title: Inhibition of gastric acid secretion in vivo and in vitro by a new calmodulin antagonist, CGS 9343B.
abstract: The new calmodulin antagonist, CGS-9343B, was found to inhibit both histamine plus 3-isobutyl-1-methylxanthine and carbachol-induced [14C]aminopyrine accumulation in dispersed, fundic mucosal cells of rats. The IC50 value for CGS-9343B inhibition of histamine plus 3-isobutyl-1-methylxanthine-induced [14C]aminopyrine accumulation was 306 nM. The drug was more potent than the H2-histamine receptor antagonist, cimetidine (1128 nM), less potent than the nonspecific calmodulin antagonists, trifluoperazine and fenoctimine (IC50 = 40 and 224 nM, respectively), and equipotent with the H+, K+-adenosine triphosphatase inhibitor, omeprazole (365 nM). CGS-9343B showed an IC50 of 369 nM for carbachol-induced [14C]aminopyrine accumulation in dispersed mucosal cells. CGS-9343B must be added to cells before or simultaneously with acid secretagogues in order to be effective. The drug did not reverse previously stimulated secretion. Unlike trifluoperazine and fenoctimine, CGS-9343B had anticamodulin activity for inhibition of calmodulin-activated (Type I) phosphodiesterase in the same range of potency as observed for the inhibition of aminopyrine accumulation. In anesthetized rats and dogs the i.v. infusion of CGS-9343B did not block histamine plus pentagastrin-stimulated acid secretion. However, i.a. administration of CGS-9343B to anesthetized rats produced a significant inhibition of acid secretion. In vivo the order of potency was omeprazole greater than cimetidine much greater than CGS-9343B. These data provide evidence for involvement of calmodulin in the acid secretory process and suggest that the pursuit of selective calmodulin antagonists such as CGS-9343B may prove useful for understanding the regulation of the hydrogen ion secretory process.
authors: Department of Pharmacology, University of South Alabama College of Medicine, Mobile.
authors: E W
authors: EW
authors: Black
authors: S J
authors: SJ
authors: Strada
authors: R L
authors: RL
authors: Garrett
authors: P R
authors: PR
authors: Kvietys
authors: W J
authors: WJ
authors: Thompson
authors: J A
authors: JA
authors: Norman
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000032:analysis; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D005744:Gastric Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001562:Benzimidazoles; D002147:Calmodulin; D000632:Aminopyrine; C052087:CGS 9343B; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D015056:1-Methyl-3-isobutylxanthine