Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-associated ventricular arrhythmias via PKC-dependent mechanism in rats.

Abstract

BACKGROUND AND PURPOSE:

Evidence indicates nociceptin/orphanin FQ (N/OFQ) may participate in the pathology of cardiac arrhythmias associated with myocardial infarction. But the role of N/OFQ in the arrhythmogenesis in acute myocardial infarction is unclear. The aim of this study was to investigate the effects of endogenous N/OFQ on infarction-associated arrhythmias.

EXPERIMENTAL APPROACH:

The expression of N/OFQ, PKC activity and ventricular arrhythmias in presence and absence of UFP-101, a specific antagonist of N/OFQ receptor, were examined following permanent coronary artery occlusion in anaesthetized rats. The effect of N/OFQ on action potential duration was examined in isolated rat cardiomyocytes.

KEY RESULTS:

It was observed that N/OFQ was increased by 41% in the myocardium after coronary artery occlusion (P < 0.01 vs. control). Pretreatment with UFP-101 (10(-7)  mol·kg(-1) , i.v.) reduced the incidence of ventricular ectopic beats by 70% and ventricular tachycardia by 51% respectively (all P < 0.05 vs. control). Meanwhile, PKC activity was elevated in the rats treated with UFP-101 (by 35%, P < 0.05 vs. control). A selective PKC inhibitor, calphostin C, completely abolished the anti-arrhythmic effects of UFP-101 (P < 0.01). N/OFQ (at 10(-11) , 10(-9) and 1 × 10(-7)  mol·L(-1) ) shortened the action potential duration by 3% (P > 0.05), 10% (P < 0.05) and 22% (P < 0.01), respectively, via N/OFQ receptor.

CONCLUSIONS AND IMPLICATIONS:

Antagonism of endogenous N/OFQ produces anti-arrhythmic effects on ventricular arrhythmias in acute myocardial infarction, possibly via modulating PKC activity and action potential of myocytes.

• Authors: Y Han, Z Guo, L L Wang, L Z Zhang, T P Yao
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 3 Pg. 614-23 (Oct 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23869704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
• Anti-Arrhythmia Agents
• Narcotic Antagonists
• Opioid Peptides
• Protein Kinase Inhibitors
• Receptors, Opioid
• Protein Kinase C
• Nociceptin Receptor
• Oprl protein, rat

Topics

• Action Potentials
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Disease Models, Animal
• Male
• Myocardial Infarction (complications, drug therapy, enzymology)
• Myocytes, Cardiac (drug effects, enzymology)
• Narcotic Antagonists
• Opioid Peptides (pharmacology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid (metabolism)
• Signal Transduction (drug effects)
• Tachycardia, Ventricular (enzymology, etiology, prevention & control)
• Time Factors
• Ventricular Premature Complexes (enzymology, etiology, prevention & control)
• Nociceptin Receptor