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

Abstract

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