Faculty Collaboration Database

GSK3beta inhibition and K(ATP) channel opening mediate acute opioid-induced cardioprotection at reperfusion. Basic Res Cardiol 2007 Jul;102(4):341-9

Date

04/24/2007

Pubmed ID

17450314

DOI

10.1007/s00395-007-0651-6

Scopus ID

2-s2.0-34250374106 (requires institutional sign-in at Scopus site)   91 Citations

Abstract

Both glycogen synthase kinase 3beta (GSK3beta) and the ATP-dependant potassium channel (K(ATP)) mediate opioid-induced cardioprotection (OIC). However, whether direct K(ATP) channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3beta inhibition is unknown. Therefore, we investigated the role of K(ATP) channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and K(ATP) channels in cardioprotection.Male Sprague-Dawley rats underwent 30 minutes ischemia with 2 hours of reperfusion and infarct size was determined. Rats given the nonselective opioid agonist, morphine (0.3 mg/kg), or the selective delta opioid agonist, BW373U86 (1.0 mg/kg), 5 minutes prior to reperfusion reduced infarct size (40.3+/-1.6*, 39.7+/-1.9* versus 60.0+/-1.1%, respectively, * P<0.001%). This protection was abrogated with prior administration of the putative sarcolemmal K(ATP) antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial K(ATP) antagonist, 5-HD (10 mg/kg). The putative sK(ATP) channel opener, P-1075 (1microg/kg) or the putative mK(ATP) channel opener, BMS-191095 (1 mg/kg) given 5 minutes prior to reperfusion also reduced infarct size (41.8+/-2.4*, 43.4+/-1.4*) and protection was abrogated by prior administration of the PI3k inhibitor wortmannin (60.0+/-1.7, 64.0+/-2.6%, respectively, * P<0.001). Cardioprotection afforded by the GSK inhibitor SB216763 (0.6 mg/kg) given 5 minutes prior to reperfusion was also partially blocked by either HMR or 5-HD and completely blocked when HMR and 5-HD were given in combination (40.8+/-1.6*, 50.4+/-1.6;; 49.4+/-1.7;, 61.6+/-1.6%, respectively, * or ; P<0.001). These data indicate that both the sK(ATP) and mK(ATP) channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via K(ATP) channel opening.

Author List

Gross ER, Hsu AK, Gross GJ

MESH terms used to index this publication - Major topics in bold

Analgesics, Opioid
Androstadienes
Animals
Benzamides
Benzopyrans
Blood Pressure
Cardiotonic Agents
Disease Models, Animal
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Guanidines
Heart Rate
Imidazoles
Indoles
Ion Channel Gating
Male
Maleimides
Morphine
Myocardial Infarction
Myocardial Reperfusion Injury
Phosphatidylinositol 3-Kinases
Piperazines
Potassium Channel Blockers
Potassium Channels
Protein Kinase Inhibitors
Pyridines
Rats
Rats, Sprague-Dawley
Sarcolemma
Signal Transduction
Time Factors