Ischemic preconditioning and the beta-adrenergic signal transduction pathway.
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 beta-adrenergic signaling pathway could act as a trigger in eliciting protection.


RESULTS
Isolated perfused rat hearts were preconditioned by 3x5 minutes of global ischemia, interspersed by 5 minutes of reperfusion. beta-Adrenergic responsivity was assessed by measurement of tissue cAMP generation after beta-adrenergic agonist administration at the end of the PC protocol. Tissue cAMP, adenylyl cyclase, and protein kinase A (PKA) activities and beta-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 beta-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 beta-adrenergic responsivity at the end of the protocol, although B(max) and K(d) values of the beta-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 beta-adrenergic desensitization was observed.


CONCLUSIONS
Ischemia-induced activation of the beta-adrenergic signaling pathway during preconditioning should also be considered a trigger in eliciting preconditioning.
Lochner
A
A
Department of Medical Physiology and Biochemistry, Faculty of Medicine, University of Stellenbosch, MRC Experimental Biology Programme, Tygerberg, Republic of South Africa. alo@gerga.sun.ac.za
Genade
S
S
Tromp
E
E
Podzuweit
T
T
Moolman
J A
JA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial / Q000009:adverse effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol