Antiarrhythmic activity of the antiopioid peptide nociceptin and its effect on the fast Na+ channels in cardiomyocytes

Abstract

The antiopioid peptide nociceptin does not affect heart resistance to the proarrhythmic effect of epinephrine or calcium chloride, but it produces an antiarrhythmic effect in the aconitine arrhythmia model. Nociceptin prolongs the QRS interval and does not affect heart rate and duration of the RQ interval. The antiarrhythmic effect of nociceptin is not related to changes in the tone of the autonomic nervous system. Nociceptin is supposed to block fast Na + channels in cardiomyocytes. Key Words: nociceptin; arrhythmias; fast Na § channelsEndogenous opioid neuropeptides play an important role in the regulation of cardiovascular system [2]. Stimulation of opiate receptors may enhance cardiac tolerance to proarrhythmic influences [3,7,9]. Functional antagonists of opioid peptides (cholecystokinin, FMRF-peptide, neuropeptide FF etc.) were found in humans and animals. They do not directly affect the opiate receptors, but produce effects that are opposite to those of opioids on the cardiovascular system [4]. The family of "antiopioids" was recently enlarged by another peptide, nociceptin (NC or orphanin FQ) [8,10]. The specific opioid receptor-like (ORL) receptors for this peptides are linked to adenylate cyclase via G-proteins [8,10]. The interaction of NC with adenylate cyclase inhibits the synthesis of cAMP [8,10], which is an endogenous proarrhythmic factor [6]. It is probable that NC-induced decrease of cAMP level enhances the electrical stability of the heart. However, the opioid peptides are also known to produce an antiarrhythmic effect [2]. To resolve this contradiction, we studied the effect of NC on the heart tolerance to proarrhythmic factors. Department of Experimental Cardiology, Institute oI Cardiology, Siberian Division of the Russian Academy of Medical Sciences, Tomsk MATERIALS AND METHODSExperiments were carried out on male Wistar rats weighing 180-200 g in which arrhythmias were provoked by intravenous epinephrine (100 9g/kg) or CaCI 2 (100 mg/kg) under light ether anesthesia. The ECG was recorded in the second standard lead (V 2) during the first 5 minutes postinjection. It was processed to obtain the incidence rates of ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation.In one experimental series arrhythmias were produced by intravenous aconitine (50 gg/kg, Sigma). To this end, aconitine (1 mg) was suspended in Tween-80 (20 ml) and mixed with 20 ml 0.9% NaCI. The suspension was administered in a dose of 1 ml/kg. The latent period from injection to the appearance of ventricular arrhythmia was documented.The agonist of ORL receptors NC (Phe-Gly-GlyPhe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Ser-AlaArg-Lys-Leu-Ala-Asp-Cln), was synthesized at the Institute of Molecular Pharmacology (Berlin). It was dissolved extempore in isotonic NaC1 solution and injected intravenously (0.1-0.4 mg/kg) 10 min prior to a proarrhythmic agent. In one experimental series the rats were injected intravenously with hexamethonium (10 mg/kg, Sigma), a blocker of peripheral autonomic ganglia.

Comparative Analysis of the Cardioprotective Properties of Opioid Receptor Agonists in a Rat Model of Myocardial Infarction

“…The choice of doses of OR ligands has been guided by 1) results from our preliminary experiments with the nonselective peptide OR agonist dalargin (H‐Tyr‐ d‐ Ala‐Gly‐Phe‐Leu‐Arg‐OH), which exhibited an antifibrillatory effect during coronary artery ligation at a dose of 150 nmol/kg; 15,16 2) our experiments with other OR ligands; 17,18 and 3) data from other investigators 7,9,19 . Therefore, all opioid peptides with the exception of nociceptin (orphinan FQ‐Phe‐Gly‐Gly‐Phe‐Thr‐Gly‐Ala‐Arg‐Lys‐Ser‐Ala‐Arg‐Lys‐Leu‐Ala‐Asn‐Gln), dermorphin‐H (Tyr‐ d‐ Ala‐Phe‐Gly‐Tyr‐Pro‐Ser‐Gly‐Glu‐Ala‐Lys‐Lys‐Ile‐NH 2 ), deltorphin‐D variant , and deltorphin‐E (Tyr‐ d‐ Ala‐Phe‐Ala‐Ile‐Gly‐Asp‐Phe‐Ser‐Ile‐NH 2 ) were used at doses of 150 and 1500 nmol/kg.…”

“…The endogenous ORL1, nociceptin, 27 was infused at doses of 0.4 mg/kg (220 nmol/kg) and 2.7 mg/kg (1500 nmol/kg). The choice of the first dose of nociceptin was guided by results from preliminary experiments showing that this peptide at 0.4 mg/kg could delay an appearance of aconitine‐induced arrhythmias 17 . All infusions were blinded.…”