Protein tyrosine kinase signaling is necessary for NO donor-induced late preconditioning against myocardial stunning.
Although protein tyrosine kinases (PTKs) signaling has been implicated in the late phase of ischemic preconditioning (PC), it is unknown whether PTK signaling is necessary for the development of nitric oxide (NO) donor-induced late PC. Thus conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles followed by a 5-h recovery period of reperfusion for 3 consecutive days (days 1, 2, and 3). On day 0 (24 h before the 6 O/R cycles on day 1), rabbits received no treatment (control), the NO donor diethylenetriamine (DETA)/NO (DETA/NO), the PTK inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), or DETA/NO plus PP2 (DETA/NO + PP2). In control rabbits (n = 6), the six O/R cycles on day 1 resulted in delayed functional recovery, indicating severe myocardial stunning. In rabbits pretreated with DETA/NO (n = 5) on day 1, myocardial stunning caused by the six O/R cycles on day 1 was markedly attenuated, with a significant reduction ( approximately 60%) in the total deficit of wall thickening (WTh) compared with controls, indicating that DETA/NO induced a late PC effect against stunning. However, in rabbits pretreated with DETA/NO + PP2 (n = 5), the total deficit of WTh was significantly greater than that in rabbits treated with DETA/NO alone and was similar to that in controls, indicating that PP2 prevented the development of DETA/NO-induced late PC. In rabbits pretreated with PP2 on day 0 (n = 4), the total deficit of WTh was similar to that in controls, indicating that PP2 does not affect myocardial stunning in itself. We conclude that a PTK-dependent signaling mechanism is necessary for the development of NO donor-induced late PC against myocardial stunning in conscious rabbits.
Tang
Xian-Liang
XL
Experimental Research Laboratory, Division of Cardiology, University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky 40292, USA.
Kodani
Eitaro
E
Takano
Hitoshi
H
Hill
Michael
M
Shinmura
Ken
K
Vondriska
Thomas M
TM
Ping
Peipei
P
Bolli
Roberto
R
D000818:Animals; D003250:Constriction; D003331:Coronary Vessels; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000517:prevention & control*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011073:Polyamines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction
C412373:AG 1879; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011073:Polyamines; D011743:Pyrimidines; C005391:diethylenetriamine; D011505:Protein-Tyrosine Kinases