thiourea and tiotidine

The effects of short-term, 7-day, treatment with synthetic 15-leucine human gastrin I, pentagastrin or sulfated cholecystokinin-8 on the activity of histamine (HA)-stimulated adenylate cyclase in membranes isolated from guinea pig gastric mucosa and H2-receptor-mediated contractions of isolated ilea were evaluated. Treatment with each of the peptides produced a decrease in the maximal rate of HA-stimulated adenylate cyclase. The decreases in the maximal rate occurred without any effect on the potency of HA or any effect on basal rates of activity. In animals treated with pentagastrin, but not with cholecystokinin octapeptide sulfate, the contractile activity of dimaprit, a selective H2-agonist, was decreased. In animals treated with pentagastrin, the contractile actions of pentagastrin on isolated ileal preparations were increased. A 7-day treatment with the H2-antagonist, tiotidine, did not alter the potency of or the maximal response for HA-stimulated adenylate cyclase activity. Co-treatment with tiotidine prevented the effects of pentagastrin on gastric mucosal HA-stimulated adenylate cyclase. Treatment with pentagastrin did not alter the sensitivity of the gastric mucosal H2-receptor to inhibition by tiotidine. The effects of treatment with gastrin on NaF-stimulated adenylate cyclase activity also were determined. Treatment with gastrin did not alter the actions of NaF, suggesting that the coupling between the Gs subunit and the catalytic subunit of adenylate cyclase was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenylyl Cyclases; Animals; Cimetidine; Digestive System; Dimaprit; Gastrins; Guinea Pigs; Histamine; In Vitro Techniques; Male; Pentagastrin; Receptors, Histamine H2; Sincalide; Thiourea

Histamine (HA), 1-1000 microM, significantly stimulated both basal and forskolin-activated cAMP generation in chicken and adult hen retina. The action of HA was reproduced by the selective H2-receptor agonists dimaprit and 4-methyl-histamine, but not by the selective H1-receptor agonist 2-thiazolylethylamine, and it was antagonized by the specific H2-receptor blockers cimetidine and tiotidine, but not by the H1-receptor blocker mepyramine. In parallel experiments, dopamine, an established retinal neuromodulator acting through the D1-type of receptor, also stimulated basal and forskolin-driven adenylate cyclase activity in homogenate of chicken retina. It is suggested that chicken retina contains HA H2-receptors which are positively coupled to the adenylate cyclase system.

Topics: Adenylyl Cyclases; Animals; Cerebral Cortex; Chickens; Cimetidine; Colforsin; Cyclic AMP; Dimaprit; Dopamine; Female; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Methylhistamines; Pyrilamine; Receptors, Histamine H1; Receptors, Histamine H2; Retina; Thiazoles; Thiourea

Cimetidine, ranitidine and famotidine are antagonists of the histamine H2-receptors on the spontaneously beating right atrium of the guinea pig. When analyzed by the classical Schild method their pA2-values are respectively: 6.3, 6.8 and 7.7 with dimaprit as agonist and 5.8, 6.5 and 7.7 with histamine as agonist. Radioligand-displacement studies with [3H]-tiotidine as radioligand resulted in pKd values for cimetidine, ranitidine and famotidine of 6.3; 6.9 and 8.2 respectively. In dimaprit-stimulated atria all antagonists added at concentrations above their Kd values depressed the maximal increase in frequency. In the presence of histamine this effect was much less pronounced and only visible at concentrations of ranitidine and famotidine around 10.Kd. The rightward shift of the curves as well as the decrease in Emax are reversible but the dissociation constants of the antagonists are small (less than 10(-3) s-1). The spontaneously beating right atrium showed receptor reserve for histamine and virtually no receptor reserve for dimaprit. The results have been interpreted in a model in which H2-antagonists act mainly by competing with the agonist for the histamine receptor site but have in addition a distinct affinity for a secondary site on the receptor. Occupation of this site by the antagonist prevents building up of the stimulus elicited by the agonist and thus decreases the Emax. In systems with receptor reserve (histamine) the effect of antagonist binding to the secondary binding site is seen only at high concentration of antagonist while in absence of receptor reserve (dimaprit) the depression of Emax is directly visible. Simulations of the model show that the affinity of this secondary binding site is 50-(famotidine) to 100-(cimetidine and ranitidine) fold lower than for the agonist binding site.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Cimetidine; Dimaprit; Famotidine; Female; Guinea Pigs; Heart; Histamine; Histamine H2 Antagonists; In Vitro Techniques; Radioligand Assay; Ranitidine; Receptors, Histamine H2; Thiourea

The effects of metronidazole and 5-aminosalicylic acid (5-ASA) on histamine receptor-effector systems in the small intestine and right atrium of the guinea pig were studied. In an apparently all-or-none manner, both caused a sinistral shift in dose-response curves for the phasic component of the contractile response to histamine at H1 receptors on the ileum. In the presence of either, the EC50 value for histamine was reduced from 0.07 to about 0.03 microM. Similarly, in an apparently all-or-none fashion, both produced an elevation in the dose-response curve for the actions of dimaprit at H2-receptors in the ileum; the response to all doses was increased about 30% with no significant change in the EC50 value. Metronidazole and 5-ASA did not alter dose-response curves for the tonic contractile response to histamine or curves generated by the cumulative addition of histamine. Also, neither altered the positive chronotropic response on isolated right atria or the phasic contractile response on isolated segments of jejunum and duodenum to histamine or dimaprit. Likewise, neither altered dose-response curves for the direct action of carbamylcholine at muscarinic receptors or for the indirect actions of dimethylphenylpiperazinium on the ileum. The effects of 5-ASA or metronidazole on the response to histamine could be prevented as well as reversed by scopolamine or tetrodotoxin. The results suggest that metronidazole and 5-ASA enhance the actions of histamine and dimaprit on the ileum by an action on myenteric plexus neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aminosalicylic Acids; Animals; Cimetidine; Computers; Dimaprit; Dose-Response Relationship, Drug; Drug Synergism; Duodenum; Female; Guinea Pigs; Heart; Histamine; Ileum; In Vitro Techniques; Jejunum; Male; Mesalamine; Metronidazole; Muscle Contraction; Myenteric Plexus; Pyrilamine; Receptors, Histamine; Scopolamine; Tetrodotoxin; Thiourea

In homogenates of guinea-pig ventricle clonidine and dimaprit both stimulate adenylate cyclase and exhibit "bell-shaped' E/[A] curves. The two properties (stimulatory and inhibitory) could be resolved using a theoretical model assuming a "down line' auto-inhibitory mechanism. In the case of clonidine a further depressive property could be seen in the presence of high concentrations of the selective H2-receptor antagonist tiotidine which is not explicable in terms of this model. The results suggest that clonidine has a direct agonistic effect on H2-receptors in guinea-pig heart. However, like dimaprit, clonidine appears to be a partial agonist because its expression is confounded by a secondary inhibitory property(ies).

Topics: Adenylyl Cyclases; Animals; Cimetidine; Clonidine; Dimaprit; Guinea Pigs; Histamine; In Vitro Techniques; Myocardium; Receptors, Histamine; Receptors, Histamine H2; Thiourea

Recent studies have suggested that cyclic AMP (cAMP) may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels (EC50 = 5.7 X 10(-6) M) and morphological changes suggestive of cell maturation along the granulocyte pathway. However, cells cultured with 10(-5) M dimaprit showed more than an 80% decrease in their cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent (halftime approximately 2.5 hr with 10(-5) M dimaprit), dose-dependent (dimaprit EC50 = 1.4 X 10(-6) M) and completely prevented by 10(-3) M cimetidine. Desensitization of HL-60 cells for 4 hr with 10(-5) M dimaprit followed by the addition of 10(-3) M cimetidine resulted in total recovery of the cAMP response in less than 24 hr. The pharmacologically inactive analog N-methyldimaprit (SK&F 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of [3H]tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Based on these results, we suggest that H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; Cell Differentiation; Cell Line; Cimetidine; Cyclic AMP; Dimaprit; Dinoprostone; Dose-Response Relationship, Drug; Histamine; Humans; Leukemia, Myeloid, Acute; Prostaglandins E; Receptors, Histamine; Receptors, Histamine H2; Thiocarbamates; Thiourea

Cumulative concentration-response curves to histamine or dimaprit were constructed on guinea-pig isolated right atria and agonist dose-ratios were determined following addition of ranitidine, cimetidine, metiamide or tiotidine alone or a combination of any two of these H2-receptor blocking drugs. The observed histamine or dimaprit dose-ratios for combinations of any two of the H2-antagonists tested were consistent with results predicted from the equation, DR1+2 = DR1 + DR2 - 1, for two antagonists competing for the same receptor sites. Therefore we conclude that all four H2-antagonists compete for the same histamine H2-receptor.

Topics: Animals; Cimetidine; Dimaprit; Drug Interactions; Furans; Guanidines; Guinea Pigs; Heart; Heart Rate; Histamine; In Vitro Techniques; Metiamide; Ranitidine; Receptors, Histamine; Receptors, Histamine H2; Thiazoles; Thiourea

Topics: Animals; Cimetidine; Dogs; Female; Gastric Mucosa; Guanidines; Guinea Pigs; Heart; Heart Rate; Histamine; Histamine H2 Antagonists; Myocardial Contraction; Thiazoles; Thiourea; Time Factors