Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent

Weishaar, Ronald E.; Quade, Mary M.; Schenden, J A; Boyd, Denise K.; Evans, Dale B.

doi:10.1016/0014-2999(85)90297-3

Cited by 36 publications

(14 citation statements)

References 28 publications

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“…9 " 29 These types of correlative studies may present several problems. Many of these agents (e.g., carbazeran, milrinone, and papavarine) also increase tissue cGMP levels.…”

mentioning

confidence: 99%

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.

Kithas

Artman

Thompson

et al. 1988

Circulation Research

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“…9 " 29 These types of correlative studies may present several problems. Many of these agents (e.g., carbazeran, milrinone, and papavarine) also increase tissue cGMP levels.…”

mentioning

confidence: 99%

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.

Kithas

Artman

Thompson

et al. 1988

Circulation Research

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“…In contrast to the reference agents, imazodan failed to exert any significant effects on either enzyme [68]. However, the novel inotropic agent sulmazole and its analogue AR-L 57 both exerted significant inhibitory effects on Na, K-ATPase activity [61].…”

Section: Mechanistic Studies With Imazodanmentioning

confidence: 84%

“…The effects of all three inotropic agents on mitochondrial oxygen consumption, as well as mitochondrial electron transport and respiratory control (an index of the coupling between oxygen consumption and electron transport), was also evaluated. At concentrations ranging from 10 pM to 300 pM, none of the agents examined exerted a significant effect on these parameters [61,68].…”

Section: Mechanistic Studies With Imazodanmentioning

confidence: 90%

“…In preliminary studies imazodan was found to exert little inhibitory effect on phosphodiesterase activity in crude cardiac homogenates [68]. In contrast, the nonselective phosphodiesterase inhibitors theophylline and isobutylmethylxanthine exerted significant inhibitory effects on this crude preparation of phosphodiesterase [61,68].…”

Section: E[[ects On Cardiac Phosphodiesterase Activitymentioning

confidence: 99%

“…Later studies with imazodan also failed to reveal a direct effect on calcium homostasis in isolated sarcoplasmic reticulum or mitrochondria [68]. The effects of all three inotropic agents on mitochondrial oxygen consumption, as well as mitochondrial electron transport and respiratory control (an index of the coupling between oxygen consumption and electron transport), was also evaluated.…”

Section: Mechanistic Studies With Imazodanmentioning

confidence: 99%

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

Weishaar¹,

Kobylarz-Singer²,

Klinkefus³

1989

Cardiovasc Drug Ther

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Intense efforts during the last decade to identify a useful positive inotropic agent to replace digitalis for the treatment of congestive heart failure have led to the discovery of several dozen potential substitutes, of which a number are currently undergoing clinical trials. In addition to producing a variety of new therapeutic entities, research in this area has also yielded valuable new information regarding the fundamental events that regulate calcium homeostasis and contractile function in the cardiac cell. For example, several of these new inotropic agents, including the calcium-channel stimulator BAY-k 8644, the sodium-channel stimulator DPI-201-186, and the sodium-calcium exchange inhibitor dichlorobenzamil, have provided considerable insight into the role of sodium and calcium in regulating contractility and the molecular events that mediate potential-dependent ion channels. Likewise, the discovery and development of agents like imazodan, amrinone, enoximone, and other selective type III phosphodiesterase inhibitors have provided new information regarding multiple molecular forms of cyclic nucleotide phosphodiesterase, compartmentation of cyclic AMP, and the importance of soluble vs. membrane-bound phosphodiesterases.

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

Evans¹,

Potoczak²,

Steffen³

et al. 1986

Drug Development Research

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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.

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Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent

Cited by 36 publications

References 28 publications

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.

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

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

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