Faculty Collaboration Database

Comparative cardiac effects of KT-362 and verapamil in isolated heart--correlation to calcium channel current depression. J Cardiovasc Pharmacol 1991 Oct;18(4):594-604

Date

10/01/1991

Pubmed ID

1724538

DOI

10.1097/00005344-199110000-00017

Scopus ID

2-s2.0-0025989138 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Direct cardiac effects of KT-362 (5-[3 [[-2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a drug that may inhibit intracellular calcium mobilization as well as extracellular calcium influx was compared to verapamil. Guinea pig hearts (n = 19) were used to examine the changes in atrial rate, atrioventricular conduction time (AVCT), coronary flow, myocardial oxygen consumption (MVO2), and isovolumetric left ventricular pressure (LVP). Both drugs concentration-dependently and reversibly decreased atrial rate, contractility, and MVO2; AVCT increased during spontaneous rhythm. The increases in AVCT and the incidence of AV dissociation were accentuated during cardiac pacing. Verapamil significantly increased coronary flow, while KT-362 did not. Median effective concentration (EC50) was about 25 times lower for verapamil in depressing LVP and about three times lower in depressing atrial rate and AV conduction. The changes in calcium channel current in voltage-clamped single canine Purkinje cells (n = 6) were also examined. Verapamil (0.3 microM) and KT-362 (7 microM) decreased peak Ca2+ channel current at maximum activation (+10 mV) by 38.1 +/- 8% and 28.6 +/- 6%, respectively, without shifting the current-voltage relationship. This study indicates that verapamil is more potent than KT-362 in depressing contractile function, heart rate, and AV conduction in isolated hearts and calcium current in isolated cardiac Purkinje cells. Moreover, there was a much greater difference between the EC50 for verapamil and that for KT-362 for the depression of indices of contractility (23-30-fold) than for the depression of sinoatrial and atrioventricular nodal function (2.5-4-fold).

Author List

Buljubasic N, Marijic J, Stowe DF, Gross GJ, Kampine JP, Bosnjak ZJ

MESH terms used to index this publication - Major topics in bold

Animals
Atrioventricular Node
Blood Pressure
Calcium Channel Blockers
Calcium Channels
Coronary Circulation
Depression, Chemical
Dogs
Electrophysiology
Guinea Pigs
Heart
Heart Conduction System
Heart Rate
In Vitro Techniques
Myocardial Contraction
Myocardium
Oxygen Consumption
Pacemaker, Artificial
Purkinje Fibers
Thiazepines
Verapamil