Mechanisms of chronotropic cardiac effects of alinidine and plasma concentration-response relationships in the conscious dog with chronic atrioventricular block

Boucher, Michel; Chapuy, Eric; Lefebvre, Marc; Mignot, A.; Duchêne-Marullaz, P

doi:10.1007/bf00168655

Cited by 5 publications

(1 citation statement)

References 27 publications

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“…In contrast, recent findings indicate that sino-atrial node modulators may prolong the refractory period by delaying repolarization (by prolonging the QT interval of the ECG) (6,8,31). This hypothesis is supported by studies in isolated cardiac preparations where zatebradine increased the action potential duration (8,46), suggesting a class 111 antiarrhythmic activity.…”

Section: Antiarrhythmic Activitymentioning

confidence: 71%

Zatebradine: Pharmacological Activity and Potential Therapeutic Benefit of Sino‐atrial Node Modulators

Bril¹,

Faivré²,

Gout³

1995

Cardiovascular Drug Reviews

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Section: Antiarrhythmic Activitymentioning

confidence: 71%

Zatebradine: Pharmacological Activity and Potential Therapeutic Benefit of Sino‐atrial Node Modulators

Bril¹,

Faivré²,

Gout³

1995

Cardiovascular Drug Reviews

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Comparison of the cromakalim antagonism and bradycardic actions of a series of novel alinidine analogues in the rat

Challinor-Rogers

Hay

McPherson³

1994

Naunyn-Schmiedeberg's Arch Pharmacol

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Alinidine, and eight derivatives, were synthesized and tested for their ability to antagonise the actions of the K+ channel opener cromakalim in rat thoracic aorta, and for their ability to induce bradycardia in rat isolated spontaneously beating right atria. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves constructed to cromakalim (0.01-30 microM) in the absence and presence of increasing concentrations of alinidine/derivative. The majority of the compounds tested caused rightward shifts in the cromakalim concentration-effect curves. Rat spontaneously beating right atria were suspended in organ baths to record rate of contraction. Addition of alinidine/derivative caused a concentration-dependent negative chronotropic response. In terms of structure-activity relationships, increasing the length of the N-allyl side-chain on the alinidine molecule (from 3 carbon (3C), to 5C) resulted in a significant increase in the activity of the compounds as both bradycardic agents and cromakalim antagonists. The most potent compounds in both cases (bradycardic agent and cromakalim antagonist) had no double bond in the side chain. The results suggest that the carbon side-chain influences the activity of alinidine-related compounds both as cromakalim antagonists and as bradycardic agents. However, while similar structure-activity relationships appear to apply for both effects in some instances, there was no significant correlation between the two actions of the alinidine analogues. The results suggest that the ability of alinidine-derivatives to induce bradycardia or to block K+ channels opened by cromakalim can be differentiated on the basis of structure.

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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

Aidonidis

Brachmann

Rizos

et al. 1995

Cardiovasc Drug Ther

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Myocardial infarction was produced in 27 anesthetized dogs by ligating the left anterior descending (LAD) coronary artery proximal to the septal branch. Nineteen of these animals survived the operation and were studied by programmed stimulation in a random sequence between the third and seventh days after the infarct. Complete electrophysiologic testing was implemented in each animal prior to and after single doses of either alinidine (1 mg/kg IV) or zatebradine (0.5 mg/kg IV). Alinidine prevented reinduction of sustained ventricular tachycardia (SVT) in only 2 of 9 dogs and zatebradine in 1 of 8 dogs. The SVT cycle length was not significantly changed in all cases in which it was still inducible despite drug administration (p > 0.05). Alinidine lengthened the effective refractory period (ERP) in the AV node (p < 0.01), whereas zatebradine did not induce a statistically significant prolongation. Conversely, zatebradine increased the left ventricular ERP, while alinidine left it almost unchanged. The rate-corrected QT interval (QTc) did not significantly differ from control values after the administration of either agents. Also, the duration and the ERP of infarctzone potentials, defined as late potentials, remained unaltered. The results indicate that the bradycardic agents alinidine and zatebradine do not exert antiarrhythmic efficacy against SVT induced during subacute myocardial infarction in conscious dogs. None of these drugs substantially changed ventricular electrophysiology or showed a drug-specific proarrhythmic effect.

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Mechanisms of chronotropic cardiac effects of alinidine and plasma concentration-response relationships in the conscious dog with chronic atrioventricular block

Cited by 5 publications

References 27 publications

Zatebradine: Pharmacological Activity and Potential Therapeutic Benefit of Sino‐atrial Node Modulators

Zatebradine: Pharmacological Activity and Potential Therapeutic Benefit of Sino‐atrial Node Modulators

Comparison of the cromakalim antagonism and bradycardic actions of a series of novel alinidine analogues in the rat

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

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