Document Detail

Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion.
MedLine Citation:
PMID:  12731455     Owner:  NLM     Status:  MEDLINE    
The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.
B Das; C Sarkar
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Methods and findings in experimental and clinical pharmacology     Volume:  25     ISSN:  0379-0355     ISO Abbreviation:  Methods Find Exp Clin Pharmacol     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-05-06     Completed Date:  2003-12-15     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7909595     Medline TA:  Methods Find Exp Clin Pharmacol     Country:  Spain    
Other Details:
Languages:  eng     Pagination:  97-110     Citation Subset:  IM    
School of Biomedical Engineering, Indian Institute of Technology, Powai, Bombay, India.
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MeSH Terms
Anti-Arrhythmia Agents / adverse effects,  pharmacology*
Antioxidants / metabolism
Arrhythmias, Cardiac / chemically induced,  drug therapy,  prevention & control
Blood Pressure / drug effects
Decanoic Acids / adverse effects,  pharmacology
Heart Rate / drug effects
Hydroxy Acids / adverse effects,  pharmacology
Ion Channel Gating
Membrane Proteins / drug effects*
Myocardial Ischemia / drug therapy*,  pathology
Myocardial Reperfusion Injury / chemically induced,  drug therapy*,  prevention & control
Myocardium / metabolism,  pathology
Nicorandil / adverse effects,  pharmacology*
Oxidative Stress / drug effects
Pinacidil / adverse effects,  analogs & derivatives*,  pharmacology*
Potassium Channel Blockers / adverse effects,  pharmacology
Potassium Channels
Sarcolemma / drug effects,  metabolism
Sulfonamides / adverse effects,  pharmacology
Survival Rate
Thiourea / adverse effects,  analogs & derivatives*,  pharmacology
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Antioxidants; 0/Decanoic Acids; 0/Hydroxy Acids; 0/Membrane Proteins; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/Sulfonamides; 0/mitochondrial K(ATP) channel; 60560-07-8/3-pyridyl pinacidil; 62-56-6/Thiourea; 624-00-0/5-hydroxydecanoic acid; 65141-46-0/Nicorandil; 85371-64-8/Pinacidil; 94301K998R/clamikalant

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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