Vol. 298, Issue 2, 613-622, August 2001

Effects of Ca²⁺ Sensitizers on Contraction, [Ca²⁺]_i Transient and Myofilament Ca²⁺ Sensitivity in Diabetic Rat Myocardium: Potential Usefulness as Inotropic Agents

Toshiteru Ishitani, Yuichi Hattori, Fumika Sakuraya, Hisao Onozuka, Takao Makino, Naoyuki Matsuda, Satoshi Gando and Osamu Kemmotsu

Departments of Pharmacology (Y.H.), Anesthesiology, and Critical Care Medicine (T.I., F.S., N.M., S.G., O.K.) and Cardiovascular Medicine (H.O., T.M.), Hokkaido University School of Medicine, Sapporo, Japan

The purpose of the present study was to investigate the effects of Ca²⁺ sensitizers EMD 57033, MCI-154, and EGIS-9377 in cardiac preparations from streptozotocin-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 intracellular Ca²⁺ ([Ca²⁺]_i) transient. The contractile responses were substantially similar in myocytes from diabetic and age-matched control rats. In contrast, the contractile and [Ca²⁺]_i responses to pimobendan and isoproterenol were significantly less in diabetic myocytes. The Ca²⁺ sensitivity of tension in -escin-skinned trabeculae from diabetic hearts was not significantly different from that of controls. The effect of EMD 57033 on myofilament responsiveness to Ca²⁺ was identical in control and diabetic preparations. The slower time course of relaxation observed in diabetic papillary muscles was further prolonged in the presence of EMD 57033. However, the extent of the increase in relaxation produced by EMD 57033 did not differ between control and diabetic muscles, and the detrimental effect on resting tension was less pronounced in the two groups. In anesthetized rats, echocardiography showed that intra-duodenal administration of EMD 57033 increased left ventricular systolic function without affecting variables of diastolic filling in both groups. Taken together, the present results suggest that Ca²⁺ sensitizers, unlike conventional inotropic agents, have the potential to increase in force of contraction to the same extent in nondiabetic and diabetic myocardium, possibly without exaggerating extremely the impairment of diastolic function in diabetes.