Antispasmodic action of propinox on the isolated human gallbladder: possible mechanism of action.
Propinox is an antispasmodic drug frequently used in the treatment of disorders of the gastrointestinal tract, the uterus and the gallbladder, but little is known about its relaxing activity in gallbladder tissue. The main objective of this study was to determine the antispasmodic activity of propinox, compared to other antispasmodics, in the gallbladder and to assess its binding affinity to receptor sites which may be involved in its mechanism of action. Antispasmodic activity of propinox, (-) scopolamine-n-butyl bromide, atropine and verapamil was determined in human gallbladders to reduce the risk of interspecies variability. Inhibitory activities (ED50) of carbachol-induced contraction were: atropine 5.03 x 10(-8) M > propinox 1.25 x 10(-7) M > verapamil 6.63 x 10(-6) M > (-) scopolamine-n-butyl bromide 5.4 x 10(-5) M. pD'2 for propinox was 6.94, indicating non competitive inhibition of carbachol action. Radioligand binding studies were performed to determine if the antispasmodic action of the drug involved binding to muscarinic receptors or calciumantagonist sites. The inhibition constant (Ki) of propinox for muscarinic receptors of guinea pig ileum smooth muscle, which contains a mixed M2-M3 receptor population, was 1.6 x 10(-6) M. Ki for brain muscarinic receptors (M1) was 1.0 x 10(-4) M, for cardiac receptors (M2) 1.2 x 10(-6) M and from salivary gland receptors (M3) 1.5 x 10(-6) M. For binding to the dihidropiridine calcium antagonist binding sites, Ki were: 4.9 x 10(-5) M for propinox and 2.2 x 10(-7) M for verapamil. For the phenylalkylamine binding sites Ki were: 5.0 x 10(-6) M for propinox and 3.5 x 10(-8) M for verapamil. For the benzothiacepine binding sites, Ki for propinox was 5.2 x 10(-6) M. The following may be concluded: 1.--The antispasmodic activity of propinox in isolated human gallbladder was comparatively less potent than that of atropine and more potent than those of verapamil and (-) scopolamine-n-butyl bromide. 2.--Propinox showed binding to muscarinic and calcium receptors that can be related to its antispasmodic activity; suggesting that the drug is an antispasmodic with anticholinergic and musculotropic activity. 3.--The dual mechanism of action, anticholinergic and calcium-blocking, would induce synergism of pharmacodynamic effects and minimize adverse events of pure antimuscarinic drugs or calcium antagonists.
Baistrocchi
R L
RL
Instituto de Farmacología y Toxicología Roemmers, Universidad de Buenos Aires.
Orti
E
E
de los Santos
A R
AR
Di Girolamo
G
G
Marti
M L
ML
Pico
J C
JC
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001665:Binding Sites; D002086:Butylscopolammonium Bromide / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008333:Mandelic Acids / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D008333:Mandelic Acids; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D002086:Butylscopolammonium Bromide; D001285:Atropine; D002217:Carbachol; D014700:Verapamil; C087283:propinox