The effects of the novel anti‐anginal compound RS 43285 on myocardial conduction in the anaesthetized dog

Allely, Maxine C.; Alps, B. J.

doi:10.1111/j.1476-5381.1988.tb11444.x

Cited by 15 publications

(11 citation statements)

References 18 publications

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“…Our earlier studies with verapamil in the critical stenosis model also showed activity for this drug at low doses (Alps et al, 1985). The doses producing S-T segment reduction and those producing detrimental myocardial conduction effects (400pgkg-m in the present study with a pacing frequency-dependent atrioventricular block at 100-400upgkg-1 in a previous study -Allely .& Alps, 1988) do not appear to be very well separated. Lew & Ban-Hayashi (1985) demonstrated that by elevating LVEDP above the ischaemia-induced increase, the global mechanical disadvantage imposed by the ischaemic zone was diminished.…”

Section: Discussionsupporting

confidence: 51%

A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia

Allely¹,

Alps²

1989

British J Pharmacology

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1 An anaesthetized canine model of transient myocardial ischemia (TMI) has been developed in which reproducible and reversible electrocardiographic (ECG) and haemodynamic responses are exacerbated by electrical pacing. 2 The model could separate the ECG and haemodynamic effects of compounds with antiischaemic properties. 3 Compounds known to possess peripheral or coronary vasodilator properties did not necessarily alleviate the ECG consequences of TMI since glyceryl trinitrate was active whereas dipyridamole was not. The effects of verapamil were complicated by its adverse conduction effects while lidoflazine inhibited the ECG changes only during the ischaemic phase and the 'metabolic modulator' oxfenicine worsened the ECG response. 4 In a model considered to lack coronary reserve, improvements observed in the ischaemic ECG and global ventricular function were considered to result from a direct myocardial effect of the drugs examined rather than by a vascular influence. This was provided to the greatest degree by the Ca2 +-entry blockers nifedipine and nicardipine, with flunarizine adopting an intermediate position.

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Section: Discussionsupporting

confidence: 51%

A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia

Allely¹,

Alps²

1989

British J Pharmacology

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“…Very little is known about the effects of ranolazine on cardiac electrophysiology. Although Allely & Alps (1988) did not find any effect of ranolazine on myocardial conduction in anesthetized dogs, clinical trials have shown a slight but clear prolongation of the QT interval in the ECG (Chaitman et al, 2004a, b). Drug-induced long QT syndrome.…”

Section: Introductionmentioning

confidence: 97%

Ranolazine: Ion‐channel‐blocking actions and in vivo electrophysiological effects

Schram

Zhang

Derakhchan

et al. 2004

British J Pharmacology

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1 Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to D-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. 2 Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC 50 of 106 mmol l À1 , whereas the IC 50 for IsK was 1.7 mmol l À1 . 3 D-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. D-Sotalol had clear proarrhythmic effects, with all D-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. 4 Effects on I Kr and I Ks were similar to those on HERG and IsK. Ranolazine blocked I Ca with an IC 50 of B300 mmol l À1 . I Na was unaffected. 5 We conclude that ranolazine inhibits I Kr by blocking HERG currents, inhibits I Ca at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike D-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I Ca at concentrations only slightly larger than those that inhibit I Kr , thus producing offsetting effects on repolarization.

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“…Ranolazine (RS-43285) [10] is a clinically used anti-anginal drug [11–13] that has also been shown to reduce ischemic damage in animal models [14–16]. The specific cardioprotective mechanism(s) of ranolazine is not well understood especially since, and contrary to other antianginal agents, it exerts its effects without significantly changing hemodynamic parameters [17].…”

Section: Introductionmentioning

confidence: 99%

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

Aldakkak

Camara

Heisner

et al. 2011

Pharmacological Research

102

100

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Ranolazine is a clinically approved drug for treating cardiac ventricular dysrhythmias and angina. Its mechanism(s) of protection is not clearly understood but evidence points to blocking the late Na+ current that arises during ischemia, blocking mitochondrial complex I activity, or modulating mitochondrial metabolism. Here we tested the effect of ranolazine treatment before ischemia at the mitochondrial level in intact isolated hearts and in mitochondria isolated from hearts at different times of reperfusion. Left ventricular (LV) pressure (LVP), coronary flow (CF), and O2 metabolism were measured in guinea pig isolated hearts perfused with Krebs-Ringer’s solution; mitochondrial (m) O2•−, Ca2+, NADH/FAD (redox state), and cytosolic (c) Ca2+ were assessed on-line in the LV free wall by fluorescence spectrophotometry. Ranolazine (5 µM), infused for 1 min just before 30 min of global ischemia, itself did not change O2•−, cCa2+, mCa2+ or redox state. During late ischemia and reperfusion (IR) O2•− emission and m[Ca2+] increased less in the ranolazine group vs. the control group. Ranolazine decreased c[Ca2+] only during ischemia while NADH and FAD were not different during IR in the ranolazine vs. control groups. Throughout reperfusion LVP and CF were higher, and ventricular fibrillation was less frequent. Infarct size was smaller in the ranolazine group than the control group. Mitochondria isolated from ranolazine-treated hearts had mild resistance to permeability transition pore (mPTP) opening and less cytochrome c release than control hearts. Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Subsequently it indirectly reduces O2•− emission, preserves bioenergetics, delays mPTP opening, and restricts loss of cytochrome c, thereby reducing necrosis and apoptosis.

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The effects of the novel anti‐anginal compound RS 43285 on myocardial conduction in the anaesthetized dog

Cited by 15 publications

References 18 publications

A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia

A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia

Ranolazine: Ion‐channel‐blocking actions and in vivo electrophysiological effects

Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts

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