Eribis peptide 94 reduces infarct size in rat hearts via activation of centrally located μ opioid receptors. J Cardiovasc Pharmacol 2012 Feb;59(2):194-7
Date
12/02/2011Pubmed ID
22130105Pubmed Central ID
PMC3275682DOI
10.1097/FJC.0b013e318241e8c7Scopus ID
2-s2.0-84857060184 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
Eribis peptide 94 (EP 94) is a novel enkephalin derivative that binds with high potency to μ and δ opioid receptors with less affinity for the κ opioid receptor. This compound has recently been shown to produce an acute reduction in myocardial infarct size in the anesthetized pig and rat partially via an endothelial nitric oxide synthase and KATP channel-dependent mechanism. EP 94 also was found to produce a chronic reduction in infarct size 24 hours postdrug administration via the upregulation of inducible nitric oxide synthase in rats. Despite these findings, no data have emerged in which the opioid receptor subtype responsible for cardioprotection has been identified and the site of action, heart, other peripheral organs, or the central nervous system, has not been addressed. In the current study, EP 94, was administered in 2 divided doses (0.5 μg/kg, intravenously) at 5 and 10 minutes into the ischemic period, and the opioid antagonists were administered 10 minutes before the onset of the 30-minute ischemic period. The selective antagonists used were the μ receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), the δ receptor antagonists naltrindole and BNTX (7-benzylidenenaltrexone), and the κ receptor antagonist nor-BNI (norbinaltorphimine). Surprisingly, only CTOP completely blocked the cardioprotective effect of EP 94, whereas naltrindole, BNTX, and nor-BNI had modest but nonsignificant effects. Because there is controversial evidence suggesting that μ receptors may be absent in the adult rat myocardium, it was hypothesized that the protective effect of EP 94 may be mediated by an action outside the heart, perhaps in the central nervous system. To test this hypothesis, rats were pretreated with the nonselective opioid antagonist, naloxone hydrochloride, which penetrates the blood-brain barrier or naloxone methiodide, the quaternary salt of naloxone hydrochloride, which does not penetrate the blood-brain barrier before EP 94 administration. In support of a central nervous system site of action for EP 94, naloxone hydrochloride completely blocked its cardioprotective effect, whereas naloxone methiodide had no effect. These results suggest that EP 94 reduces infarct size (expressed as a percent of the area at risk) in the rat primarily via activation of central μ opioid receptors.
Author List
Gross GJ, Hsu A, Nithipatikom K, Bobrova I, Bissessar EMESH terms used to index this publication - Major topics in bold
AnimalsBlood-Brain Barrier
Cardiotonic Agents
Enkephalins
Male
Myocardial Infarction
Narcotic Antagonists
Rats
Rats, Sprague-Dawley
Receptors, Opioid, mu
