α1A- but not α1B-adrenergic receptors precondition the ischemic heart by a staurosporine-sensitive, chelerythrine-insensitive mechanism

Objective: Brief periods of ischemia stimulate an endogenous mechanism in the heart that protects the myocardium, from subsequent ischemic injury. alpha(1)-Adrenergic receptors (ARs) have been implicated in this process. However, the lack of sufficiently selective antagonists has made it difficult to determine which alpha(1)-AR subtype protects the heart from ischemic injury. The goal of this study was to identify the alpha(1)-AR subtype that is involved in ischemic preconditioning. Methods: We developed transgenic mice that express constitutively active mutant (CAM) forms of the alpha(1A)-AR or the alpha(1B)-AR regulated by their endogenous promoters. Hearts isolated from transgenic and non-transgenic mice were perfused by the Langendorff method using an ischemic preconditioning perfusion protocol or a non-preconditioning perfusion protocol prior to 30-min ischemia and 40-min reperfusion. Contractile function was continuously monitored through an intraventricular balloon. Results: The contractile function of non-transgenic hearts perfused according to the ischemic preconditioning protocol completely recovered from 30-min ischemia. However, non-transgenic hearts perfused according to the non-preconditioning protocol recovered only 60% of their contractile function. The contractile function of CAM alpha(1A)-AR hearts, but not CAM alpha(1B)-AR hearts, completely recovered from 30-min ischemia even though they were perfused according to the non-preconditioning protocol. Thus, CAM alpha(1A)-AR hearts, but not CAM alpha(1B)-AR hearts, were inherently preconditioned against ischemic injury. Staurosporine, but not chelerythrine, completely reversed the preconditioning effect of CAM alpha(1A)-ARs. Conclusions: These data demonstrate that alpha(1A)-ARs protect the heart from ischemic injury through a staurosporine-sensitive signaling pathway that is independent of protein kinase C. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.