In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs.
Heart Vessels
; 36(7): 1088-1097, 2021 Jul.
Article
in En
| MEDLINE
| ID: mdl-33763729
ABSTRACT
To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Atrial Fibrillation
/
Ranolazine
/
Halothane
/
Heart Atria
/
Heart Conduction System
/
Heart Rate
/
Anesthesia, Inhalation
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Heart Vessels
Journal subject:
CARDIOLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Japan