Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase.
Adenosine and acetylcholine (ACh) trigger preconditioning by different signaling pathways. The involvement of phosphatidylinositol 3-kinase (PI3-kinase), a protein tyrosine kinase, and Src family tyrosine kinase in preconditioning was evaluated in isolated rabbit hearts. Either wortmannin (PI3-kinase blocker), genistein (tyrosine kinase blocker), lavendustin A (tyrosine kinase blocker), or 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2; Src family tyrosine kinase blocker) was given for 15 min to bracket a 5-min infusion of either adenosine or ACh (trigger phase). The hearts then underwent 30 min of regional ischemia. Infarct size for ACh alone was 9.3 +/- 3.5% of the risk zone versus 34.3 +/- 4.1% in controls. All four inhibitors blocked ACh-induced protection. When wortmannin or PP2 was infused only during the 30-min ischemic period (mediator phase), ACh-induced protection was not affected (7.4 +/- 2.1% and 9.7 +/- 1.7% infarction, respectively). Adenosine-triggered protection was not blocked by any of the inhibitors. Therefore, PI3-kinase and at least one protein tyrosine kinase, probably Src kinase, are involved in the trigger phase of ACh-induced, but not adenosine-induced, preconditioning. Neither PI3-kinase nor Src kinase is a mediator of the protection of ACh.
Qin
Qining
Q
Department of Physiology, University of South Alabama, Mobile 36688, USA.
Downey
James M
JM
Cohen
Michael V
MV
D000109:Acetylcholine / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006439:Hemodynamics; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D011743:Pyrimidines; D014665:Vasodilator Agents; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D000241:Adenosine; D000109:Acetylcholine