Intracellular actions of APP 201–533, a novel cardiotonic agent: Increase in Ca++sensitivity and economization of the myocardial contractile process

Herzig, J. W.; Bormann, G; Botelho, L.S.; Erdmann, E; Salzmann, R; Solaro, R J

doi:10.1016/0022-2828(83)91016-7

Cited by 6 publications

(4 citation statements)

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“…APP201-533 is one of the earlier compounds with equipotent influences on both mechanisms. Moreover, an economization of ATP cost vs. contractile performance supports the notion of a positive inotropic effect with this compound (46).…”

Section: Other Compoundsmentioning

confidence: 90%

Calcium‐Sensitizing Drugs: Positive Inotropy by Enhanced Sensitivity of the Contractile Apparatus to Calcium

Donck

1996

Cardiovascular Drug Reviews

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Section: Other Compoundsmentioning

confidence: 90%

Calcium‐Sensitizing Drugs: Positive Inotropy by Enhanced Sensitivity of the Contractile Apparatus to Calcium

Donck

1996

Cardiovascular Drug Reviews

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“…After preloading, occasional sarcomere length determinations by Ne/He Laser (632.8 nm) light diffraction yielded sarcomere lengths of 2.31 + 0.016 ~tm (X +_ SE, n = 9). The composition of the incubation solutions was as follows: (in mM) Na2ATP 10, MgCI2 12, EGTA 5, CaCI2 0-5, imidazole 20, NaN3 5, phosphoenol pyruvate 5, pyruvate kinase 20 U/ml; pH 6.7, pCa 8.0-4.32, at 22~ In some experiments, the incubation solutions contained an additional 0.1% N-methyl-2-pyrrolidone and/or 500 ~tM APP 201-533 (3-amino-6-methyl-5-phenyl-2(1H)-pyridinone), a cardiotonic agent known to increase the Ca sensitivity of the cardiac contractile system (12).…”

Section: Ca § Activation Of the Skinned Cardiac Fibresmentioning

confidence: 99%

“…Therefore, APP, at a concentration of 500 ~M (see (12)), was applied to skinned fibre preparations from left papillary muscle, from control and isoprenaline-pretreated rabbit Langendorff hearts. In both kinds of preparation APP led to a slight (12 %-15 %) increase in maximum Ca-activated tension and to a leftward displacement of the Ca activation curves (Fig.…”

Section: Ca ++ Sensitization By App 201-533mentioning

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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“…(2) achieving cardiac selectivity over vascular and respiratory actions; and (3) achieving selective positive inotropic activity over heart rate (chronotropic) increases. 62 Of these challenges, the first one is a significant problem for which the literature is surprisingly sparse. Despite the immense interest in the H2-mediated gastric acid system and literature for H2-antagonists in that regard, one finds very few studies where differences in structure activity relationships (SAR) for H2-cardiac receptors vs. H2-gastric receptors are revealed.…”

Section: Interaction With Cell Surface Receptorsmentioning

confidence: 99%

In search of the digitalis replacement

Erhardt¹

1987

J. Med. Chem.

110

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There are now several new CT drugs undergoing clinical study for the treatment of CHF. While most of these new agents are like digitalis in that they possess significant inotropic activity, they differ from digitalis in that they tend to also have pronounced vasodilator properties. Such compounds, because they are not pure CT agents, should not be regarded as true digitalis replacements. Despite the increased understanding about the cAMP cascade and about cardiac muscle contraction in general, the long search for a specific digitalis replacement cannot be regarded as having been accomplished. It should also be noted that the initial clinical assessment for any of these new compounds will be complicated by the fact that they are tested in only the latter stages of CHF where prognosis is very poor and the possibility of showing significant improvement in mortality is extremely difficult. It will be unfortunate if the potential for positive inotropic agents (pure CT drugs) is compromised by clinical studies that employ mixed inotropic-vasodilator compounds in extremely sick patient populations. The continued use of the digitalis glycosides for such a long period of history implies that at least some subpopulation of CHF patients should derive benefit from therapy with an appropriately selective CT drug. Neither the appropriate drug nor the appropriate specific patient population, both of which are needed to properly address the eventual role of inotropic therapy in CHF, have, as yet, been identified.

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Intracellular actions of APP 201–533, a novel cardiotonic agent: Increase in Ca++sensitivity and economization of the myocardial contractile process

Cited by 6 publications

References 0 publications

Calcium‐Sensitizing Drugs: Positive Inotropy by Enhanced Sensitivity of the Contractile Apparatus to Calcium

Calcium‐Sensitizing Drugs: Positive Inotropy by Enhanced Sensitivity of the Contractile Apparatus to Calcium

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

In search of the digitalis replacement

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