Study for the Abnormality of Intracellular Ca^<2+> Regulation in Failing Hearts

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In cardiac myocytes the Ca-induced Ca release from the sarcoplasmicr reticulum (SR) plays pivotal roles in Ca transients. FK-506 binding protein (FKBP) binds to the SR Ca release channels (ryanodine receptors : RyRs) and stabilizes the SR Ca release channel gating. Recent bilayer studies showed that an immunosuppressant agent, FK506 can dissociate FKBP from RyRs, thereby increasing SR Ca leak. Although the displacement of FKBP is an important aspect in failing heart, its relevance to physiological Ca regulation is still undefined. We examined the effects of FK506 on steady-state (SS) twitch Ca transients (CaT), post rest (PR) caffeine-induced CaT (as an index of SR Ca content) and Ca sparks (as an index of SR Ca leak) using laser scanning confocal microscopy and fluo-3 in rat ventricular myocytes. (1) In intact myocytes, FK506 (50 μM) increased SS (0.5Hz) twitch CaT amplitude and Ca spark frequency during rest periods, but did not change the PR twitch- and caffeine- CaT. (2) In myocytes treated either with thapsigargin and low extracellular Ca concentration, FK506 did not change the SS twitch and PR caffeine CaTs, and (3) In myocytes treated with both thapsigargin and low extracellular Ca concentration, SS twitch CaT and PR caffeine CaT largely reduced, and FK506 significantly accelerated the reduction. In conclusion, the SR Ca leak by displacement of FKBP from RyRs may not be enough to disturb normal excitation-contraction coupling in intact myocytes. However, when the SR Ca uptake was reduced and the sarcolemmal Ca extrusion was, the displacement could induce a significant SR Ca loss.