Document Detail


The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca2+ overload.
MedLine Citation:
PMID:  21658026     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Reduced cardiac contractility has been associated with disrupted myocardial Ca(2+) signalling. The 1,4 benzothiazepine K201 (JTV-519) acts on several Ca(2+) handling proteins and improves cardiac contractility in vivo in a variety of animal models of myocardial dysfunction. However, it is unclear whether this improvement depends on the systemic effects of K201 or if K201 reverses the effects of Ca(2+) dysregulation, regardless of the cause.
EXPERIMENTAL APPROACH: The effect of K201 on cardiac mechanical function was assessed in isolated working hearts from adult rabbits, using a ventricular pressure-volume catheter. In separate experiments, the effect of K201 was investigated in hearts following pharmacologically induced Ca(2+) overload using elevated extracellular [Ca(2+) ] ([Ca(2+) ](o) ) and β-adrenoceptor stimulation.
KEY RESULTS: K201 induced a concentration-dependent decline in systolic function (peak pressure, dP/dt(max) and preload recruitable stroke work), lusitropy (reduced dP/dt(min) and increased end diastolic pressure) and stroke volume, independent of decreased heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol·L(-1) [Ca(2+) ](o) and 150 nmol·L(-1) isoprenaline declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1 µmol·L(-1) K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt(max) and dP/dt(min) .
CONCLUSIONS AND IMPLICATIONS: K201 significantly improved mechanical function of the heart during Ca(2+) overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca(2+) and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo.
Authors:
A Kelly; E B Elliott; R Matsuda; N Kaneko; G L Smith; C M Loughrey
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  165     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-27     Completed Date:  2012-05-15     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1068-83     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / physiology
Cardiotonic Agents / pharmacology*
Heart / drug effects*,  physiology
Male
Myocardial Contraction / drug effects
Myocytes, Cardiac / drug effects,  physiology
Rabbits
Receptors, Adrenergic, beta / physiology
Thiazepines / pharmacology*
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/K201 compound; 0/Receptors, Adrenergic, beta; 0/Thiazepines; 7440-70-2/Calcium
Comments/Corrections

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