The effect of fendiline on cAMP metabolism and activity of the isolated uterus of the rat.
Increasing concentrations of fendiline inhibit various types of muscle activation (KCl, oxytocin and electrical stimulation), as well as spontaneous rhythmic activity of the isolated uterus of the rat. Contrary to verapamil and nifedipine, fendiline in micromolar concentrations (from 1.5 to 15.5 mumol) affects various types of muscle activation almost to the same degree. Fendiline probably influences a common pathway in calcium metabolism in all types of muscle activation. The relaxant effect of fendiline does not depend on cAMP, being even associated with a significant decrease of the level of this nucleotide during electrical stimulation of the isolated uterus of the rat. Fendiline may have its place in the therapy of premature delivery and abortion, particularly because it exhibits lower selectivity in relation to the type of activation of the smooth muscle. Fendiline induces a stronger inhibition of the tonic than of the phasic component of contraction produced by oxytocin and KCl. Fendiline is more active against the oxytocin-induced contraction, probably due to an additional action on the fast Na+ channels. These findings indicate that KCl and oxytocin act through different calcium channels (voltage and receptor calcium channels). Our experiments in which fendiline inhibited more strongly the tonic than the phasic component of KCl-produced contraction also confirm the hypothesis on the existence of voltage calcium channels (or subtypes of one voltage calcium channel) in the isolated uterus of the rat. By adding calcium to the medium, almost all types of muscle activation are established, after the inhibitory action of fendiline, except its depressive action on the electrical stimulation of the isolated rat uterus. Calcium most effectively antagonizes the inhibitory effect of fendiline on spontaneous rhythmic activity. The finding that certain types of activation, after the inhibitory action of fendiline, occur to a different degree by addition of calcium to the medium, are also indirect confirmation of the existence of different calcium channels. Halothane, in a concentration of 1 vol %, did not change the relaxant action of fendiline during electrical stimulation and during spontaneous rhythmic activity.
Milovanović
S R
SR
Varagić
V M
VM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D005275:Fendiline / Q000494:pharmacology*; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D010121:Oxytocin / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014590:Uterine Contraction / Q000187:drug effects*
D002121:Calcium Channel Blockers; D010627:Phenethylamines; D010121:Oxytocin; D011189:Potassium Chloride; D000242:Cyclic AMP; D005275:Fendiline; D006221:Halothane