(Circulation. 1999;100:958-966.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Ischemic Preconditioning and the ß-Adrenergic Signal Transduction Pathway
From the Department of Medical Physiology and Biochemistry, Faculty of Medicine, University of Stellenbosch, MRC Experimental Biology Programme, Tygerberg, Republic of South Africa; and the Max Planck Institute, Bad Nauheim, Germany (T.P.).
Correspondence to Prof A. Lochner, Department of Medical Physiology and Biochemistry, Faculty of Medicine, University of Stellenbosch, PO Box 19063, Tygerberg 7505, Republic of South Africa. E-mail alo{at}gerga.sun.ac.za
Background—Previous studies from our laboratory showed cyclic increases in tissue cAMP during a multiple-cycle preconditioning (PC) protocol, followed by attenuated cAMP accumulation during sustained ischemia. The aim of this study was to determine whether ischemia-induced activation of the ß-adrenergic signaling pathway could act as a trigger in eliciting protection.
Methods and Results—Isolated perfused rat hearts were preconditioned by 3x5 minutes of global ischemia, interspersed by 5 minutes of reperfusion. ß-Adrenergic responsivity was assessed by measurement of tissue cAMP generation after ß-adrenergic agonist administration at the end of the PC protocol. Tissue cAMP, adenylyl cyclase, and protein kinase A (PKA) activities and ß-adrenergic receptor characteristics were assessed at different times. The role of cAMP generation in eliciting PC was studied by investigation of functional recovery during reperfusion after 25 minutes of global ischemia after (1) cAMP increases in the trigger period were prevented with the ß-adrenergic blocker alprenolol 7.5x10-5 mol/L and (2) increases in cAMP were elicited by administration of forskolin 10-7 and 10-6 mol/L or isoproterenol 10-8, 10-7, and 10-6 mol/L. Intermittent ischemia resulted in reduced ß-adrenergic responsivity at the end of the protocol, although Bmax and Kd values of the ß-adrenergic receptor population and adenylyl cyclase and PKA activities were increased. Abolishment of cyclic increases in cAMP before sustained ischemia attenuated myocardial protection against ischemia, whereas agonists elicited protection. No clear correlation between protection and ß-adrenergic desensitization was observed.
Conclusions—Ischemia-induced activation of the ß-adrenergic signaling pathway during preconditioning should also be considered a trigger in eliciting preconditioning.
Key Words: ischemia • reperfusion • receptors, adrenergic, beta
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