Attenuation by R 56865, a Novel Cytoprotective Drug, of Regional Myocardial Ischemia- and Reperfusion-Induced Electrocardiographic Disturbances in Anesthetized Rabbits

Verscheure, Y.; Pouget, G.; Courtois, F; Grand, Bruno Le; John, Gareth W.

doi:10.1097/00005344-199501000-00020

Cited by 10 publications

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“…By blocking this channel with a sodium and calcium overload inhibitor, R56865, cardioprotection against reperfusion‐induced injury can be achieved (Donck et al , 1993). R56865 has been shown to suppress reperfusion‐induced arrhythmia in anaesthetized rats (Garner et al , 1990) and rabbits (Verscheure et al , 1995), and to decrease reperfusion‐induced myocardial necrosis in pigs (Klein 1995). These observations suggest that blocking tetrodotoxin‐sensitive non‐inactivating sodium channels can reduce excess sodium influx and subsequent calcium overload in cardiomyocytes subjected to ischaemia and reperfusion, potentially resulting in cardioprotection.…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that CP‐060 S and R56865 share the common property of calcium overload inhibition. Recently, calcium overload inhibition in the myocardium has attracted a great deal of attention because several studies have suggested that it can ameliorate ischaemia and reperfusion‐induced myocardial damage in rats, rabbits and pigs (Garner et al , 1990; Verscheure et al , 1995; Klein et al , 1995). In view of its properties of calcium channel blocking effect and calcium overload inhibition, it is our hypothesis that CP‐060 S may ameliorate ischaemia‐ and reperfusion‐induced myocardial damage.…”

Section: Introductionmentioning

confidence: 99%

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The protective effects of CP‐060S on ischaemia‐ and reperfusion‐induced arrhythmias in anaesthetized rats

Koga¹,

Fukazawa²,

Suzuki³

et al. 1998

British J Pharmacology

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1 CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective e ect of CP-060S against ischaemia-and reperfusion-induced arrhythmia was evaluated in anesthetized rats. 2 Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion. 3 In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular ®brillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30 ± 300 mg kg 71 ) dose-dependently suppressed the incidences of arrhythmias. Signi®cant decreases occurred at 100 mg kg 71 in VF (incidence: 42%) and mortality (8%), and at 300 mg kg 71 in VT (50%), VF (33%) and mortality (8%). This protective e ect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30 ± 1000 mg kg 71 ) we tested, in terms of e ective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be su cient to explain its potency. 4 In the same model, co-administration of ine ective doses of diltiazem (300 mg kg 71 ) and a sodium and calcium overload inhibitor, R56865 (100 mg kg 71 ), produced signi®cant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of R56865 at the same dose with CP-060S (300 mg kg 71 ) did not add to the e ect of a single treatment of CP-060S. 5 In the ischaemia-induced arrhythmia model, CP-060S (300 mg kg 71 ) signi®cantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg 71 ) was ine ective. 6 These results suggest that CP-060S inhibits both ischaemia-and reperfusion-induced arrhythmia. The combination of the calcium channel blocking e ect and the calcium overload inhibition was hypothesized to contribute to these potently protective e ects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The protective effects of CP‐060S on ischaemia‐ and reperfusion‐induced arrhythmias in anaesthetized rats

Koga¹,

Fukazawa²,

Suzuki³

et al. 1998

British J Pharmacology

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“…Left ventricular pressure (LVP) was measured from male New‐Zealand White rabbits using established protocols ( Verscheure et al ., 1995 ). In brief, animals were anaesthetized by i.v.…”

Section: Methodsmentioning

confidence: 99%

“…The mean arterial pressure (MAP) was calculated as MAP=DAP+(SAP−DAP)/3. A four‐limb electrocardiogram (ECG) was recorded in lead II for determination of heart rate (R–R interval) ( Verscheure et al ., 1995 ). Arrhythmic events were defined as stated with the Lambeth convention ( Walker et al ., 1988 ).…”

Section: Methodsmentioning

confidence: 99%

A novel steroid‐like compound F90927 exerting positive‐inotropic effects in cardiac muscle

Pignier

Keller

Vié

et al. 2006

British J Pharmacology

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1 Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. 2 F90363 is a racemic mixture composed of the stereoisomers (À)-F90926 and ( þ )-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10 3 times higher than F90927 and most likely resulting from an unspecific interaction. 3 The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca 2 þ current I Ca(L) as a main target of F90927, while excluding other components of cardiac Ca 2 þ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. a-and b-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. 4 However, vessel contraction and stiffening of the cardiac muscle at high doses (430 mM, 0.36 mg kg À1 , respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

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“…In view of the pronounced in vitro cardioprotective effects described above for KC 12291, the compound was examined for potential in vivo antiischemic activity in an anesthetized rabbit model of ischemia-induced ST segment elevation (44). Rabbits anesthetized with sodium pentobarbital were subjected to a 10-min reversible occlusion of the main coronary artery.…”

Section: Effects In Isolated Perfused Heartsmentioning

confidence: 99%

KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties

John

Létienne

Grand

et al. 2004

Cardiovascular Drug Reviews

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KC 12291 was designed as a voltage-gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non-inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+ loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+ current. In isolated atria and Langendorff-perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+ loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activity in vivo in the absence of major hemodynamic effects. Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+ current, represent, therefore, promising potential antiischemic and cardioprotective drugs.

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Attenuation by R 56865, a Novel Cytoprotective Drug, of Regional Myocardial Ischemia- and Reperfusion-Induced Electrocardiographic Disturbances in Anesthetized Rabbits

Cited by 10 publications

References 0 publications

The protective effects of CP‐060S on ischaemia‐ and reperfusion‐induced arrhythmias in anaesthetized rats

The protective effects of CP‐060S on ischaemia‐ and reperfusion‐induced arrhythmias in anaesthetized rats

A novel steroid‐like compound F90927 exerting positive‐inotropic effects in cardiac muscle

KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties

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