Depressed [Ca2+]i responses to isoproterenol and cAMP in isolated cardiomyocytes from experimental diabetic rats.

Experimentally, diabetic rat hearts are characterized by diminished responses to beta-adrenergic stimulation. Among the aberrant responses are diminished beta-adrenoceptor number and depressed contractile protein activity. In this study, intracellular Ca2+ concentration ([Ca2+]i) was determined by microfluorescence in response to beta-adrenergic stimulation to understand the basis for the changes in the beta-adrenergic pathway in diabetic myocardium. In quiescent myocytes, isoproterenol caused a decrease in [Ca2+]i, which was blocked by timolol and thapsigargin. This suggests that the beta-agonist-induced [Ca2+]i changes are mediated, in part, by sarcoplasmic reticulum Ca-adenosinetriphosphatase. Diabetic myocytes showed a blunted response to isoproterenol, which was reversed by insulin treatment. In electrically stimulated myocytes, isoproterenol and 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) increased [Ca2+]i and contraction in a concentration-dependent manner. Electrically stimulated diabetic myocytes demonstrated a depressed maximum [Ca2+]i response to isoproterenol and 8-bromo-cAMP without a change in sensitivity. These data suggest that in addition to alterations in beta-adrenoceptor function there are postreceptor defects in diabetic myocardium that may impair the regulation of [Ca2+]i in diabetic myocardium.