Document Detail


Effect of zatebradine on contractility, relaxation and coronary blood flow.
MedLine Citation:
PMID:  8426013     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: The purpose of this study was to compare the effects of zatebradine on heart rate, contractility and relaxation with those of its structural analog verapamil. We used isoproterenol, a potent beta-agonist, to see how these effects were modulated by sympathetic activation. We also compared the effects of zatebradine and verapamil on coronary blood flow and coronary blood flow reserve. BACKGROUND: Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node. METHODS: Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 micrograms of verapamil (Group II, n = 8). After the effects of each drug reached a plateau, a continuous infusion of isoproterenol was started and measurements were obtained again and compared with a third group of measurements from control hearts infused with isoproterenol after receiving only saline solution (n = 8). We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the intracoronary administration of these drugs (n = 8 for each). All preparations were atrially paced to negate any bradycardiac effects of the drugs. RESULTS: In the group that received zatebradine, mean (+/- SE) heart rate decreased from 143 +/- 8 to 99 +/- 4 beats/min (p < 0.01) and there was no significant change in either peak left ventricular systolic pressure, dP/dt or tau. In contrast, verapamil produced a lesser decrease in heart rate (136 +/- 7 to 120 +/- 7 beats/min, p < 0.05) but produced substantial decreases in peak left ventricular pressure (100 +/- 3 to 45 +/- 4 mm Hg, p < 0.01) and dP/dt (68% decrease, p < 0.01) and an increase in tau (+26%, p < 0.05). Isoproterenol restored these variables toward normal values in the hearts treated with verapamil, although left ventricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol significantly increased left ventricular pressure and contractility and decreased tau; however, heart rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive hyperemia. Conversely, verapamil increased coronary flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values. CONCLUSIONS: Although structurally similar to verapamil, zatebradine is a highly specific bradycardic agent. It has little direct effect on left ventricular developed pressure, contractility, relaxation and coronary vascular tone. Furthermore, the bradycardic effect of zatebradine unlike that of verapamil, is not overcome by doses of isoproterenol that increase developed pressure and contractility and improve relaxation. Because of its highly specific bradycardic effect, this drug may potentially be useful in treating patients with ischemic heart disease or congestive heart failure.
Authors:
J A Breall; J Watanabe; W Grossman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  21     ISSN:  0735-1097     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  1993 Feb 
Date Detail:
Created Date:  1993-03-01     Completed Date:  1993-03-01     Revised Date:  2010-03-24    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  471-7     Citation Subset:  AIM; IM    
Affiliation:
Charles A. Dana Research Institute, Boston, Massachusetts.
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzazepines / chemistry,  pharmacology*
Cardiovascular Agents / pharmacology*
Coronary Circulation / drug effects*
Depression, Chemical
Heart Rate / drug effects*
Isoproterenol / pharmacology
Myocardial Contraction / drug effects*
Swine
Verapamil / pharmacology
Grant Support
ID/Acronym/Agency:
HL07374/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Benzazepines; 0/Cardiovascular Agents; 52-53-9/Verapamil; 7683-59-2/Isoproterenol; 85175-67-3/zatebradine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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