Pharmacological Actions of APP 201-533, a Novel Cardiotonic Agent

Salzmann, R; Bormann, G; Herzig, J. W.; Markstein, R.; Scholtysik, G

doi:10.1097/00005344-198505000-00027

Cited by 22 publications

(9 citation statements)

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“…A Ca-sensitizing mechanism has been documented for the structural analog AR-L 115 (13,37), as well as for a number of other drugs (24,25,28,30,32,33,35) in skinned myocardial fibers. A Ca-sensitizing action of AR-L 57 in skinned fibers of porcine hearts was found in preliminary studies (J. C. A. van Meel, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

1988

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Contractile dysfunction of reversibly injured, reperfused myocardium can be enhanced by inotropic interventions. A decrease in the Ca-sensitivity of contractile proteins with slow recovery during reperfusion has been suggested as a potential mechanism underlying this postischemic dysfunction. We therefore tested the effects of the cardiotonic agent AR-L 57 (1 mg/kg i.v.) in six anesthetized, vagotomized dogs during constant atrial pacing at 192 +/- 6 beats/min. Before ischemia, AR-L 57 increased left ventricular pressure from 131 +/- 22 to 138 +/- 21 mm Hg and maximum dP/dt from 3,022 +/- 1,427 to 4,337 +/- 2,608 mm Hg/s. Mean systolic thickening velocity of the posterior myocardium was increased from 8.9 +/- 1.1 to 11.7 +/- 1.1 mm/s. After release of a 15 min LCX-occlusion which caused complete regional akinesia, baseline function in the posterior myocardium was severely depressed and only gradually returned towards control values over 8 h of reperfusion. AR-L 57 increased systolic thickening velocity at 10 min, 4 and 8 h reperfusion to a similar extent as before ischemia. With reference to a purported Ca-sensitizing mechanism underlying the positive inotropic action of AR-L 57, our data suggest no change in the Ca-sensitivity of reperfused myocardium.

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Section: Discussionmentioning

confidence: 99%

Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

1988

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“…The decrease in AV conduction time produced by a 10-fold increase in dose was about 12% for both IBMX and theophylline. The doses (AVCTED 10%) which produced a 10% decrease in AV conduction time were 21 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] nmol for I BMX and 1.1 [0.7-1.6] ;imol for theophylline.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, nearly a dozen agents have been developed such as amrinone (1, 2), AR-L 115 BS (sulmazole) (3, 4), MDL 17043 (5, 6), milrinone (7,8), MDL 19205 (piroximone) (9-11), OPC-8212 (12, 13), UD-CG 115 BS (14), 16), LY175326 (17), APP 201-533 (18,19), DPI 201-106 (20). Of these agents, except for DPI 201-106 (20), inhibition of cyclic AMP phosphodiesterase (PDE) and a resultant increase in intracellular cyclic AMP in myocardium have been proposed to be involved as a mechanism for the positive inotropic effect, although this may not be the sole mechanism.…”

Section: Abstract-cardiacmentioning

confidence: 99%

“…Of these agents, except for DPI 201-106 (20), inhibition of cyclic AMP phosphodiesterase (PDE) and a resultant increase in intracellular cyclic AMP in myocardium have been proposed to be involved as a mechanism for the positive inotropic effect, although this may not be the sole mechanism. Indeed, PDE inhibitory activity in crude enzyme or purified enzyme (isozyme III) preparations has been demonstrated for amrinone (21,22), sulmazole (23-25), MDL 17043 (6, 25), milrinone (7), piroximone (11), OPC-8212 (13), UD-CG 115 BS (14), and APP 201-533 (18). Elevation of intra cellular cyclic AMP in myocardium at drug concentrations producing a positive inotropic effect has been demonstrated for amrinone (21,22), sulmazole (25), MDL 17043 (25), milrinone (7), piroximone (26), OPC-8212 (13,27), UD-CG 115 BS (14), and APP 201-533 (19).…”

Section: Abstract-cardiacmentioning

confidence: 99%

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Cardiac versus Coronary Vasodilator Actions of Isobutylmethylxanthine in Dogs: Comparison with Theophylline

Takahashi

Wada

Taira

1986

Japanese Journal of Pharmacology

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Abstract-Cardiacand coronary vasodilator effects of isobutylmethylxanthine (I BMX) and theophylline were compared in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. I BMX (1 nmol-1 /mol) and theophylline (30 nmol-10 /tmol) were injected intra arterially.In paced papillary muscle preparations, both agents increased the force of contraction.In spontaneously beating papillary muscle preparations, both agents increased the rate of ventricular automaticity.In SA node preparations, both agents increased sinus rate. In AV node preparations, both agents decreased AV conduction time only when they were injected into the artery supplying the AV node.In all preparations, both agents increased coronary blood flow. However, both agents were not homogeneously effective on these cardiovascular variables, but showed selectivity in the following order: Ventricular muscle contraction coronary blood flow>SA nodal automaticity -*.AV nodal conduction>ventricular automaticity.These results indicate that IBMX and theophylline have almost an identical profile in their cardiac and coronary vasodilator effects.The two agents were different in that IBMX was 40-50 times as potent as theophylline in producing these effects.Thus, both agents appeared to express their cardiovascular profiles mainly through inhibition of cyclic AMP phosphodiesterase, although theophylline has been claimed to have additional actions.Recently, an intensive search has been carried out to find new non-sympathomimetic and non-glycoside positive inotropic agents (simply called novel positive inotropic agents hereafter) which can replace digitalis. As a result, nearly a dozen agents have been developed such as amrinone (1, 2), AR-L 115

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“…A further argument for the significance of this effect of APP for its cardiotonic action (besides its phosphodiesterase inhibition, cf. (32)) is derived from the observation that, in guinea pig atria, APP's positive inotropie effect, in absolute terms, is independent of the extracellular Ca concentration, in the range between 0.6 and 2.5 mM Ca (R. Salzmann, unpublished communication) and may therefore not be mediated by an enhanced influx of Ca ions. Phenomenologically, as APP induced a leftward shift of the Ca activation curve -and this was even more pronounced in isoprenaline induced heart failure ( Fig.…”

Section: The Effect Of App 201-533 On the Ca ++ Activation Curvementioning

confidence: 99%

Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533

Herzig

Wd²,

Salzmann³

1987

Basic Res Cardiol

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In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.

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Pharmacological Actions of APP 201-533, a Novel Cardiotonic Agent

Cited by 22 publications

References 0 publications

Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

Cardiac versus Coronary Vasodilator Actions of Isobutylmethylxanthine in Dogs: Comparison with Theophylline

Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533

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