Positive Inotropic and Electrophysiological Effects of APP 201-533 Can Be Explained by an Increase of Cardiac Cyclic AMP

Scholtysik, G; Honerjäger, P; Markstein, R.; Bormann, G

doi:10.1097/00005344-198505000-00028

Cited by 6 publications

(3 citation statements)

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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%

“…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). Thus, it was of interest to know whether and how these agents are different in cardiovascular profile from classical PDE inhibitors.…”

Section: Abstract-cardiacmentioning

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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Abstract-cardiacmentioning

confidence: 99%

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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Physiological and pharmacological modulation of cardiac contractile proteins

Pagani

Silver

1989

Drug Development Research

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Pagani, E.D., and P.J. Silver: Physiological and pharmacological modulation of cardiac contractile proteins. Drug Dev. Res. 18:279-293, 1989.The contractile-relaxation cycle of cardiac muscle is dependent upon the coordination of a variety of membrane and cytosolic events. The functional activities of the structures responsible for these events can be altered by endogenous modulators, on both a beatto-beat or a long-term basis, in order to optimize cardiac performance and meet the circulatory and nutritional needs of the body. This review focuses on the force-generating structures, or myofibrils, of cardiac muscle, its activation by intracellular calcium, and the ways that activation of the myofibrillar proteins can be modulated by physiological and pharmacological mechanisms. Activation of the myofibrillar proteins is regulated by the troponin-tropomyosin system of the actin (thin) filament; when troponin C binds calcium, sites along the thin filament are made available for myosin (thick) filament interaction. There are a number of physiological mechanisms that influence the affinity of troponin C for calcium, three of which include troponin I phosphorylation, intracellular pH, and muscle length. The relative affinity of troponin C for calcium decreases in parallel with a reduction in muscle length and intracellular pH and in parallel with an increase in troponin I phosphorylation. The type of myosin (isozyme) present in cardiac tissue also regulates myofibrillar activity. Ventricular muscle can contain up to three isozymes of myosin ( V l , V2, and V3). Myofibrils containing only the V1 myosin isozyme can have an ATPase activity two to threefold higher than myofibrils containing only the V3 myosin isozyme. The type of myosin isozyme present in cardiac tissue is determined by a variety of factors: thyrotoxicosis and strenuous exercise tend to increase the relative amount of the V1 isozyme, whereas insulin 280Pagani and Silver and thyroxine insufficiency as well as aortic and pulmonary stenosis tend to decrease the relative amount of the V1 isozyme. Besides these physiological mechanisms, there are a variety of pharmacological agents that have been shown to alter the calcium activation (sensitize or desensitize) and/or maximal activity (potentiate or attenuate) of the cardiac contractile proteins. Some cardiotonic agents which increase the calcium sensitivity of the contractile proteins are AR-L 11 5BS (Sulmazole), pimobendan,. However, some of these compounds are not selective and have ancillary activities, such as inhibiting cyclic nucleotide phosphodiesterase, so a single direct link to cardiotonic activity cannot be made. In addition to this class of agents, some calmodulin antagonists also can modulate cardiac contractile protein activity via modulation of calcium binding to troponin C. Some of the calcium-binding protein modulators, such as calmidazolium, trifluoperazine, perhexiline, and bepridil are several times more potent in increasing myofibrillar ATPase activity than either AR-L 1 15BS or ...

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Drugs Affecting Cardiac Calcium Metabolism

Honerjäger¹

1988

Calcium in Drug Actions

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Positive Inotropic and Electrophysiological Effects of APP 201-533 Can Be Explained by an Increase of Cardiac Cyclic AMP

Cited by 6 publications

References 0 publications

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

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

Physiological and pharmacological modulation of cardiac contractile proteins

Drugs Affecting Cardiac Calcium Metabolism

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