thiourea and 2-methylhistamine

The potential for itch production in human skin of the synthetic analogues of histamine, 2-methyl histamine (an H1-receptor agonist) and 4-methyl histamine and dimaprit (H2-receptor agonists) has been studied in vivo and compared with histamine. Itch thresholds for 2-methyl histamine were consistently much higher than for histamine (P < 0.001). The H1-receptor antagonist chlorpheniramine raised the itch thresholds to 2-methyl histamine and histamine significantly (P < 0.001). Pruritus was not obtained with either 4-methyl histamine or dimaprit. No evidence of synergism between 2-methyl histamine and either 4-methyl histamine or dimaprit was found. The results suggest that histamine-induced pruritus is mediated in part through the H1-receptor and in part via an additional (but probably non-H2) mechanism.

Topics: Adult; Chlorpheniramine; Dimaprit; Female; Histamine; Humans; Male; Methylhistamines; Pruritus; Receptors, Histamine H1; Receptors, Histamine H2; Skin; Thiourea

Histamine is known to modulate immune responses through the induction of suppressor cell subsets. The inhibition studies with antagonists suggest that the H2 agonist accounts for most of the suppression. This work studies the effects of various concentrations of 3-methyl histamine (as negative control), histamine, and pure H1 (2-methyl histamine, 2-pyridyl ethylamine) and H2 (4-methyl histamine, dimaprit) receptor agonists on the mitogenic (phytohemagglutinin A) proliferative response of normal human lymphocytes. At high concentrations of agonists (10(-3), 10(-4) M) the suppression induced by the two types of agonists is comparable to that of histamine. At lower concentrations (10(-6) M) the suppression is seen only in the presence of the H2 agonist. The suppression induced by the two agonists is generally reversed in the presence of an H2 receptor antagonist. The H1 receptor antagonist did not abolish and even increased the suppression induced by histamine and the two agonists.

Topics: Cimetidine; Dimaprit; Diphenhydramine; Dose-Response Relationship, Drug; Histamine; Humans; Immunosuppressive Agents; Lymphocyte Activation; Methylhistamines; Phytohemagglutinins; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Thiourea

4-Methylhistamine relaxed potassium-constricted perfused rabbit middle cerebral arteries at low concentrations (3 X 10(-11) - 3 X 10(-8) M) and constricted them at high concentrations (3 X 10(-7) - 10(-4) M). The relaxation was antagonized by either cimetidine (3 X 10(-7) or 10(-6) M) or mepyramine (3 X 10(-8) M) given 20 min before testing a series of increasing concentrations of 4-methylhistamine, whereas the constriction was slightly potentiated by cimetidine and reversed by mepyramine. The reduction of relaxation was enhanced by a combination of both blockers. These results suggest the involvement of both H1- and H2-receptors in the 4-methylhistamine-induced relaxation. When dimaprit was compared with 4-methylhistamine, it acted only as a relaxing agent, not as a constricting agent. The dimaprit-induced relaxation was antagonized by either cimetidine (3 X 10(-7) M) or mepyramine (3 X 10(-8) M). The inhibition of relaxation was enhanced with a combination of both blockers. This supports the hypothesis that the dimaprit-induced relaxation in the rabbit cerebral artery is also mediated through both H1- and H2-receptors. The H1-agonists 2-methylhistamine and 2-pyridyl ethylamine induced two kinds of responses: an initial relaxation at low concentrations which was reversed by mepyramine (3 X 10(-8) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M); this relaxation was followed at higher concentrations by a vasoconstriction which was antagonized by mepyramine (3 X 10(-8), 3 X 10(-7) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M). Relaxation by these agents therefore seems to involve the participation of H1-receptors. The pharmacological effects of the histaminergic agonists and antagonists used could be explained by assuming that a distinction exists in the rabbit middle cerebral artery between the receptors concerned in H1-mediated relaxation and H1-mediated constriction.

Topics: Animals; Cerebral Arteries; Cimetidine; Dimaprit; Drug Interactions; Histamine; In Vitro Techniques; Methylhistamines; Muscle Relaxation; Muscle, Smooth, Vascular; Phenethylamines; Pyrilamine; Rabbits; Receptors, Histamine; Receptors, Histamine H1; Thiourea

When histamine (Hi) and other agonists were applied intraventricularly, Hi caused a dose-dependent inhibition of the avoidance response in rats; its ED50 was 3.60 micrograms. 1-methylHi, 1-methylimidazole acetic acid and imidazole acetic acid which are major metabolites of Hi produced no inhibitory effect even at 50 micrograms. H1-agonists (2-methylHi and 2-thiazolylethylamine) also depressed the avoidance response; their dose-response lines run parallel to that of Hi. The depressant effects of H2-agonists (4-methylHi and dimaprit) were relatively weak; their dose-response lines were not parallel to that of Hi. When antagonists were pretreated intravenously, Hi action was clearly antagonized by diphehydramine and pyrilamine, but not by cimetidine or ranitidine. Intraventricular injection of Hi mixed with cimetidine or ranitidine did not change the effect induced by Hi alone. The avoidance response was not affected by noradrenaline, dopamine or 5-hydroxytryptamine. Although acetylcholine (ACh) suppressed the avoidance response dose-dependently, its effect was much weaker than that of Hi. Pretreatment with cholinergic blocking drugs (atropine and scopolamine) antagonized ACh action but not Hi action. From these results, it is assumed that the inhibitory effect of Hi on the avoidance response is preferentially linked to the H1-receptor. After intraventricular application of 3H-Hi, the highest radioactivity was determined in the hypothalamus.

Topics: Acetylcholine; Animals; Avoidance Learning; Dimaprit; Diphenhydramine; Dose-Response Relationship, Drug; Histamine; Histamine Antagonists; Hypothalamus; Injections, Intraventricular; Kinetics; Male; Methylhistamines; Pyrilamine; Rats; Rats, Inbred Strains; Scopolamine; Thiazoles; Thiourea

The effect of histamine (0.01-200 microM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2-methyl-histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2-methyl-histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2-methyl-histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H2 receptor agonist dimaprit (10-400 microM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 microM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H1 receptors and a relaxant response partly mediated through H1 receptors and partly via unspecific mechanisms. However, an H2 mediated relaxant effect cannot be excluded.

Topics: Aged; Dimaprit; Female; Histamine; Humans; In Vitro Techniques; Male; Methylhistamines; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Phentolamine; Potassium; Pulmonary Artery; Pulmonary Veins; Pyrilamine; Thiourea

At least wo histamine receptors have been pharmacologically defined. Using the appropriate agonists and antagonists, the possible involvement of these receptor types in the production of reaginic antibodies in the rodent was investigated. After injecting mice with dinitrophenyl-ovalbumin (DNP-OA), maximal serum reaginic titers occurred on day 11 as measured by heterologous passive cutaneous anaphylaxis. If the mice were dosed daily (i.p.) with the H1 agonist, 2-methylhistamine, or the H2 antagonist, metiamide, the titers of reaginic antibodies on day 11 were significantly higher than the controls. The titers were significantly lower than the controls if an H2 agonist (4-methylhistamine, dimaprit, or impromidine) or if the H1 antagonist, pyrilamine, was administered daily. None of these agents significantly affected total serum IgG titers as measured by ELISA. However, if the mice were injected with DNP-OA on day 0, then dosed daily with metiamide, pyrilamine, or 4 methylhistamine beginning on day 32, the titers of reaginic antibodies elicited by a second injection of DNP-OA given on day 36 were not significantly different from the titers of the non-drug treated mice. Thus, under these conditions, with these agents, the results suggest that histamine receptors may be involved in modulating the production of reaginic antibodies during a primary immunological response, H1 receptor agonists enhanced, while H2 receptor agonists suppressed the responses, and the reverse effect was observed with the appropriate antagonists. However, histamine receptors appear not to be measurably involved in the development of the secondary reaginic response.

Topics: Animals; Antibody Formation; Dimaprit; Histamine; Histamine Antagonists; Immunoglobulin E; Male; Methylhistamines; Metiamide; Mice; Reagins; Receptors, Histamine; Thiourea

Topics: Animals; Blood Pressure; Cats; Dimaprit; Electric Stimulation; Female; Histamine; Histamine Antagonists; Hypothalamus; Male; Methylhistamines; Metiamide; Sympathomimetics; Thiourea; Time Factors