The effect of sarcoplasmic reticulum Ca2+ leak on contractile activity of guinea pig heart myocytes depends on activity of sarcoplasmic reticulum Ca2+-ATPase and Na+/Ca2+ exchanger

Decreased expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA), overexpression of Na+/Ca2+ exchanger (NCX) and diastolic SR Ca2+ leak from the ryanodine receptors (RyRs) are believed to contribute to the decrease of myocyte contraction in failing heart. In this work we induced Ca2+ leak through RyRs in isolated myocytes of guinea pig hearts by 20 mu M FK-506. The SR Ca2+ leak resulted in (1) decreased amplitude of cell shortening and of Ca2+ transients, (2) decreased rate of Ca2+ transients decay (3) enhanced diastolic Ca2+ loss. The effect of FK-506 on amplitude of cell shortening was reversed and that on diastolic Ca2+ loss blocked by partial inhibition of NCX due to lowering Ne concentration in superfusion solution from 144 mM to 100 mM. The amplitude of cell shortening and Ca2+ transients decreased by FK-506 was significantly increased by 10(-7) M thapsigargin. In conclusion, the effect of SR Ca2+ leak induced by FK-506 on myocyte contraction is strictly dependent on activity of SERCA and NCX.