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In vivo and in vitro effects of the novel antiarrhythmic ipazilide on cardiac and vascular smooth muscle function
Author(s) -
Ezrin Alan M.,
Lee King C.,
Harris Alex L.,
Silver Paul J.
Publication year - 1992
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430270204
Subject(s) - disopyramide , preload , contractility , sotalol , vascular resistance , cardiology , medicine , vascular smooth muscle , in vivo , hemodynamics , antiarrhythmic agent , cardiac function curve , pharmacology , anesthesia , heart failure , heart disease , biology , smooth muscle , atrial fibrillation , microbiology and biotechnology
Ipazilide fumarate is a novel antiarrhythmic currently undergoing clinical evaluation. Since most antiarrhythmics have adverse cardiovascular side effects, we examined the potential effects of ipazilide on cardiac muscle and vascular hemodynamic function utilizing in vivo and in vitro models. The cardiovascular effects of ipazilide and selected reference antiarhythmics, disopyramide and sotalol, at relevant antiarrhythmic concentrations were compared. All agents decreased cardiac contractility, as evident by reductions in dP/dt and cardiac output in anesthetized dogs, and by decreases in contractile force in isolated guinea pig papillary muscles. In vivo, ipazilide was approximately 3–10 × less potent than disopyramide or sotalol while in vitro, ipazilide produced a greater decrease in contractility at a relatively high concentration (30 μM). All three agents increased cardiac preload as reflected by increases in left ventricular end diastolic pressure and right atrial pressure, with ipazilide 2–3 × less potent than disopyramide or sotalol. Differential effects on vascular function were also evident with the three agents. Disopyramide and sotalol significantly increased systemic vascular resistance, and either pulmonary vascular resistance (disopyramide) or left coronary arterial vascular resistance (sotalol); ipazilide did not significantly affect any of these parameters. In isolated rat arterial or canine coronary arterial smooth muscle, ipazilide produced concentration‐related vasorelaxation, with EC 50 values ranging from 11–300 μM. Efficacy of ipazilide was higher in depolarized vascular tissue. In conclusion, since previous preclinical studies have indicated equal or greater antiarrhythmic activity of ipazilide relative to disopyramide or sotalol, the current data indicate the possibility for lessened in vivo hemodynamic effects of ipazilide at efficacious antiarrhythmic dosages. © 1992 Wiley‐Liss, Inc.