Stimulus interval-dependent differences in Ca2+ transients and contractileresponses of diabetic rat cardiomyocytes

Objective: The aim of this study was to gain further insights into the cons equences of insulin-dependent diabetes mellitus on cardiomyocyte calcium ha ndling. Methods: The effects of steady state and transient changes in stimu lus frequency on the intracellular Ca2+ transient and cell shortening were examined in left ventricular cardiomyocytes isolated from the hearts of con trol and streptozotocin-induced diabetic rats. Results: During steady state stimulation diabetic rat cardiomyocytes displayed a slower decay of the Ca 2+ transient and longer times for maximum cell shortening and re-lengthenin g. At 1.5 mM extracellular [Ca2+], increasing stimulus frequency over the r ange 0.2-1.0 Hz led to an increase in resting and peak [Ca2+], as well as t he amplitude of the transient in both the control and diabetic groups. At f requencies greater than 0.4 Hz the amplitude of the transient was significa ntly depressed in diabetic rat cells and this was not normalized by increas ing extracellular [Ca2+] to 2.5 mM. Recovery of sarcoplasmic reticulum (SR) Ca2+ release was measured from the time course of restitution of the intra cellular Ca2+ transient. in both control and diabetic rat cardiomyocytes re covery of the transient occurred in two phases. In diabetic rat myocytes, t he initial rapid phase of restitution at intervals <1 s was markedly slowed . The fraction of Ca2+ recirculating between the SR and the cytosol was est imated from the decline in amplitude of transients following post-rest pote ntiation. There was no difference in this fraction between control and diab etic rat cells either at 1.5 or 2.5 mM extracellular [Ca2+]. Conclusion: Th e blunted frequency response of diabetic rat cardiomyocytes at frequencies greater than 0.4 Hz is consistent with reduced SR Ca2+ uptake leading to re duced SR Ca2+ content and subsequent release. At stimulus intervals greater than 1 Hz this is likely to be exacerbated by slower recovery of SR Ca2+ r elease. Despite the evidence for depressed SR Ca2+ uptake, the relative amo unt of Ca2+ recirculating within diabetic rat cardiomyocytes remains unalte red. This is most likely due to an accompanying reduction in Ca2+ efflux fr om the cell due either to depressed Na+/Ca2+ exchanger activity, or an elev ation in intracellular Na+ levels. (C) 2000 Elsevier Science B.V. All right s reserved.