Hemodynamic Effects of MDL 17,043, a New Cardiotonic Agent, in Patients with Congestive Heart Failure

Arbogast, R; Brandt, Christian; Haegele, K. D.; Fincker, J. L.; Schechter, Paul J.

doi:10.1097/00005344-198311000-00013

Cited by 33 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amrinone [4][5][6] and mihinone [7,8] (bipyridine derivatives), enoximone [9][10][11] and piroximone [12,13] (imidazolone derivatives), sulmazole [14,15] (a benzimidazole derivative), vesnarinone (0PC-8212) [16][17][18][19] (a quinolinone derivative), and some newer agents belong to this class of cardiotonics. Since most of these agents increase cyclic AMP levels during the induction of the positive inotropic effect, it is crucial to elucidate whether or not cyclic AMP is involved in the positive inotropic effect of the newly developed agents as the subcellular mechanism of action.…”

Section: Amp Zsy-39 Thiazole Derivative Canine Ventricular Myoeardiummentioning

confidence: 99%

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Endoh

Satoh

Norota

et al. 1990

Cardiovasc Drug Ther

View full text Add to dashboard Cite

A newly synthesized 1,3-thiazole derivative ZSY-39 increased the force of contraction in a concentration-dependent manner in association with elevation of tissue cyclic AMP levels in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37 degrees C. ZSY-39 shortened the duration of isometric contractions mainly by abbreviation of the relaxation time. The maximal response to and EC50 of ZSY-39 were 0.7 (isoproterenol = 1.0) and 4.6 x 10(-5) M. Bupranolol (3 x 10(-7) M) did not affect the positive inotropic effect of ZSY-39. The time course of increases in the force of contraction induced by ZSY-39 (10(-4) M) coincided with that of cyclic AMP accumulation. The concentration-response curve for the increase in the force of contraction produced by ZSY-39 was superimposable on that of the elevation of cyclic AMP levels. Carbachol (3 x 10(-6) M) shifted the concentration-response curve for the increase in force by ZSY-39 to the right and downward, and decreased the accumulation of cyclic AMP induced by ZSY-39 (10(-4) M). ZSY-39 (10(-5) M) enhanced significantly the positive inotropic effect of isoproterenol. The relationship between the force of contraction and cyclic AMP levels after the administration of ZSY-39 was not modified by the addition of carbachol or isoproterenol. These findings indicate that cyclic AMP plays an important role in the positive inotropic effect of ZSY-39 on canine ventricular muscle.

show abstract

Section: Amp Zsy-39 Thiazole Derivative Canine Ventricular Myoeardiummentioning

confidence: 99%

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Endoh

Satoh

Norota

et al. 1990

Cardiovasc Drug Ther

View full text Add to dashboard Cite

show abstract

“…Cardiac performance was improved effectively by enoximone given intravenously to more than 300 patients with severe congestive heart failure (NYHA class I11 or IV) (2)(3)(4)(5)11,13,17,18,(20)(21)(22)(28)(29)(30).…”

Section: Clinicalmentioning

confidence: 99%

“…At doses greater than 3 mgkg, more pronounced increases in heart rate were observed. These principal hemodynamic alterations have been shown to result from the direct positive inotropic and vasodilator actions of enoximone (4,5,11,12,23). A venodilator effect or a direct effect on left ventricular compliance or both are suggested additional effects of enoximone (4,12,18).…”

Section: Clinicalmentioning

confidence: 99%

Enoximone

Dage¹,

Roebel²,

Gibson³

et al. 1986

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

“…These PDE III inhibitors increase cyclic AMP in myocardial and smooth muscle cells by the selective inhibition of PDE III that has a high affinity for cyclic AMP and inhibitable with cyclic GMP (4,45,68). These agents act by increasing intracellular Ca 2+ mobilization (20) and have a favorable hemodynamic effect by short-term application in patients with acute heart failure or CHF (2,36,48,51,61). However, clinical trials revealed that they increase morbidity and mortality of patients with CHF (9,43,66).…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of SCH00013: A Novel Ca²⁺ Sensitizer

Endoh

Sugawara

Mineshima

2001

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Cardiotonic agents that facilitate cardiac pump function by direct improvement of contractile dysfunction are indispensable for the treatment of hemodynamic disorders in acute myocardial failure and the aggravating phase of congestive heart failure. Cardiotonic agents currently available for the treatment of hemodynamic crisis in congestive heart failure are catecholamines, selective phosphodiesterase (PDE) III inhibitors and digitalis, all of which are Ca 2+ mobilizers. Considering the number of serious adverse effects of these clinically available cardiotonic agents, development of agents that act via a novel mechanism of action may contribute to the progress of pharmacotherapy of congestive heart failure. Ca 2+ sensitizers that act by increasing in myofilament Ca 2+ sensitivity may be able to overcome the disadvantage of Ca 2+ mobilizers. Ca 2+ sensitizers do not increase activation energy, do not produce Ca 2+ overload and may be effective even under pathophysiological states such as acidosis, myocardial stunning and heart failure. SCH00013 {(4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one)} is a novel Ca 2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca 2+ transients. SCH00013 does not have a positive chronotropic effect and has a weak PDE III inhibitory action and class III antiarrhythmic action. SCH00013 prolonged the survival in a animal heart failure model with genetic cardiomyopathy. The oral bioavailability of SCH00013 is high and equivalent to that via intravenous administration. The unique pharmacological profiles of SCH00013 imply that this agent may be potentially beneficial for pharmacotherapy of contractile dysfunction in congestive heart failure.

show abstract

Hemodynamic Effects of MDL 17,043, a New Cardiotonic Agent, in Patients with Congestive Heart Failure

Cited by 33 publications

References 0 publications

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Enoximone

Pharmacology of SCH00013: A Novel Ca²⁺ Sensitizer

Contact Info

Product

Resources

About

Hemodynamic Effects of MDL 17,043, a New Cardiotonic Agent, in Patients with Congestive Heart Failure

Cited by 33 publications

References 0 publications

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Effects of a new 1,3-thiazole Derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle

Enoximone

Pharmacology of SCH00013: A Novel Ca2+ Sensitizer

Contact Info

Product

Resources

About

Pharmacology of SCH00013: A Novel Ca²⁺ Sensitizer