n-methylnaloxone and tyrosyl-arginyl-phenylalanyl-lysinamide

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

We previously reported that i.v. DAMGO (Tyr-D-Ala-Gly-NMePhe-Gly-ol), a selective mu-opioid agonist, causes an increase in blood pressure with no change in heart rate in unanesthetized sheep and subsequently demonstrated that DAMGO attenuates baroreflex-mediated bradycardia. To determine the site and mechanism by which mu-agonists inhibit baroreflex sensitivity, we have carried out further investigations by using DAMGO and another mu-agonist, DALDA (Tyr-D-Arg-Phe-Lys-NH2). The bradycardic response to norepinephrine (NE) was significantly blunted after i.v. DAMGO or DALDA in both nonpregnant and pregnant sheep. In contrast, the tachycardic response to sodium nitroprusside (SNP) remained unchanged in the presence of DAMGO or DALDA. In view of the highly restricted distribution of DALDA across the blood-brain barrier (BBB), we hypothesized that the blunting of reflex-mediated bradycardia by mu-opioid agonists can occur peripherally. Pretreatment with the quaternary opioid antagonist, naloxone methiodide (NM), completely blocked the attenuation of baroreflex sensitivity by DAMGO and DALDA in both nonpregnant and pregnant animals. These data suggest that in addition to central mechanisms, mu-opioid agonists can inhibit baroreflex sensitivity at a peripheral site, most likely by inhibiting vagal influence on heart-rate control rather than by acting directly at baroreceptors.

Topics: Animals; Anti-Arrhythmia Agents; Baroreflex; Bradycardia; Catheters, Indwelling; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Naloxone; Narcotic Antagonists; Nitroprusside; Norepinephrine; Oligopeptides; Pregnancy; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Sheep

We sought to test the hypothesis that an intravenous dose of H-Tyr-D-Arg-Phe-Lys-NH2, a highly mu-receptor selective opioid peptide, suppresses baroreflex sensitivity through a peripheral mechanism.. A transient change in mean arterial pressure was produced in chronically instrumented pregnant ewes by norepinephrine or sodium nitroprusside in the absence or in the presence of H-Tyr-D-Arg-Phe-Lys-NH2, a highly mu-selective opioid peptide. In some studies naloxone methiodide, a peripheral opioid antagonist, was infused starting 60 minutes before the administration of H-Tyr-D-Arg-Phe-Lys-NH2 and maintained for a total of 90 minutes. Linear plots were obtained when the changes in mean arterial pressure during the pressure rise were plotted against the changes in heart rate and the sensitivity of the baroreflex was derived as the slope of the linear regression line.. We observed (1) lower baroreflex sensitivity after H-Tyr-D-Arg-Phe-Lys-NH2 administration with a hypertensive stimulus; (2) unchanged baroreflex sensitivity after H-Tyr-D-Arg-Phe-Lys-NH2 administration with a hypotensive stimulus; and (3) unchanged baroreflex sensitivity after H-Tyr-D-Arg-Phe-Lys-NH2 administration with a hypertensive stimulus in the presence of naloxone methiodide.. H-Tyr-D-Arg-Phe-Lys-NH2 suppresses the hypertensive but not the hypotensive arm of the baroreflex through peripheral opioid receptors. These results suggest that mu-opioid receptors are present in the vagus nerves and that the activation of these opioid receptors inhibits reflex bradycardia in pregnant sheep.

Topics: Animals; Baroreflex; Blood Pressure; Bradycardia; Female; Heart Rate; Naloxone; Nitroprusside; Norepinephrine; Oligopeptides; Pregnancy; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Sheep; Tachycardia