Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion

Aidonidis, Isaac; Brachmann, Johannes; Rizos, Ioannis; Zacharoulis, Achilleas; Stavridis, I.; Toutouzas, P.; Kübler, W.

doi:10.1007/bf00878087

Cited by 9 publications

(7 citation statements)

References 36 publications

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“…Mean arterial blood pressure after 7 weeks was 162±15 mmHg compared with 87±14 mmHg in normotensive control rats (P < 0.001), and heart-to-body weight ratios were increased by 19%. Bradycardia was induced in groups of normo-and hypertensive rats by repeated intraperitoneal injections over 5 weeks of alinidine, a K ATP channel antagonist that increases the A-V node refractive period [32], at a dose that acutely reduced heart rate from 380±20 beats min )1 to 288±10 beats min )1 (P < 0.001). Final heart rates after alinidine treatment were 28% lower in normotensive rats and 16% lower in hypertensives.…”

Section: Pressure Overload Hypertrophymentioning

confidence: 99%

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

2005

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Angiogenesis and improved left ventricular function as a consequence of long-term bradycardia were first demonstrated in normal hearts, either electrically paced (rabbits, pigs) or treated with a selective sinus blocking drug alinidine (rats). Here we review the evidence that chronic heart rate reduction can have similar effects in the heart with compromised vascular supply, due to either hypertensive or haemodynamic overload hypertrophy (rats, rabbits) or ischaemic damage (rats, rabbits, pigs). Bradycardia induced over several weeks increased capillarity in all hypertrophied hearts, and in border and remote left ventricular myocardium of infarcted hearts. In some, but not all cases, coronary blood flow was improved by heart rate reduction, suggesting enlargement of the resistance vasculature in some circumstances. Cardiac or left ventricular function indices, which were depressed by hypertrophy or ischaemic damage, were preserved or even enhanced by chronic heart rate reduction. The expansion of the capillary bed in the vascularly compromised heart induced by bradycardia may be stimulated by mechanical stretch of the endothelium and/or VEGF activated by chamber dilation and myocyte stretch. The increased number of capillaries and more homogeneous distribution of capillary perfusion would support the better pump function, even in the absence of higher coronary flow. The beneficial impact of chronic heart rate reduction on myocardial angiogenesis and function in cardiac hypertrophy and infarction may be major factor in the success of beta-blockers in treatment of human heart failure.

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Section: Pressure Overload Hypertrophymentioning

confidence: 99%

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

2005

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“…Chronic bradycardia was created by constant infusion of alinidine (Boehringer Ingelheim Pharmaceuticals), a K ATP channel antagonist that increases the atrioventricular node refractive period, 14 with an osmotic pump (Alzet). The infusion rate of 0.7 mg · h Ϫ1 · kg Ϫ1 was determined in pilot experiments.…”

Section: Animal Modelmentioning

confidence: 99%

Bradycardia Induces Angiogenesis, Increases Coronary Reserve, and Preserves Function of the Postinfarcted Heart

Zhou

Zheng

et al. 2004

Circulation

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Background-We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction. Methods and Results-Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia. Conclusions-Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.

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“…The potent bradycardiac effect of zatabradine has been observed in various animal models with the dose range of 0.05 mg/kg to 5 mg/kg administered by an IV bolus (12)(13)(14). The magnitude of the effect of the drug on heart rate has been found to be similar in normal…”

Section: Heterogeneity Of Zatebradine Effect On Cardiac Conduction Symentioning

confidence: 91%

“…Zatebradine also exerted beneficial effects in a number of models of ischemic regional ventricular dysfunction (12)(13)(14). Although no proarrhythmic properties were observed in these studies, no observations have addressed the possibility of the differential actions of the drug on the various components of the conduction system as a function of dose.…”

mentioning

confidence: 94%

Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

Sen

Cui²,

Liming³

et al. 2002

J Cardiovasc Pharmacol Ther

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Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single i.v. bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC(50) was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC(50) of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s(1/2) (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC(50) for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC(50) 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.

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Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion

Cited by 9 publications

References 36 publications

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

Angiogenesis in ischaemic and hypertrophic hearts induced by long-term bradycardia

Bradycardia Induces Angiogenesis, Increases Coronary Reserve, and Preserves Function of the Postinfarcted Heart

Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

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