Document Detail


A novel secretagogue increases cardiac contractility by enhancement of L-type Ca2+ current.
MedLine Citation:
PMID:  20599796     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
N'1-(3,3,6,8-tetramethyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yliden)-2-cyanoethanohydrazide (TTYC) increases secretion of glucagon-like peptide-1 and intracellular Ca(2+) concentration in GLUTag cells. The purpose of the present study was to examine if TTYC exerts positive inotropic effects on isolated rabbit ventricular myocytes and in vivo heart in anesthetized rats, and if so to further define the potential mechanism of action. Contractility was assessed in vitro using changes in fractional shortening (FS) of myocyte sarcomere length and in vivo using changes in the velocity of left ventricular pressure. Changes in L-type Ca(2+) current of ventricular myocytes were evaluated using whole-cell voltage-clamp techniques. TTYC increased FS of myocyte sarcomere length in a concentration-dependent manner. The positive inotropic effect was not abrogated by beta-adrenergic blockade (propranolol) or protein kinase A inhibition. TTYC enhanced peak L-type Ca(2+) current in a voltage-dependent manner (current amplitudes increased by 4.0-fold at -10 mV and 1.5-fold at +10 mV). Voltage-dependence of steady-state activation of L-type Ca(2+) current was shifted by 15 mV in the negative direction. Inactivation time course of the L-type Ca(2+) currents at voltages of -10 to 20 mV was significantly slowed by 0.3 microM TTYC. In vivo studies demonstrated that TTYC increased cardiac contractility in a dose-dependent manner. In conclusion, TTYC is a novel L-type Ca(2+) current activator with positive cardiac inotropic effects. Negative shifting of the voltage-dependence of L-type Ca(2+) current activation and reduced inactivation are two mechanisms responsible for the enhanced L-type Ca(2+) current that contribute to the positive inotropic effects.
Authors:
Zhi Su; Deborah L Widomski; Xiaoqin Liu; James T Limberis; Jonathon Green; Gilbert Diaz; Ruth L Martin; Bryan F Cox; Gary A Gintant
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Publication Detail:
Type:  Journal Article     Date:  2010-06-22
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-08-17     Completed Date:  2010-09-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1000-6     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. zhi.su@abbott.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*,  pharmacology
Glucagon-Like Peptide 1 / metabolism,  pharmacology
Heart / drug effects
Male
Muscle Cells / metabolism
Myocardial Contraction / drug effects*,  physiology
Myocytes, Cardiac / cytology,  drug effects,  metabolism
Patch-Clamp Techniques
Rabbits
Rats
Rats, Sprague-Dawley
Chemical
Reg. No./Substance:
7440-70-2/Calcium; 89750-14-1/Glucagon-Like Peptide 1

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