Fenoverine: a novel synchronizer of smooth muscle motility by interference with cellular calcium flow.
Several in vivo and in vitro test models were used to study the mechanism of action of fenoverine, a novel synchronizer of smooth muscle motility. In vivo, the effects of fenoverine were tested in the rabbit proximal colon, recording its ability to modify the electromyographic activity, either spontaneous or electrically elicited, in the presence or absence of atropine. Fenoverine did not influence the spontaneous motility nor did it modify the effects of atropine, but it significantly reduced the contractions elicited by electrical stimulation. In vitro, isolated rabbit and rat colon and isolated rat myometrium were used. In rabbit colon, fenoverine failed to influence the spontaneous motility as well as the effects of atropine, while significantly inhibiting the electrically elicited excitatory junction potential. Fenoverine also significantly inhibited the isometric contractions induced in rat myometrium and colon by electrical stimulation, by depolarization with hyperpotassic solution, as well as those induced by acetylcholine in calcium-free/EGTA medium, with ID50 ranging from 8.10(-7) to 3.1.10(-6) M except in the isolated colon following K+ depolarization (5.10(-5) M), all actions compatible with a calcium-modulating mechanism. Based on the reported data, it is concluded that fenoverine does not act as a muscarinic or opiate-receptor antagonist, but that its main mechanism of action is due to modulation of the calcium gradient across the muscular cell membrane by regulating the influx of the extracellular calcium and/or the release of the intracellular pool.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003106:Colon / Q000187:drug effects; D004533:Egtazic Acid / Q000494:pharmacology; D004558:Electric Stimulation; D004576:Electromyography; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D010276:Parasympatholytics / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010640:Phenothiazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D010879:Piperazines
D000109:Acetylcholine; D001285:Atropine; D002118:Calcium; D004533:Egtazic Acid; D010276:Parasympatholytics; D010640:Phenothiazines; D011188:Potassium; C048314:fenoverine; D010879:Piperazines