Depressed phosphatidic acid-induced contractile activity of failing cardiomyocytes.
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.
Tappia
Paramjit S
PS
Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre (R3020), 351 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6. ptappia@sbrc.ca
Maddaford
Thane G
TG
Hurtado
Cecilia
C
Panagia
Vincenzo
V
Pierce
Grant N
GN
D000818:Animals; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000175:diagnosis / Q000201:enzymology / Q000503:physiopathology*; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry; D010712:Phosphatidic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism; D016277:Ventricular Function, Left
D010712:Phosphatidic Acids; D010738:Type C Phospholipases; D002118:Calcium