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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacology of Loprinone (E-1020), a New Pyridinone Inodilator, as a Therapeutic Agent for Acute Heart Failure (1993)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 11 (1993), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.1993.tb00199.x
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacology of SCH00013: A Novel Ca2+ Sensitizer (2001)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 19 (2001), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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 Ca2+ 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. Ca2+ sensitizers that act by increasing in myofilament Ca2+ sensitivity may be able to overcome the disadvantage of Ca2+ mobilizers. Ca2+ sensitizers do not increase activation energy, do not produce Ca2+ 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 Ca2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca2+ 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 car-diomyopathy. 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.〈section xml:id="abs1-2"〉〈title type="main"〉SUMMARYThe positive inotropic effect of Ca2+ sensitizers may not be associated with excessive energy consumption of the heart or the Ca2+ overload that may often exacerbate myocardial dysfunction and provoke lethal arrhythmias during long-term administration. SCH00013 elicits a positive inotropic effect mainly through an increase in myofilament Ca2+ sensitivity without increasing the heart rate. Lack of a positive chronotropic effect may be an important benefit because tachycardia causes an excessive energy consumption and drives the negative force-frequency relationship in severe CHF patients. In addition, SCH00013 possesses class III antiarrhythmic action. While the major potential disadvantage of Ca2+ sensitizers is postulated to be aggravation of the diastolic dysfunction in a failing heart, the effect of SCH00013 on diastolic function was much less than that induced by EMD 57033 in rabbit ventricular myocytes. SCH00013 had little effect on the rate of cardiac relaxation, an indication that the aggravation of diastolic dysfunction may not be a serious complication compared with other Ca2+ sensitizers such as EMD 57033. SCH00013 has a high oral bioavailability in dogs and a high safety margin in rats. It does not induce mutagenic effects on in vitro and in vivo experimental setups. These pharmaco-dynamic and pharmacokinetic profiles of SCH00013 indicate that the compound possesses highly promising pharmacological characteristics suitable for the treatment of CHF patients in the clinical setting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.2001.tb00075.x
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  • 3
    Electronic Resource
    Electronic Resource
    Chronic dexamethasone administration decreases noradrenaline-stimulated, but not serotonin-stimulated, phosphoinositide metabolism in the rat brain (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 616-620 
    Details
    ISSN: 1432-1912
    Keywords: Dexamethasone ; Glucocorticoids ; Phosphoinositide metabolism ; α1-Adrenoceptors ; 5-HT2-receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was undertaken to investigate the effects of chronic administration of dexamethasone on the noradrenaline- and serotonin-stimulated (5-HT-stimulated) phosphoinositide metabolism in hippocampus and frontal cortex of the rat brain. For determination of phosphoinositide metabolism, slices from selected regions of the rat brain (hippocampus or frontal cortex) were loaded with myo- [3H] inositol and stimulated with the agonists (noradrenaline or 5-HT) in the presence of LiCl (7.5 mM). Administration of dexamethasone (1 mg/kg/day) every 2nd day for 14 days markedly reduced the noradrenaline-stimulated phosphoinositide metabolism in the rat hippocampus (IP1: 60% of the control value). In the rat frontal cortex, the noradrenaline-stimulated phosphoinositide metabolism was less depressed by the chronic administration of dexamethasone (IP1: 84% of the control value). However, the chronic administration of dexamethasone did not affect the 5-HT-stimulated phosphoinositide metabolism in the rat brain. The binding characteristics of α1-adrenoceptors and 5-HT2A receptors were unaffected by the chronic treatment with dexamethasone. These results indicate that chronic administration of dexamethasone induces regional and neurotransmitter-specific changes of phosphoinositide metabolism in rat brain. The results suggest that the reduction of noradrenaline-stimulated phosphoinositide metabolism is due do modification of the intracellular signal transduction system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167180
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  • 4
    Electronic Resource
    Electronic Resource
    Chronic dexamethasone administration decreases noradrenaline-stimulated, but not serotonin-stimulated, phosphoinositide metabolism in the rat brain (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 616-620 
    Details
    ISSN: 1432-1912
    Keywords: Key words Dexamethasone ; Glucocorticoids ; Phosphoinositide metabolism ; α1-Adrenoceptors ; 5-HT2-receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study was undertaken to investigate the effects of chronic administration of dexamethasone on the noradrenaline- and serotonin-stimulated (5-HT-stimulated) phosphoinositide metabolism in hippocampus and frontal cortex of the rat brain. For determination of phosphoinositide metabolism, slices from selected regions of the rat brain (hippocampus or frontal cortex) were loaded with myo- [3H] inositol and stimulated with the agonists (noradrenaline or 5-HT) in the presence of LiCl (7.5 mM). Administration of dexamethasone (1 mg/kg/day) every 2nd day for 14 days markedly reduced the noradrenaline-stimulated phosphoinositide metabolism in the rat hippocampus (IP1: 60% of the control value). In the rat frontal cortex, the noradrenaline-stimulated phosphoinositide metabolism was less depressed by the chronic administration of dexamethasone (IP1: 84% of the control value). However, the chronic administration of dexamethasone did not affect the 5-HT-stimulated phosphoinositide metabolism in the rat brain. The binding characteristics of α1-adrenoceptors and 5-HT2A receptors were unaffected by the chronic treatment with dexamethasone. These results indicate that chronic administration of dexamethasone induces regional and neurotransmitter-specific changes of phosphoinositide metabolism in rat brain. The results suggest that the reduction of noradrenaline-stimulated phosphoinositide metabolism is due to modification of the intracellular signal transduction system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167180
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  • 5
    Electronic Resource
    Electronic Resource
    The time course of changes in cyclic nucleotide levels during cholinergic inhibition of positive inotropic actions of isoprenaline and theophylline in the isolated canine ventricular myocardium (1980)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 312 (1980), S. 175-182 
    Details
    ISSN: 1432-1912
    Keywords: Adrenergic-cholinergic interaction ; Cyclic AMP ; Cyclic GMP ; Carbachol ; Theophylline ; Ventricular contraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The time course of changes in cyclic AMP and cyclic GMP levels during the cholinergic inhibition of the positive inotropic actions of isoprenaline and theophylline was assessed in the isolated canine right ventricular myocardium. 1. Carbachol (3×10−6 mol/l) caused biphasic changes in force of contraction and cyclic AMP levels when administered during the positive inotropic response to isoprenaline (10−6 mol/l): a positive inotropic action superimposed on the slowly developing negative inotropic action which was preceded by a reduction of cyclic AMP levels. The positive and negative inotropic actions of, and the reduction of cyclic AMP levels induced by carbachol in the presence of isoprenaline were inhibited by atropine (3×10−7 mol/l). The cyclic GMP levels were increased after the administration of carbachol in the presence of isoprenaline in a monophasic manner and reached a maximal level 120 s after the administration; the elevation was also abolished by atropine. The half-time (T 1/2) for cyclic GMP elevation after the administration of carbachol was about 50 s. 2. Carbachol (3×10−6 mol/l) administered during the positive inotropic response to theophylline (2×10−3 mol/l) abolished the inotropic action of theophylline in a monophasic manner:T 1/2, 40 s; a reduction of cyclic AMP levels (T 1/2, 10 s) and an elevation of cyclic GMP levels (T 1/2, 20 s) preceded the changes in force of contraction caused by carbachol. 3. The present results indicate that the reduction of cyclic AMP levels occurred immediately after the administration of carbachol during cholinergic inhibition of the positive inotropic actions of isoprenaline and theophylline; the elevation of cyclic GMP levels and reduction of force of contraction occurred following the changes in cyclic AMP levels. Considering the mediator role of cyclic AMP in cardiac contraction, it appears that the reduction of cyclic AMP levels is responsible for the cholinergic inhibition of the actions of isoprenaline and theophylline in the canine ventricular myocardium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569727
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  • 6
    Electronic Resource
    Electronic Resource
    α-adrenoceptors mediating the positive inotropic effect of phenylephrine in the right ventricular muscle of the monkey (Macaca fuscata) (1982)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 318 (1982), S. 370-373 
    Details
    ISSN: 1432-1912
    Keywords: α-Adrenoceptors ; Positive inotropic effect ; Phenylephrine ; Ventricular contraction ; Monkey (Macaca fuscata)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The property of adrenoceptors mediating the positive inotropic effect (PIE) in the ventricular muscle of the Japanese monkey (Macaca fuscata) was investigated by the use of phenylephrine (PE) and adrenoceptor antagonists. The intrinsic activity (0.6) and the pD2-value (5.41) for PE were comparable to those in other mammalian species. The β-adrenoceptor antagonist, pindolol (3×10−8 mol/l) shifted only the upper part of the concentration-response curve (CRC) for PE to the right; the pD2-value for PE was not significantly affected by pindolol. On the other hand, phentolamine (10−6 mol/l) shifted the lower part of the CRC for PE more than the upper part. In the presence of both pindolol and phentolamine the curve was shifted to the right in a parallel manner. The time required for twitch relaxation was negatively correlated to the degree of PIE of PE in the presence of phentolamine but not pindolol. These results indicate that both β- and α-adrenoceptors mediate the positive inotropic action in the ventricular muscle of the Japanese monkey and that in contrast to the action via β-adrenoceptors the action via α-adrenoceptors is not accompanied by the “relaxant effect”.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00501181
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  • 7
    Electronic Resource
    Electronic Resource
    Acetylcholine and adenosine activate the G protein-gated muscarinic K+channel in ferret ventricular myocytes (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 351 (1995), S. 610-617 
    Details
    ISSN: 1432-1912
    Keywords: Key words Ferret ; Ventricular myocytes ; Acetylcholine ; Adenosine ; Muscarinic K+ channel ; G protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The properties of the K+ channel activated by acetylcholine (ACh) and adenosine (Ado) were examined in single ferret ventricular myocytes using patch-clamp techniques. In the whole-cell configuration, ACh and Ado induced an inwardly rectifying K+ current and shortened the action potential duration. The effect of ACh was blocked by atropine, while the Ado effect was interrupted by 8-cyclopentyl,1,2-dipropyl xanthine, a specific Ado A1 receptor antagonist. In cell-attached recordings, ACh and Ado added to the pipette solution activated a single population of inwardly rectifying K+ channels, distinct from the i K1 channel. The channel had a slope conductance of ∼40 pS in symmetrical 150 mM K+ solutions and a mean open time of 0.8 ms. Excision of the patch into the inside-out patch configuration in guanosine triphosphate (GTP)-free solution abolished the channel activity. The channel was reversibly reactivated by adding GTP to the intracellular side of the patch. GTPγS activated the channel irreversibly. When the inside-out patch was treated with the A protomer of pertussis toxin (PTX), intracellular GTP no longer activated the K+ channel. The results show that ferret ventricular myocytes possess a K+ channel activated by both muscarinic and Ado A1 receptors. Its electrophysiological properties and the gating by a PTX-sensitive G protein in a membrane-delimited fashion are identical with those of the muscarinic K+ channels in nodal and atrial tissues of other species. In conclusion, the G protein-gated muscarinic K+ channel is expressed in ferret ventricular myocardium and may underlie the direct negative inotropism of ACh and Ado in this tissue.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00170160
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  • 8
    Electronic Resource
    Electronic Resource
    Relationship between relaxation and cyclic GMP formation caused by nicorandil in canine mesenteric artery (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 322 (1983), S. 319-321 
    Details
    ISSN: 1432-1912
    Keywords: Cyclic GMP ; Vasodilation ; Nicorandil ; Mesenteric artery ; Dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the isolated canine mesenteric artery relaxation caused by nicorandil [N-(2-hydroxyethyl)nicotinamide nitrate ester; SG-75] in the presence of noradrenaline was accompanied by a concomitant elevation of cGMP level, whilst the cAMP level was not changed by the drug. The relaxation and cGMP level after the administration of nicorandil showed a good correlation. In this respect nicorandil is very similar to nitrogen oxide-containing vasodilators.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508349
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  • 9
    Electronic Resource
    Electronic Resource
    Cyclic AMP metabolism in intact rat ventricular cardiac myocytes: Interaction of carbachol with isoproterenol and 3-isobutyl-1-methylxanthine (1993)
    Springer
    Molecular and cellular biochemistry 119 (1993), S. 195-201 
    Details
    ISSN: 1573-4919
    Keywords: 3-isobutyl-1-methylxanthine ; carbachol, propranolol, cyclic AMP accumulation ; rat ventricular myocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Experiments were carried out to elucidate the characteristics of regulation of cyclic AMP levels in intact myocardial cells. For this purpose, the influence of isoproterenol, a nonselective cyclic nucleotide phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and carbachol on cyclic AMP levels was investigated in isolated rat cardiac myocytes. The extent of cyclic AMP accumulation induced by isoproterenol was much less than that produced by IBMX: submaximal concentrations of isoproterenol and IBMX elevated the cyclic AMP level 2.4- and 4.8-fold of the control level, respectively. Both agents in combination increased the cyclic AMP level markedly 48-fold. Carbachol inhibited the cyclic AMP accumulation induced by isoproterenol, IBMX and their combination by 30%, 60% and 80% of the respective response. The extent of inhibition produced by carbachol of the cyclic AMP accumulation induced by IBMX + isoproterenol was smaller than that caused by propranolol, and carbachol produced only a marginal additional inhibitory action to that of propranolol, implying that carbachol does not affect the process of cyclic AMP degradation. The present findings indicate that in intact cardiac myocytes the rate of cyclic AMP degradation catalyzed by PDE may be a crucial process of cyclic AMP turnover. This view is supported by the observations that the inhibitory action of carbachol on the effect of isoproterenol was less than that on the effect of IBMX, and that the inhibitory action of carbachol was markedly enhanced by the simultaneous presence of IBMX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00926871
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacological characteristics of endothelin receptors in the rabbit ventricular myocardium: The nonselective endothelin receptor antagonist PD 145065 antagonizes the positive inotropic effect of endothelin-3 but not of endothelin-1 (1996)
    Springer
    Molecular and cellular biochemistry 160-161 (1996), S. 67-74 
    Details
    ISSN: 1573-4919
    Keywords: endothelin-1 ; endothelin-3 ; positive inotropic effect ; PD 145065 ; nonselective endothelin receptor antagonist ; [125I]endothelin-1 ; [125I]endothelin-3 ; receptor binding ; rabbit ventricular myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal response being approximately 65% of the maximal response to isoproterenol. ET-1 induced a positive inotropic effect over the concentration range below 10−9 M, at which ET-3 did not produce a positive inotropic effect, but the maximal response to ET-1 was equivalent to or slightly lower than that of ET-3. The nonselective ET receptor antagonist PD 145065 effectively antagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10−5 M. PD 145065 decreased the positive inotropic effect induced by ET 1 at lower concentrations (〈 10−9 M) but it did not affect the main portion of the concentration-response curve for the positive inotropic effect, i.e., the effect induced by high concentrations (〉 10−9 M) of ET-1. PD 145065 antagonized also the positive inotropic effect of sarafotoxin S6c. PD 145065 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [125Iuc]ET-3 with high affinity but they scarcely affected the [1251]ET-1 binding. These findings indicate that different subtypes of the ET receptor are responsible for the induction of the positive inotropic effect of ET-3 and ET-1. ET receptors involved in the production of the positive inotropic effect in the rabbit ventricular myocardium have pharmacological characteristics that are different from those of conventional ET receptors originally classified based on the pharmacological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by ETB receptors that are inhibitable with RES-701-1. ETA2 receptors that are resistant to ETA selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00240033
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