AbstractAim: To clarify the time‐related changes in cardiac function and the mechanism underlying the cardiac dysfunction present in diabetes mellitus, we studied mechanical responses induced byα1‐ andβ‐adrenoceptors, the Ca2+‐entry promoter Bay K 8644‐ and ryanodine (an agent known to inhibit Ca2+release from the sarcoplasmic reticulum) in papillary muscles from streptozotocin (STZ)‐induced diabetic and age‐matched control rats.Methods: Male Wistar rats received a single injection of STZ (60 mg kg−1) via the tail vein to induce diabetes. For the mechanical studies, papillary muscle preparations were suspended in an organ bath and isometric contractions were measured in 1‐, 4‐, and 10‐week STZ‐induced diabetic and age‐matched control rats.Results: In 1‐week diabetic rats, the contractions induced by isoproterenol, methoxamine and Bay K 8644 were unchanged (vs. age‐matched controls). In 4‐week diabetic rats, (a) the isoproterenol‐ and Bay K 8644‐induced contractions were impaired, (b) sensitivity to ryanodine was reduced, whereas (c) the methoxamine‐induced contraction was unchanged. In 10‐week diabetic rats, the isoproterenol‐ and Bay K 8644‐induced contractile responses were impaired and the sensitivity to ryanodine was reduced, but in sharp contrast the methoxamine‐induced contraction was enhanced. Both the mRNA level for theα1Aadrenoceptor (but not theα1Borα1DmRNAs) andα1Aadrenoceptor protein were increased in 10‐week diabetic rats (vs. age‐matched controls).Conclusion: These results suggest that impairments ofβ‐adrenergic and Ca2+‐handling mechanisms occur early in the development of cardiomyopathy in STZ‐induced diabetic rats, and that this is followed by augmentation ofα1Aadrenoceptor‐mediated inotropy due toα1Aadrenoceptor upregulation.