Time-Dependent Interaction of a New H2-Receptor Antagonist, IT-066, with the Receptor in the Atria of Guinea Pig

• Published in: Japanese journal of pharmacology 1991, Vol.57(1), pp.13-23
• Main Authors: Muramatsu, Makoto, Hirose-Kijima, Haruko, Aihara, Hironaka, Otomo, Susumu
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive - physiology; Biological and medical sciences; Cimetidine - pharmacology; Digestive system; Famotidine - metabolism; Famotidine - pharmacology; Guinea Pigs; Heart Atria - drug effects; Heart Atria - metabolism; Heart Rate - drug effects; Histamine H2 Antagonists - metabolism; Kinetics; Male; Medical sciences; Myocardium - metabolism; Pharmacology. Drug treatments; Piperidines - metabolism; Piperidines - pharmacology; Pyridines - metabolism; Pyridines - pharmacology; Receptors, Histamine H2 - metabolism; Stimulation, Chemical; Time Factors
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.57.13

3-Amino-4-[4-[4-(l-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-l,2-dione hydrochloride (IT-066) showed a highly potent and long lasting H2-receptor blocking action in guinea pig atria. The inhibitory effect of IT-066 on the histamine-induced positive chronotropic response increased concentration- and time-dependently. A short period of treatment with IT-066 shifted the concentration-response curve of histamine to the right in parallel, without decreasing the maximal response to histamine. With prolongation of the treatment, the concentration-response curve shifted further to the right with time-dependent suppression of the maximal response to histamine. The inhibitory effect of IT-066 was irreversible. The dissociation constant for histamine (KA) was not changed by prolongation of the time of incubation with IT-066. The dissociation constant for IT-066 (Kb) was decreased with the prolongation of the treatment. Kinetic analysis of the time-dependent inhibition showed a two-step reaction: the first was reversible and the second was irreversible. Preincubation of the atria with ranitidine, however, protected the H2-receptor from the apparently irreversible antagonism of IT-066. These results suggest that IT-066 has a time-dependent and irreversible interaction with the H2-receptor and that the interaction may be responsible for the potent and long lasting H2-receptor blocking action of IT-066.