Cardioprotective effects of BMS-180448, a prototype mitoK(ATP) channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury.
To investigate the involvement of reperfusion-induced salvage kinases (RISK) as possible signaling molecules for the cardioprotective effects of BMS-180448, a prototype mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel opener, we measured its cardioprotective effects in a rat model of ischemia/reperfusion (I/R) heart injury, together with western blotting analysis of five different signaling proteins. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, BMS-180448 (1, 3 and 10 microM) significantly increased reperfusion left ventricular developed pressure (LVDP) and 30-min reperfusion double product (heart rate x LVDP) in a concentration-dependent manner, while decreasing left ventricular end-diastolic pressure (LVEDP) throughout reperfusion period in a concentration-dependent manner. SDS-PAGE/western blotting analysis of left ventricle reperfused for 30 min revealed that BMS-180448 significantly decreased phospho-GSK3beta at high concentration, whereas it tended to increase slightly phospho-eNOS and phospho-p70S6K with concentration. However, BMS-180448 had no effect on phospho-Akt and phospho-Bad. These results suggest that the cardioprotective effects of BMS-180448 against I/R heart injury may result from direct activation of mitoK(ATP) channel in cardiomyocytes, with the minimal role of RISK pathway in the activation of this channel and the cardioprotective effects of BMS-180448.
Lee
Ju-Han
JH
Department of Applied Biochemistry, Division of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju 380-701, Korea.
Jung
In-Sang
IS
Lee
Sung-Hun
SH
Yang
Min-Kyu
MK
Hwang
Ji-Hye
JH
Lee
Hak-Dong
HD
Cho
Yu-Sun
YS
Song
Min-Jin
MJ
Yi
Kyu-Yang
KY
Yoo
Sung-Eun
SE
Kwon
Suk-Hyung
SH
Kim
Bokyung
B
Lee
Chang-Soo
CS
Shin
Hwa-Sup
HS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C084684:BMS 180448; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3