Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels.

Abstract

We examined the role of the sarcolemmal and mitochondrial ATP-sensitive potassium (K(ATP)) channel in a rat model of myocardial infarction after stimulation with the selective delta(1)-opioid receptor agonist TAN-67. Hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk. TAN-67 significantly reduced infarct size/area at risk (29.6 +/- 3.3) versus control (63. 1 +/- 2.3). The sarcolemmal-selective K(ATP) channel antagonist HMR 1098, administered 10 min before TAN-67, did not significantly attenuate cardioprotection (26.0 +/- 7.3) at a dose (3 mg/kg) that had no effect in the absence of TAN-67 (56.3 +/- 4.3). Pretreatment with the mitochondrial selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before the 30-min occlusion completely abolished TAN-67-induced cardioprotection (54.3 +/- 2.7), but had no effect in the absence of TAN-67 (62.6 +/- 4.1), suggesting the involvement of the mitochondrial K(ATP) channel. Additionally, we examined the antiarrhythmic effects of TAN-67 in the presence or absence of 5-HD and HMR 1098 during 30 min of ischemia. Control animals had an average arrhythmia score of 10.40 +/- 2.41. TAN-67 significantly reduced the arrhythmia score during 30 min of ischemia (2.38 +/- 0. 85). 5-HD and HMR 1098 in the absence of TAN-67 produced an insignificant decrease in the arrhythmia score (8.80 +/- 2.56 and 4. 20 +/- 1.07, respectively). 5-HD administration before TAN-67 treatment abolished its antiarrhythmic effect (4.71 +/- 1.11). However, HMR 1098 did not abolish TAN-67-induced protection against arrhythmias (1.67 +/- 0.80). These data suggest that delta(1)-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial K(ATP) channel in mediating these cardioprotective effects.

• Authors: R M Fryer, A K Hsu, H Nagase, G J Gross
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 294 Issue 2 Pg. 451-7 (Aug 2000) ISSN: 0022-3565 [Print] United States
• PMID: 10900218 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Analgesics, Opioid
• Anti-Arrhythmia Agents
• Benzamides
• Decanoic Acids
• Hydroxy Acids
• Potassium Channel Blockers
• Potassium Channels
• Quinolines
• Receptors, Opioid, delta
• TAN 67
• 5-hydroxydecanoic acid
• Adenosine Triphosphate
• HMR 1098

Topics

• Adenosine Triphosphate (physiology)
• Analgesics, Opioid (antagonists & inhibitors, therapeutic use)
• Animals
• Anti-Arrhythmia Agents (antagonists & inhibitors, pharmacology)
• Arrhythmias, Cardiac (prevention & control)
• Benzamides (pharmacology)
• Blood Pressure (drug effects)
• Decanoic Acids (pharmacology)
• Drug Interactions
• Heart Rate (drug effects)
• Hydroxy Acids (pharmacology)
• Male
• Mitochondria, Heart (drug effects, physiology)
• Myocardial Infarction (prevention & control)
• Myocardial Ischemia (complications)
• Myocardial Reperfusion Injury (prevention & control)
• Potassium Channel Blockers
• Potassium Channels (drug effects, physiology)
• Quinolines (antagonists & inhibitors, therapeutic use)
• Rats
• Rats, Wistar
• Receptors, Opioid, delta (agonists)
• Sarcolemma (drug effects, physiology)
• Ventricular Fibrillation (prevention & control)