytes there was a loss of PA-induced increase in active cell shortening and Ca 2+ transients. PA did not alter resting cell length. Both diastolic and systolic [Ca 2+] were significantly elevated in the failing cardiomyocytes. In vitro assessment of the cardiac sarcolemmal (SL) PLC activity revealed that the impaired failing cardiomyocyte response to PA was associated with a diminished stimulation of SL PLC activity by PA. Our results identify an important defect in the PA–PLC signaling pathway in failing cardiomyocytes, which may have significant implications for the depressed contractile function during CHF.