Connexin 43 (Cx43) is the predominant protein forming gap junctions in ventricular myocardium. The protein is central for the cardioprotection by ischemic preconditioning, since the protection is abolished in isolated cardiomyocytes and in in situ hearts from heterozygous Cx43-deficient mice. Apart from the sarcolemma, Cx43 is also present at the inner membrane of cardiomyocyte mitochondria. Heat shock protein 90 (Hsp90) as well as the translocases of the outer and inner membrane (TOM and TIM complexes, respectively) play a role in the import of Cx43 into the mitochondria. The inhibition of Hsp90 by geldanamycin results in a decrease of Cx43 specifically at the mitochondria and abolishes pharmacological preconditioning by diazoxide in isolated rat hearts. Reduced mitochondrial Cx43 content attenuates the ADP-stimulated respiration and the generation of reactive oxygen species (ROS), which is central to the signal transduction cascade of ischemic preconditioning's cardioprotection. Cardiomyocytes isolated from heterozygous Cx43-deficient mice ? in contrast to wildtype cells - have a deficit in the production of ROS specifically in response to diazoxide. In contrast to ischemic preconditioning, ischemic postconditioning is effective both in wildtype and in heterozygous Cx43-deficient mice.