Sabiporide reduces ischemia-induced arrhythmias and myocardial infarction and attenuates ERK phosphorylation and iNOS induction in rats.

Abstract

The aim of the present study was to investigate the effects of sabiporide, a potent and selective NHE1 inhibitor, on myocardial ischemia-induced arrhythmias and myocardial infarction and the possible pathways related to the cardioprotection afforded by sabiporide treatment. Anesthetized rats were subjected to myocardial ischemia via left main coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Administration of sabiporide (0.01-3.0 mg/kg) prior to coronary artery occlusion dose-dependently reduced ischemia-induced arrhythmias and infarct size with an ED50 value of 0.14 mg/kg. Administration of sabiporide (1.0 mg/kg) prior to reperfusion also reduced infarct size by 38.6%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase and troponin I. In addition, sabiporide (1.0 mg/kg) given prior to coronary artery occlusion or immediately before reperfusion significantly reduced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and the expression of the inducible nitric oxide synthase (iNOS) following myocardial ischemia-reperfusion. This study demonstrates that sabiporide is a potent and effective cardioprotective agent during myocardial ischemia and reperfusion, by reducing serious ventricular arrhythmias and myocardial infarct size. The cardioprotection afforded by sabiporide is attributed in part to inhibition of ERK1/2 phosphorylation and suppression of iNOS expression.

• Authors: Henri Doods, Dongmei Wu
• Journal: BioMed research international (Biomed Res Int) Vol. 2013 Pg. 504320 ( 2013) ISSN: 2314-6141 [Electronic] United States
• PMID: 23484128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Guanidines
• Muscle Proteins
• Slc9a1 protein, rat
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Mitogen-Activated Protein Kinase 3
• sabiporide

Topics

• Animals
• Arrhythmias, Cardiac (enzymology, etiology, pathology, prevention & control)
• Cardiotonic Agents (pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Enzymologic (drug effects)
• Guanidines (pharmacology)
• Mitogen-Activated Protein Kinase 3 (biosynthesis)
• Muscle Proteins (biosynthesis)
• Myocardial Infarction (complications, enzymology, pathology, prevention & control)
• Myocardial Reperfusion Injury (complications, enzymology, pathology, prevention & control)
• Nitric Oxide Synthase Type II (biosynthesis)
• Phosphorylation (drug effects)
• Rats
• Rats, Wistar
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)