Abstract
We examined the role of the sarcolemmal and mitochondrial ATP-sensitive potassium (KATP) channel in a rat model of myocardial infarction after stimulation with the selective δ1-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 KATP 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 KATP 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 δ1-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial KATP channel in mediating these cardioprotective effects.
Footnotes
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Send reprint requests to: Garrett J. Gross, Ph.D., Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226-3548.
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↵1 This study was funded in part by a predoctoral research grant from the American Heart Association (to R.M.F.) and National Institutes of Health Grant HL08311 (to G.J.G.).
- Abbreviations:
- KATP
- ATP-sensitive potassium channel
- PKC
- protein kinase C
- IPC
- ischemic preconditioning
- MAP
- mitogen-activated protein
- 5-HD
- 5-hydroxydecanoic acid
- IS
- infarct size
- AAR
- area at risk
- TTC
- triphenyltetrazolium chloride
- IS/AAR
- IS expressed as a percentage of AAR
- PVC
- premature ventricular contraction
- VF
- ventricular fibrillation
- LV
- left ventricular weight
- MBP
- mean arterial blood pressure
- BTXN
- 7-benzylidenenaltrexone
- Received February 29, 2000.
- Accepted April 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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