n-methylnaloxone and Myocardial-Infarction

Both central and peripheral opioid receptors activation produce cardioprotection. This study investigates the role of central and peripheral opioid receptors in intravenous morphine preconditioning (MPC) and ischemic preconditioning (IPC).. Sixty-five anesthetized, open chests, male Sprague-Dawley rats were assigned to one of nine groups after intrathecal catheter placement. IPC was induced by three cycles of intermittent occlusion of left anterior descending artery (5 min occlusion interspersed with 5 min of reperfusion). MPC was induced by three consecutive intravenous infusions of 100 μg/kg morphine over five minutes. The opioid receptors antagonist naloxone methiodide (NM), was intravenously or intrathecally, at a dose of 20 mg/kg or 20 μg/kg, given 10 min before IPC or MPC (IVNM + IPC, ITNM + IPC, IVNM + MPC, ITNM +MPC). Control group (CON) and intravenously or intrathecally administered NM (IVNM, ITNM) were used as negative controls, respectively. All hearts were subjected to 30 min of ischemia follow by 2 h of reperfusion. Infarct size, as a percentage of the area at risk, was determined by 2, 3, 5-triphenyltetrazolium staining. Heart rate and mean arterial blood pressure were monitored.. The infarct size was significantly reduced in the IPC and MPC groups compared with control. The additional of intravenous or intrathecal NM both reversed the cardioprotective effects of MPC. In comparison only intravenous administration of NM before IPC could attenuate the cardioprotection.. MPC could mimic IPC, produce a similar cardioprotective effect. Both central and peripheral opioid receptors mediate in the cardioprotection of MPC, however, only peripheral opioid receptors in IPC.

Topics: Animals; Ischemic Preconditioning, Myocardial; Male; Morphine; Myocardial Infarction; Myocardial Reperfusion Injury; Naloxone; Narcotic Antagonists; Narcotics; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid

Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine and ischemic preconditioning (IPC). We investigated the relative role of central versus peripheral opioid receptors in intrathecal morphine preconditioning (ITMPC).. Forty-eight anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 7 treatment groups (n = 6-7) after successful intrathecal catheter placement. ITMPC was achieved by 3 consecutive 5-min intrathecal infusions of morphine (1.0 microg/kg each). This was repeated in the presence of either IV (IV naloxone methiodide + ITMPC) or intrathecally (intrathecal naloxone methiodide [ITNM] + ITMPC) administered naloxone methiodide. This compound was also given via these same routes in the absence of ITMPC (IV naloxone methiodide + ITNM). Intrathecal normal saline and IPC were used as negative and positive controls, respectively. Myocardial ischemia and reperfusion injury were induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size, as a percentage of the area-at-risk, was determined by 2,3,5-triphenyltetrazolium staining.. The infarct size/area-at-risk were significantly reduced in the IPC (22% +/- 3%) and ITMPC (26% +/- 5%) groups compared with the control group (48% +/- 9%) (P < 0.01). The addition of ITNM reversed the cardioprotective effects of ITMPC (45% +/- 4%), whereas IV administration of the drug did not have any effect on ITMPC (28% +/- 9%, P < 0.01).. Intrathecally administered morphine can produce cardioprotective effects via the activation of central opioid receptors, without the apparent involvement of peripheral opioid receptors.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Cardiotonic Agents; Coronary Vessels; Heart Rate; Injections, Spinal; Ischemic Preconditioning, Myocardial; Male; Morphine; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid

The effects of the selective delta-1 (delta(1)) opioid receptor agonist, DPDPE, and the selective delta(2) opioid receptor agonist, DSLET, have been studied on the ventricular fibrillation threshold (VFT) in rats with an experimental post-infarction cardiosclerosis (CS). It has been found that CS induced a significant decrease in VFT. This CS-induced decrease in VFT was significantly reversed by intravenous administration of DPDPE (0.1 mg/kg) 10 min before VFT measurement. On the contrary, intravenous injection of DSLET (0.5 mg/kg) exacerbated the CS-induced cardiac electrical instability. Pretreatment with the selective delta opioid receptor antagonist, ICI 174,864 (0.5 mg/kg), completely abolished the changes in VFT produced by both DPDPE and DSLET. Previous administration of a nonselective peripherally acting opioid receptor antagonist, naloxone methiodide (5 mg/kg) also completely reversed the antifibrillatory action of DPDPE. Naloxone methiodide and ICI 174,864 alone had no effect on VFT. Pretreatment with the nonselective K(ATP) channel blocker, glibenclamide (0.3 mg/kg), or with the mitochondrial selective K(ATP) channel blocker, 5-hydroxydecanoic acid (5-HD, 5 mg/kg), completely abolished the DPDPE-induced increase in cardiac electrical stability. Glibenclamide and 5-HD alone had no effect on VFT. These results demonstrate that the delta opioid receptor plays an important role in the regulation of electrical stability in rats with post-infarction cardiosclerosis. We propose that peripheral delta(1) opioid receptor stimulation reverses CS-induced electrical instability via mitochondrial K(ATP) channels. On the contrary, delta(2) opioid receptor stimulation may exacerbate the CS-induced decrease in VFT. Further studies are necessary to determine the delta opioid receptor subtype which mediates the antifibrillatory effect of DPDPE and pro-fibrillatory effect of DSLET.

Topics: Adenosine Triphosphate; Analgesics, Opioid; Animals; Decanoic Acids; Disease Models, Animal; Drug Antagonism; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Glyburide; Hydroxy Acids; Male; Mitochondria, Heart; Myocardial Infarction; Myocardium; Naloxone; Potassium Channels; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid, delta; Sclerosis; Ventricular Fibrillation

It has been shown that mu-opioid receptor stimulation by intravenous administration of the selective mu receptor agonist DALDA in a dose of 0.1 mg/kg prevented ischemic and reperfusion arrhythmias in rats subjected to coronary artery occlusion (10 min) and reperfusion (10 min), and also increased the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis. These effects were abolished by pre-treatment with the selective mu receptor antagonist CTAP in a dose of 0.5 mg/kg or by prior injection of the opioid receptor antagonist naloxone methiodide (2 mg/kg) which does not penetrate the blood-braib barrier. Both antagonists by themselves had no effect on the incidence of occlusion or reperfusion-induced arrhythmias or on the ventricular fibrillation threshold. Pre-treatment with ATP-sensitive K+ channel (KATP channel) blocker glibenclamide in a dose of 0.3 mg/kg completely abolished the antiarrhythmic effect of DALDA. We believe that DALDA prevents occurrence of electrical instability during ischemia and reperfusion and increases the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis via stimulation of peripheral mu-opioid receptor which appear to be coupled to the KATP channel.

Topics: Animals; Electrocardiography; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Naloxone; Oligopeptides; Peptide Fragments; Peptides; Potassium Channels; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid, mu; Sclerosis; Somatostatin

Previously, our laboratory has shown that opioid receptors are involved in ischemic preconditioning (PC) in the intact rat heart; however, it is not known whether this cardioprotection is mediated by central or peripheral mechanisms. To test this hypothesis, both naloxone (NL), the non-selective opioid receptor antagonist and naloxone methiodide (QNL), its quaternary derivative which does not cross the blood-brain barrier, were used to determine if opioid receptor-induced myocardial protection occurs via a central or peripheral locus of action in inactin-anesthetized, open-chested, Wistar rats. In group I, the control group was subjected to 30 min of occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, QNL (10 mg/kg, i.v.) was administered 10 min before the 30 min of occlusion. Groups IV and V consisted of a dose-response effect of QNL on ischemic PC in which QNL (0.3 or 10 mg/kg, i.v., respectively) was given 10 min prior to ischemic PC. In addition, in groups VI and VII, one of two doses of naloxone (1 or 3 mg/kg, i.v.) was administered 10 min before ischemic PC. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by tetrazolium staining. Ischemic PC reduced IS to 9 +/- 2% (P < 0.05) v control (53 +/- 4%). The low dose of QNL partially blocked the cardioprotective effect of ischemic PC; whereas the high dose completely abolished its cardioprotective effect. The high dose of QNL had no effect on IS alone. Similarly, the low dose of NL did not antagonize the cardioprotective effect of ischemic PC; however, the high dose completely abolished ischemic PC. These results indicate that the cardioprotective effect of ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart.

Topics: Animals; Heart; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Molecular Structure; Myocardial Infarction; Myocardium; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid