Cardiovascular pharmacology of the cardiotonic, imazodan (Cl‐914)

Abstract

of the cardiotonic, imazodan (CI-914). Drug Dev. Res. 9:143-157, 1986. lmazodan is a novel pyridazinone derivative. It was evaluated in excised cardiac tissue, anesthetized dogs and monkeys, and conscious dogs. Imazodan, 10-5-10-3M, produced dose-dependent increases in guinea pig atrial and rabbit papillary muscle contractility. In anesthetized dogs and rhesus monkeys, imazodan, 0.001-1 .O mg/kg IV, produced dosedependent increases of 10-150% in myocardial contractility (dPldt max of left ventricular pressure), and decreases of 1-31% in aortic blood pressure. Heart rate increases were minimal (0-34%) in comparison to the changes in contractility and they occurred only at the higher doses. The positive inotropic action of imazodan was not blocked by @-adrenoceptor blockade with propranolol. Forelimb perfusion studies in the anesthetized dog demonstrated that imazodan produces a dose-dependent direct peripheral vasodilator action. This agent was also demonstrated to be a highly effective cardiotonic when administered orally (0.1-1 .O mg/kg) to conscious dogs. The results of these studies indicate that imazodan is an orally effective cardiotonic that possesses balanced positive inotrophic and peripheral vasodilator activities and possesses a wide margin of cardiac safety.

Mesenteric Arteriopathy in the Rat Induced by Phosphodiesterase III Inhibitors: An Investigation of Morphological, Ultrastructural, and Hemodynamic Changes

“…The initial morphological changes induced by these compounds has been characterized following a single high dose of a potent PDE III inhibitor, SK&F 95654, to dogs (17), but the pathogenesis of this toxic effect has not been determined. Furthermore, although PDE III inhibitors are potent vasodilators at pharmacological doses (6,11,30) the hemodynamic effects of these agents at toxicological doses have not been fully defined.…”

New mechanisms for positive inotropic agents: Focus on the discovery and development of imazodan

“…The invivo cardiovascular effects of imazodan were initially evaluated in the anesthetized open-chest dog. In this model imazodan produced a significant dose-related increase in myocardial contractility [67]. This increase is accompained by a dose-dependent decrease in blood pressure, with a minimal increase in heart rate.…”

“…Imazodan (CI-914) was synthesized in 1980, and initial studies in isolated guinea-pig left atria revealed that it exerted a positive inotropic effect [66]. Subsequent studies showed that imazodan also exerted a cardiotonic effect when administered intravenously to the anesthetized dog or orally to the conscious dog [67].…”

“…Evans and coworkers [67] have shown that although pretreatment of anesthetized dogs with the beta-receptor antagonist propranolol blocks the increase in heart rate produced by imazodan, propranolol does not significantly attenuate imazodaninduced increases in myocardial contractility or decreases in blood pressure. Pretreatment with propranalol, however, significantly blocks the effects of the beta-receptor agonist isoproterenol on all three parameters [67], and also blocks the reflective increase in contracility produced by the calcium-channel blocker nifedipine (personal observation).…”

Imazodan (CI‐914)

“…The direct cardiac stimulant properties of imazodan have been characterized in vitro using left atrial tissue excised from guinea pigs and right ventricular papillary muscle excised from rabbits (10). The effects of imazodan and of the reference cardiotonic agents amrinone and ouabain on peak developed tension of these tissues are summarized in Tables 1 and 2.…”