Effects of Ca2+ sensitizers on contraction, [Ca2+](i) transient and myofilament Ca2+ sensitivity in diabetic rat myocardium: Potential usefulness as inotropic agents

The purpose of the present study was to investigate the effects of Ca2+ sen sitizers EMD 57033, MCI-154, and EGIS-9377 in cardiac preparations from str eptozotocin-induced diabetic rats. In enzymatically dissociated ventricular myocytes loaded with the Ca2+ probe indo 1, these Ca2+ sensitizers caused an increase in cell shortening without a significant effect on the intracel lular Ca2+ ([Ca2+](i)) transient. The contractile responses were substantia lly similar in myocytes from diabetic and age-matched control rats. In cont rast, the contractile and [Ca2+](i) responses to pimobendan and isoproteren ol were significantly less in diabetic myocytes. The Ca2+ sensitivity of te nsion in beta -escin-skinned trabeculae from diabetic hearts was not signif icantly different from that of controls. The effect of EMD 57033 on myofila ment responsiveness to Ca2+ was identical in control and diabetic preparati ons. The slower time course of relaxation observed in diabetic papillary mu scles was further prolonged in the presence of EMD 57033. However, the exte nt of the increase in relaxation produced by EMD 57033 did not differ betwe en control and diabetic muscles, and the detrimental effect on resting tens ion was less pronounced in the two groups. In anesthetized rats, echocardio graphy showed that intra-duodenal administration of EMD 57033 increased lef t ventricular systolic function without affecting variables of diastolic fi lling in both groups. Taken together, the present results suggest that Ca2 sensitizers, unlike conventional inotropic agents, have the potential to i ncrease in force of contraction to the same extent in nondiabetic and diabe tic myocardium, possibly without exaggerating extremely the impairment of d iastolic function in diabetes.