Copyright © 2004, European Society of Cardiology
1A- but not 1B-adrenergic receptors precondition the ischemic heart by a staurosporine-sensitive, chelerythrine-insensitive mechanism
aDepartment of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA
bDepartment of Cardiology, University of California, San Francisco, CA 94143, United States
* Corresponding author. Tel.: +1 216 444 2058; fax: +1 216 444 9263. Email address: perezd{at}ccf.org
Objective: Brief periods of ischemia stimulate an endogenous mechanism in the heart that protects the myocardium from subsequent ischemic injury. 
1-Adrenergic receptors (ARs) have been implicated in this process. However, the lack of sufficiently selective antagonists has made it difficult to determine which 1-AR subtype protects the heart from ischemic injury. The goal of this study was to identify the 1-AR subtype that is involved in ischemic preconditioning.
Methods: We developed transgenic mice that express constitutively active mutant (CAM) forms of the 1A-AR or the 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 1A-AR hearts, but not CAM 1B-AR hearts, completely recovered from 30-min ischemia even though they were perfused according to the non-preconditioning protocol. Thus, CAM 1A-AR hearts, but not CAM 1B-AR hearts, were inherently preconditioned against ischemic injury. Staurosporine, but not chelerythrine, completely reversed the preconditioning effect of CAM 1A-ARs.
Conclusions: These data demonstrate that 1A-ARs protect the heart from ischemic injury through a staurosporine-sensitive signaling pathway that is independent of protein kinase C.
KEYWORDS Alpha 1 adrenergic receptors; Ischemic preconditioning; Transgenic mouse; Ischemia
1 Current address: GlaxoSmithKline, Research Triangle Park, NC, United States.
Time for primary review 24 days
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