Effect of 1-acyl-5,6-dialkoxy-2-alkylthiobenzo[d] imidazoles on the action potential duration and isometric contraction in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles.
BACKGROUND
Studies have shown that some benzo[d]imidazole derivatives (1-(5,6-dimethoxy-2-methylthio-1H-benzo[d]imidazol-1-yl)-1-ethanone (1), 1-(6-ethylthio-5H[1,31dioxolo[4',5':4,5] benzo[d]imidazol-5-yl)-1-propanone (2), 1-(2-ethylthio-6,7-dihydro-1H[1,4]dioxino [2:3':4,5]benzo[d]imidazol-1-yl)-1-pro-panone (3) and 2,3,9,10-tetrahydro-8H [1,4]dioxino[2' 3":4',5']benzo[4,5]imid-azo[2,1-b][1,3]thiazin-10-one (4)) possess strong cardiotonic activity. The goal of this study was to investigate the effect of compounds 1-4 on the action potential (AP) duration and contractile force in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles.


METHODS
The experiments were carried out on the guinea pig papillary muscles and atrium. Isometric contraction and transmembrane potential were recorded using a force transducer and standard microelectrode technique.


RESULTS
Compounds 1-4 exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atrium and papillary muscles, more pronounced in atrium. In response to 1 micromol/L carbachol the AP duration at a 90 % repolarization in atrium shortened more than 70 %, the isometric contraction decreased to the similar level as well. Compounds 1 and 4 significantly antagonized the shortening of the AP duration induced by carbachol and increased it. Compound 1 abolished the reduction of isometric contraction as well. Derivative 3 significantly lengthened (31 ms) the AP duration at a 90 % repolarization in papillary muscles, while 1 and 4 failed to affect this index. The selective blockade of the rapid component of the delayed rectifier potassium current (Ikr) by dl-sotalol (1 micromol/L) did not show the substantial influence on benzimidazole effects.


CONCLUSIONS
These findings support the hypothesis that the tested benzo[d] imidazole derivatives abolish the influence of carbachol on AP and the isometric contraction by inhibition of acetylcholine-activated potassium current (KACh) in guinea pig atrial myocytes and therefore may be beneficial for the prognosis of patients with advanced heart failure and atrial fibrillation.
Garaliene
Vida
V
Institute of Cardiology, Kaunas University of Medicine, Kaunas, Lithuania. vida.garaliene@gmail.com
Labanauskas
Linas
L
Brukstus
Algirdas
A
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects
D001562:Benzimidazoles; D007093:Imidazoles; D018721:Muscarinic Agonists; D002217:Carbachol