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Morphine preconditioning attenuates neutrophil activation in rat models of myocardial infarction
1Department of Emergency Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. M002183@ms.skh.org.tw
Abstract:
Previous results from our laboratory have suggested that morphine can attenuate neutrophil activation in patients with acute myocardial infarction. To elucidate if morphine preconditioning (PC) has the same effects via activation of neutrophil endopeptidase 24.11 (NEP), we measured serum levels of intercellular adhesion molecule-1 (ICAM-1), gp100MEL14 and NEP in adult Wistar rats subjected to ten different protocols (n = 10 for each) at baseline, immediately after and 2 h after morphine PC. All groups were subjected to 30 min of occlusion and 2 h of reperfusion. Similarly, morphine-induced PC was elicited by 3-min drug infusions (100 micrograms/kg) interspersed with 5-min drug-free periods before the prolonged 30-min occlusion. Infarct size (IS), as a percentage of the area at risk (AAR), was determined by triphenyltetrazolium staining. Pretreatment with morphine increased NEP activities (9.86 +/- 1.98 vs. 5.12 +/- 1.10 nmol/mg protein in control group; p < 0.001). Naloxone (mu-opioid receptor antagonist) (4.82 +/- 1.02 nmol/mg protein) and phosphoramidon (NEP inhibitor) (4.66 +/- 1.00 nmol/mg protein) inhibited morphine-activated NEP, whereas glibenclamide (ATP-sensitive potassium channel antagonist) and chelerythrine (protein kinase C inhibitor) had no effects. The ICAM-1 and gp100MEL14 of the third sampling were lowest for those with morphine PC (280 +/- 30 ng/ml and 2.2 +/- 0.7 micrograms/ml; p < 0.001), but naloxone (372 +/- 38 ng/ml and 3.8 +/- 0.9 micrograms/ml) and phosphoramidon (382 +/- 40 ng/ml and 4.2 +/- 1.1 micrograms/ml) abolished the above phenomenon. IS/AAR were definitely lowest for those with morphine PC (24 +/- 7%; p < 0.05). Morphine preconditioning increases NEP activities to attenuate shedding of gp100MEL14 and to ICAM-1 and, thus, provides myocardial protection.
Insights
Morphine preconditioning (PC) activates neutrophil endopeptidase 24.11 (NEP), reducing inflammatory markers and infarct size in myocardial infarction models. This protective effect is mediated by NEP activation, offering potential therapeutic benefits.
Area of Science:
- Cardiology
- Pharmacology
- Immunology
Background:
- Previous research suggests morphine attenuates neutrophil activation in acute myocardial infarction.
- Neutrophil activation plays a critical role in myocardial ischemia-reperfusion injury.
Purpose of the Study:
- To investigate if morphine preconditioning (PC) protects against myocardial infarction by activating neutrophil endopeptidase 24.11 (NEP).
- To elucidate the specific mechanisms underlying morphine's cardioprotective effects.
Main Methods:
- Adult Wistar rats underwent 30 minutes of occlusion and 2 hours of reperfusion following various preconditioning protocols.
- Morphine-induced PC involved drug infusions prior to ischemia.
- Serum levels of intercellular adhesion molecule-1 (ICAM-1), gp100MEL14, and NEP activity were measured.
- Infarct size (IS) as a percentage of the area at risk (AAR) was determined.
- Specific antagonists (naloxone, phosphoramidon, glibenclamide, chelerythrine) were used to probe the involvement of opioid receptors, NEP, and potassium channels.
Main Results:
- Morphine PC significantly increased NEP activity compared to controls.
- Naloxone and phosphoramidon inhibited morphine-induced NEP activation.
- Morphine PC led to the lowest levels of ICAM-1 and gp100MEL14.
- The reduction in ICAM-1 and gp100MEL14 was abolished by naloxone and phosphoramidon.
- Morphine PC resulted in the smallest infarct size relative to the area at risk.
- Glibenclamide and chelerythrine did not affect morphine-induced NEP activation or cardioprotection.
Conclusions:
- Morphine preconditioning enhances myocardial protection through the activation of NEP.
- This activation attenuates the shedding of gp100MEL14 and reduces ICAM-1 levels, thereby mitigating ischemia-reperfusion injury.
- The findings highlight a novel therapeutic pathway involving NEP for managing myocardial infarction.