Antiarrythymic evaluation of verapamil, nifedipine, perhexiline and SKF 525-A in four canine models of cardiac arrhythmias

Bergey, James L.; McCallum, J.; Nocella, Karen

doi:10.1016/0014-2999(81)90167-9

Cited by 15 publications

(6 citation statements)

References 19 publications

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“…Verapamil also has been reported to suppress two electrophysiological manifestations of ouabain toxicity in ca nine Purkinje fibers: delayed afterdepolari zation [Rosen and Danilo, 1980] and accel eration of phase 4 depolarization [Tse and Han, 1978]. Our results are in general agree ment with those of Bergey et al [1981], who compared verapamil, nifedipine, and perhexiline in several experimental models of cardiac arrhythmias. Verapamil, but not ni fedipine or perhexiline, displayed antiarrhythmic activity against ouabain-induced arrhythmias.…”

Section: Discussionsupporting

confidence: 83%

Comparative Effects of Verapamil, Diltiazem and Felodipine during Experimental Digitalis-Induced Arrhythmias

Lr¹,

Rm²,

Sl³

et al. 1987

Pharmacology

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We compared the abilities of three different calcium (Ca²⁺) entry blockers, verapamil, diltiazem and felodipine to abolish ouabain-induced ventricular ectopy (100 × ectopic/total beats, VE) in anesthetized, closed-chest dogs. Ventricular tachycardia (VT) was produced in anesthetized, bilaterally vagotomized, closed-chest dogs by an average dose of 65 ± 19 μg/kg ouabain. 30 min after establishing VT, either verapamil (25–50 μg/kg + 5–10 μg/kg/min), diltiazem (50–100 μg/kg + 20–50 μg/kg/min), felodipine (3 μg/kg + 0.3 μg/kg/min) or saline was administered for another 30 min. Verapamil, at the higher dose utilized, practically abolished ouabain-induced VT (97 ± 3 to 8 ± 19% VE); diltiazem was moderately effective (96 ± 4 to 50 ± 8% ectopy) at 100 μg/kg, and felodipine exerted no antiarrhythmic effects in this model. All three Ca²⁺ entry blockers lowered mean aortic pressure, felodipine lowering this parameter most prominently. Thus, these structurally and electrophysiologically dissimilar Ca²⁺ entry blockers differed in their abilities to abolish the digitalis glycoside-induced arrhythmias in vivo. The superiority of verapamil may be related to its multiple, additional electrophysiologic effects.

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Section: Discussionsupporting

confidence: 83%

Comparative Effects of Verapamil, Diltiazem and Felodipine during Experimental Digitalis-Induced Arrhythmias

Lr¹,

Rm²,

Sl³

et al. 1987

Pharmacology

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“…It could therefore be argued that plasma levels following intravenous infusion of drug can rise more rapidly prior to equilibrium with the myocardial compartment, whereas those following oral administration being slower in onset allow greater time for equilibrium with the myocardium. Although a number of clinically effective antiarrhythmic agents have been found to be effective in suppressing post myocardial infarction arrhythmias in conscious dogs, efficacy is often associated with severe central nervous system disorders (Carmeliet et al, 1978;Bergey et al, 1981). Whilst no specific neurological observations were carried out, no gross behavioural observations indicative of adverse effects due to central nervous system penetration were made during the experiments on conscious dogs, thus supporting our hypothesis that this agent has restricted access to the CNS.…”

Section: Discussionsupporting

confidence: 67%

BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents

Allan¹,

Donoghue

Follenfant

et al. 1986

British J Pharmacology

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1 BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features ofpotency with reduced central nervous system penetration. 2 BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC5o, 2.2 x 10-6 M and 1.8 x 10-6 M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. 3 In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-') caused a dosedependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. 4In conscious dogs, intravenous infusion (total dose, 1.5 mg kg 1) or oral administration of BW A256C (1.25-5mg kg-') caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. 5In the conscious dog, BWA256C was approximately 7 times more potent and was also longer acting than flecainide. 6 Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity.

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“…DAM acts as a chemical phosphatase, exerts its biological effects by altering protein phosphorylation, and blocks contractions through the inhibition of myosin ATPase activity such that the rise of intracellular [Ca 2ϩ ] i elicited by an AP fails to generate force (2,6). However, DAM also alters repolarization and reduces AP durations (APD) in several species of cardiac tissues, such as cat ventricular muscles (43), dog Purkinje fibers (4), and guinea pig papillary muscle (27). In contrast, DAM prolonged APDs in rat Purkinje fibers (12,13) and mouse ventricles (3).…”

mentioning

confidence: 99%

Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the electrophysiology of perfused mouse hearts

Baker¹,

Wołk²,

Choi³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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concentration ([Ca 2ϩ ]i) handling and vulnerability to arrhythmias in a species-dependent manner. The effects of uncouplers were investigated in perfused mouse hearts labeled with rhod-2/AM or 4-[␤-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) to map [Ca 2ϩ ]i transients (emission wavelength ϭ 585 Ϯ 20 nm) and action potentials (APs) (emission wavelength Ͼ 610 nm; excitation wavelength ϭ 530 Ϯ 20 nm). Confocal images showed that rhod-2 is primarily in the cytosol. DAM (15 mM) and cyto-D (5 M) increased AP durations (APD 75 ϭ 20.0 Ϯ 3 to 46.6 Ϯ 5 ms and 39.9 Ϯ 8 ms, respectively, n ϭ 4) and refractory periods (45.14 Ϯ 12.1 to 82.5 Ϯ 3.5 ms and 78 Ϯ 4.24 ms, respectively). Cyto-D reduced conduction velocity by 20% within 5 min and DAM by 10% gradually in 1 h (n ϭ 5 each). Uncouplers did not alter the direction and gradient of repolarization, which progressed from apex to base in 15 Ϯ 3 ms. Peak systolic [Ca 2ϩ ]i increased with cyto-D from 743 Ϯ 47 (n ϭ 8) to 944 Ϯ 17 nM (n ϭ 3, P ϭ 0.01) but decreased with DAM to 398 Ϯ 44 nM (n ϭ 3, P Ͻ 0.01). Diastolic [Ca 2ϩ ]i was higher with cyto-D (544 Ϯ 80 nM, n ϭ 3) and lower with DAM (224 Ϯ 31, n ϭ 3) compared with controls (257 Ϯ 30 nM, n ϭ 3). DAM prolonged [Ca 2ϩ ]i transients at 75% recovery (54.3 Ϯ 5 to 83.6 Ϯ 1.9 ms), whereas cyto-D had no effect (58.6 Ϯ 1.2 ms; n ϭ 3). Burst pacing routinely elicited long-lasting ventricular tachycardia but not fibrillation. Uncouplers flattened the slope of AP restitution kinetic curves and blocked ventricular tachycardia induced by burst pacing. optical action potentials; action potentials; intracellular calcium; restitution kinetics MOLECULARLY ENGINEERED MICE have been extensively used to genetically alter a specific component of a complex signaling process and to develop models of human diseases. Transgenic mice are used as models for various cardiac diseases and offer an effective strategy to elucidate the mechanisms underlying long QT-related arrhythmias, metabolic diseases, and the pathology of heart failure (29). A limitation of mouse models is the small size of the heart, making it difficult to study changes in contractility, electrophysiology, and vulnerability to arrhythmias in intact hearts. The challenge of measuring changes in cardiac phenotype has been partly overcome by applying optical technique to map electrical activity, but a major technical difficulty in the application of optical techniques to measure action potentials (APs) and intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) transients has been the distortion of the signals by movement due to muscle contractions.Several approaches have been used to reduce movement artifacts: 1) perfusion in Ca 2ϩ -free Tyrode solution to abolish contractions, an approach applicable to amphibian hearts (38); 2) design perfusion chambers to mechanically stabilize the heart (18, 37); 3) perfusion with an inhibitor of L-type voltage- Chemical uncouplers can potentially provide a practical approach to block movement artifacts and have been used to...

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Antiarrythymic evaluation of verapamil, nifedipine, perhexiline and SKF 525-A in four canine models of cardiac arrhythmias

Cited by 15 publications

References 19 publications

Comparative Effects of Verapamil, Diltiazem and Felodipine during Experimental Digitalis-Induced Arrhythmias

Comparative Effects of Verapamil, Diltiazem and Felodipine during Experimental Digitalis-Induced Arrhythmias

BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents

Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the electrophysiology of perfused mouse hearts

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