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Remy S. Leeuwin - One of the best experts on this subject based on the ideXlab platform.
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Flunarizine but not theophylline modulates Inotropic responses of the isolated rat heart to diazepam.
European journal of pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive Inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative Inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these Inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive Inotropic response to diazepam significantly; the negative Inotropic response was reduced as well. At the lower concentrations of diazepam the negative Inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either Inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative Inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.
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PK 11195 antagonizes the positive Inotropic response of the isolated rat heart to diazepam but not the negative Inotropic response
European Journal of Pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Abstract The influence of the ligand PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide), antagonist of the peripheral-type benzodiazepine receptor, on the Inotropic response of the perfused rat heart to diazepam (7-chloro-5-phenyl-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) was studied. Diazepam induced a positive Inotropic response which was preceded by a transient negative Inotropic response. Concentrations of 10−7 M PK 11195 were ineffective, whereas concentrations of 10−6 and 10−5 M PK 11195 reduced the positive Inotropic response significantly. At 5 · 10−5 M PK 11195 the response was completely abolished. The negative Inotropic response was not changed by either concentration of PK 11195 used. It is concluded that the positive Inotropic response of the isolated rat heart to diazepam may well be mediated through peripheral-type benzodiazepine receptors; the negative Inotropic response must be related to other (more complex) mechanisms.
Arie Zeegers - One of the best experts on this subject based on the ideXlab platform.
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Flunarizine but not theophylline modulates Inotropic responses of the isolated rat heart to diazepam.
European journal of pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive Inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative Inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these Inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive Inotropic response to diazepam significantly; the negative Inotropic response was reduced as well. At the lower concentrations of diazepam the negative Inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either Inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative Inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.
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PK 11195 antagonizes the positive Inotropic response of the isolated rat heart to diazepam but not the negative Inotropic response
European Journal of Pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Abstract The influence of the ligand PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide), antagonist of the peripheral-type benzodiazepine receptor, on the Inotropic response of the perfused rat heart to diazepam (7-chloro-5-phenyl-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) was studied. Diazepam induced a positive Inotropic response which was preceded by a transient negative Inotropic response. Concentrations of 10−7 M PK 11195 were ineffective, whereas concentrations of 10−6 and 10−5 M PK 11195 reduced the positive Inotropic response significantly. At 5 · 10−5 M PK 11195 the response was completely abolished. The negative Inotropic response was not changed by either concentration of PK 11195 used. It is concluded that the positive Inotropic response of the isolated rat heart to diazepam may well be mediated through peripheral-type benzodiazepine receptors; the negative Inotropic response must be related to other (more complex) mechanisms.
Henk Van Wilgenburg - One of the best experts on this subject based on the ideXlab platform.
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Flunarizine but not theophylline modulates Inotropic responses of the isolated rat heart to diazepam.
European journal of pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive Inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative Inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these Inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive Inotropic response to diazepam significantly; the negative Inotropic response was reduced as well. At the lower concentrations of diazepam the negative Inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either Inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative Inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.
Henk Van Wilgenburg - One of the best experts on this subject based on the ideXlab platform.
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PK 11195 antagonizes the positive Inotropic response of the isolated rat heart to diazepam but not the negative Inotropic response
European Journal of Pharmacology, 1996Co-Authors: Remy S. Leeuwin, Arie Zeegers, Henk Van WilgenburgAbstract:Abstract The influence of the ligand PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide), antagonist of the peripheral-type benzodiazepine receptor, on the Inotropic response of the perfused rat heart to diazepam (7-chloro-5-phenyl-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) was studied. Diazepam induced a positive Inotropic response which was preceded by a transient negative Inotropic response. Concentrations of 10−7 M PK 11195 were ineffective, whereas concentrations of 10−6 and 10−5 M PK 11195 reduced the positive Inotropic response significantly. At 5 · 10−5 M PK 11195 the response was completely abolished. The negative Inotropic response was not changed by either concentration of PK 11195 used. It is concluded that the positive Inotropic response of the isolated rat heart to diazepam may well be mediated through peripheral-type benzodiazepine receptors; the negative Inotropic response must be related to other (more complex) mechanisms.
Eva Delpón - One of the best experts on this subject based on the ideXlab platform.
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New therapeutic targets for the development of positive Inotropic agents.
Discovery medicine, 2011Co-Authors: Juan Tamargo, Juan Duarte, Ricardo Caballero, Eva DelpónAbstract:Heart failure is associated with significant morbidity and mortality despite significant advances in therapies developed for it. Because impaired cardiac contractility plays a central role in systolic HF, drugs increasing cardiac contractility (positive Inotropics) have been widely used for HF treatment. Conventional Inotropics that increase cAMP and intracellular Ca2+ levels improve symptoms and hemodynamics, but also increase myocardial oxygen demands, cardiac arrhythmias, and mortality, which decreases their overall therapeutic benefit-risk ratio in HF. Thus, we need new Inotropic agents with different mechanisms of action that improve clinical outcomes. This review describes the mechanism of action and preliminary clinical results obtained with these new investigational positive Inotropic agents.
