Document Detail

Effects of cardioselective KATP channel antagonism on basal, stimulated, and ischaemic myocardial function in in vivo failing canine heart.
MedLine Citation:
PMID:  11834613     Owner:  NLM     Status:  MEDLINE    
Inhibition of cardiomyocyte-specific ATP-sensitive potassium (K(ATP)) channels prolongs the action potential during intense ischaemia with attendant antiarrhythmic effects. However, this is accompanied by contractile depression in some models. These changes may be particularly troublesome in dilated cardiomyopathic hearts that display basal systolic dysfunction, limited energy reserve, and prolonged repolarization favouring arrhythmia. Mechanical effects of selective myocyte K(ATP) channel blockade on basal, beta-adrenergic stimulated, and ischemic responses were therefore tested in dogs with cardiac failure induced by tachypacing. Cardiovascular function was assessed by pressure - dimension relationships in 10 conscious, chronically instrumented dogs (sonomicrometry/micromanometry), with or without cardiac failure. Cardiomyocyte K(ATP) channels were inhibited by HMR 1098, and data obtained under basal conditions, during epinephrine infusion to raise metabolic demand, during regional ischaemia, and with combined ischaemia+epinephrine. HMR 1098 had no effect on baseline cardiac function nor did it induce arrhythmia in normal or failing hearts. Epinephrine raised cardiac work 65% and oxygen consumption 55%, yet HMR 1098 had no functional effect in either heart condition. Regional ischaemia with or without epinephrine co-stimulation depressed regional and global function, yet both were also unaffected by HMR 1098. There was minimal arrhythmia without HMR 1098, and drug infusion did not alter this. Thus, myocyte-K(ATP) channels play a negligible role modulating intact in vivo cardiac contraction or arrhythmia in normal and failing heart with and without increased metabolic demand and/or regional ischaemia. This supports the feasibility of administering such agents to depressed hearts, despite underlying contractile and electrophysiologic abnormalities.
Walter F Saavedra; Nazareno Paolocci; David A Kass
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  British journal of pharmacology     Volume:  135     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2002 Feb 
Date Detail:
Created Date:  2002-02-08     Completed Date:  2002-05-20     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  657-62     Citation Subset:  IM    
Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions Baltimore, Maryland 21287, USA.
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MeSH Terms
Benzamides / pharmacology,  therapeutic use
Cardiotonic Agents / pharmacology,  therapeutic use
Electrocardiography / drug effects
Heart Failure / drug therapy,  metabolism*,  physiopathology*
Myocardial Ischemia / drug therapy,  metabolism*,  physiopathology*
Potassium Channel Blockers*
Potassium Channels / physiology
Grant Support
P50-52307//PHS HHS
Reg. No./Substance:
0/Benzamides; 0/Cardiotonic Agents; 0/HMR 1098; 0/Potassium Channel Blockers; 0/Potassium Channels

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