Morphine mimics preconditioning via free radical signals and mitochondrial K(ATP) channels in myocytes.

Abstract

BACKGROUND:

We tried to determine whether morphine mimics preconditioning (PC) to reduce cell death in cultured cardiomyocytes and whether opioid delta(1) receptors, free radicals, and K(ATP) channels mediate this effect.

METHODS AND RESULTS:

Chick embryonic ventricular myocytes were studied in a flow-through chamber while flow rate, pH, and O(2) and CO(2) tension were controlled. Cardiomyocyte viability was quantified with propidium iodide (5 micromol/L), and production of free radicals was measured with 2',7'-dichlorofluorescin diacetate. PC with 10 minutes of simulated ischemia before 10 minutes of reoxygenation or morphine (1 micromol/L) or BW373U86 (10 pmol/L) infusion for 10 minutes followed by a 10-minute drug-free period before 1 hour of ischemia and 3 hours of reoxygenation reduced cell death to the same extent (*P:<0.05) (PC, 20+/-1%, n=7*; morphine, 32+/-4%, n=8*; BW373U86, 21+/-6%; controls, 52+/-5%, n=8). Like PC, morphine and BW373U86 increased free radical production 2-fold before ischemia (0.35+/-0.10, n=6*; 0.41+/-0.08, n=4* versus controls, 0.15+/-0.05, n=8, arbitrary units). Protection and increased free radical signals during morphine infusion were abolished with either the thiol reductant 2-mercaptopropionyl glycine (400 micromol/L), an antioxidant; naloxone (10 micromol/L), a nonselective morphine receptor antagonist; BNTX (0.1 micromol/L), a selective opioid delta(1) receptor antagonist; or 5-hydroxydecanoate (100 micromol/L), a selective mitochondrial K(ATP) channel antagonist.

CONCLUSIONS:

These results suggest that direct stimulation of cardiocyte opioid delta(1) receptors leads to activation of mitochondrial K(ATP) channels. The resultant increase of intracellular free radical signals may be an important component of the signaling pathways by which morphine mimics preconditioning in cardiomyocytes.

• Authors: B C McPherson, Z Yao
• Journal: Circulation (Circulation) Vol. 103 Issue 2 Pg. 290-5 (Jan 16 2001) ISSN: 0009-7322 [Print] United States
• PMID: 11208691 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Decanoic Acids
• Free Radicals
• Hydroxy Acids
• Narcotic Antagonists
• Potassium Channel Blockers
• Potassium Channels
• Protein Isoforms
• Receptors, Opioid, delta
• Naloxone
• 5-hydroxydecanoic acid
• Morphine
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Cell Death
• Cells, Cultured
• Chick Embryo
• Decanoic Acids (pharmacology)
• Free Radicals (metabolism)
• Heart Ventricles
• Hydroxy Acids (pharmacology)
• Intracellular Membranes (metabolism)
• Ischemic Preconditioning, Myocardial
• Mitochondria, Heart (metabolism)
• Morphine (pharmacology)
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Naloxone (pharmacology)
• Narcotic Antagonists (pharmacology)
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (metabolism)
• Protein Isoforms (metabolism)
• Receptors, Opioid, delta (metabolism)