A novel secretagogue increases cardiac contractility by enhancement of L-type Ca2+ current.
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.
Su
Zhi
Z
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. zhi.su@abbott.com
Widomski
Deborah L
DL
Liu
Xiaoqin
X
Limberis
James T
JT
Green
Jonathon
J
Diaz
Gilbert
G
Martin
Ruth L
RL
Cox
Bryan F
BF
Gintant
Gary A
GA
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008297:Male; D032342:Muscle Cells / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D052216:Glucagon-Like Peptide 1; D002118:Calcium