Effect of four 5-hydroxytryptamine type 4 receptor agonists on rat cardiac Iκ1 channels and proarrhythmic risk stratification / 中国药理学与毒理学杂志
Chinese Journal of Pharmacology and Toxicology
;
(6): 534-540, 2017.
Article
in Chinese
| WPRIM
| ID: wpr-611116
ABSTRACT
OBJECTIVE To compare the effect of four 5-hydroxytryptamine type 4 (5-HT4) receptor agonistscisapride,zacopride,macopride and 2-[1-(4-piperonyl) piperazinyl]-benzothiazole (BZTZ),on rat cardiac inward rectifier potassium channel (IK1)and heart rhythm.METHODS The whole-cell configuration of patch-clamp technique was used to record effects of 5-HT4 receptor agonists onIk1 in enzymatic dissociated rat ventricular myocytes or Kir2.1 transfected HEK 293 cells.Western blotting was used to observe the expression of Kir2.1 channel exposed 24 h to agents in ventricular myocytes.Langendorff-perfused hearts were perfused with four agents respectively for 30 min.The electrocardiogram was recorded simultaneously.RESULTS BZTZ,cisapride and mosapride 0.1-10 μmol· L-1 decreasedIk1 in a concentrationdependent manner.At the same concentration (1 μmol· L-1),BZTZ showed the most potent inhibition onIκ1 (P<0.01),followed by cisapride.Mosapride showed slight inhibition efficiency.However,zacopride enhanced Iκ1 (P<0.01).In Kir2.1 heterologous expression systems,zacopride activated Kir2.1 current (P<0.01) while mosapride had no effect.In ex vivo Langendorff-perfused hearts,BZTZ and cisapride 1μmol· L-1 elicited singnificant rhythm disturbances,and the total of premature ventricular beats (PVB) were 159±28 and 61±13.50% (4/8) (P<0.05) and 25% (1/8) of the hearts exhibited ventricular tachycardia (VT),while 37.5% (3/8) and 12.5% (1/8) of the hearts exhibited ventricular fibrillation (VF),respectively.Mosapride and zacopride had no side effects on heart rhythm.Zacopride also suppressed BZTZ-or cisapride-induced arrhythmias.BZFZ had the strongest proarryhthmic potency among the 5-HT4 agonists,followed by cisapride,mosapride and zacopride.CONCLUSION Iκ1 might be an independent risk factor for arrhythmogenesis and a new target for screening safe 5-HT4 receptor agonists and gastrointestinal prokinetic agents.
Full text:
Available
Index:
WPRIM (Western Pacific)
Type of study:
Etiology study
/
Prognostic study
/
Risk factors
Language:
Chinese
Journal:
Chinese Journal of Pharmacology and Toxicology
Year:
2017
Type:
Article
Similar
MEDLINE
...
LILACS
LIS