Hearts from animal models of type 2 diabetes present with abnormal contractility patterns. The role of altered α1-adrenergic signalling in this is not understood. In this study we report overexpression and altered regulation of α1-adrenergic receptors in two models of type 2 diabetic rat hearts. In combination with reduced contractile performance, papillary muscles from these hearts presented with an enhanced ability to react to α1-adrenergic stimulation. Concurrently, these muscles were protected against anoxia/reoxygenation induced damage. This protection could be abolished by pretreatment with the α1-adrenergic antagonist, prazosin. Overexpression of α1-adrenergic receptors may therefore be a two-edged sword: supplying a contractile reserve that can protect against anoxia/reoxygenation induced effects on inotropic ability on the one hand but also predisposing the hearts to elevated induction of intracellular Ca2+ release and possible arrhythmic effects on the other hand.