piperidines and 2-methylhistamine

The effects of histamine on high-voltage-activated Ca2+ channels in the histaminergic neurons acutely dissociated from the rat tuberomammillary nucleus were investigated in the nystatin-perforated patch recording mode under voltage-clamp conditions. Histamine suppressed the high-voltage-activated Ca2+ channel currents in neurons which were positive for histidine decarboxylase with immunocytochemistry. The half-maximum inhibitory concentration and maximum inhibition were 2.6 x 10(-7) M and 16.6+/-1.90%, respectively. An H3 receptor agonist, R(-)-alpha-methylhistamine, mimicked the response to histamine, and thioperamide, an H3 receptor antagonist, inhibited the response to histamine. On the other hand, neither 2-methylhistamine, an H1 receptor agonist, nor dimaprit, an H2 receptor agonist, had a significant effect on the Ca2+ channel currents. Pretreatment with pertussis toxin blocked the inhibitory effect of histamine on Ca2+ channels, suggesting the involvement of Gi/Go proteins in the action of histamine. Omega-conotoxin-GVIA, omega-agatoxin-IVA, nicardipine, and omega-conotoxin-MVIIC blocked the high-voltage-activated Ca2+ channel currents by 15.6, 4.3, 27.1, and 31.2% of the total current, respectively, suggesting the existence of N-, P-, L-, and Q-type Ca2+ channels. A current that was insensitive to these blockers was also found. This residual current, "R-type", was completely suppressed by the addition of 200 microM Cd2+. Histamine significantly inhibited both the N- and P-type current components among these five types of Ca2+ channel currents. We concluded that histamine suppresses the N- and P-type Ca2+ channels in histaminergic neurons through an H3 receptor which is linked to a pertussis toxin-sensitive G-protein.

Topics: Animals; Calcium; Calcium Channels; Calcium Channels, N-Type; Depression, Chemical; Dimaprit; Histamine; Histamine Agonists; Histamine Antagonists; Ion Channel Gating; Mammillary Bodies; Methylhistamines; Nerve Tissue Proteins; Neurons; Nicardipine; omega-Agatoxin IVA; omega-Conotoxin GVIA; omega-Conotoxins; Patch-Clamp Techniques; Peptides; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Spider Venoms; Tuber Cinereum; Virulence Factors, Bordetella

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

Effects of histamine and related compounds on the bovine iris dilator were investigated. Histamine caused a concentration-related contraction of the bovine iris dilator and IC50 was 1.57 x 10(-7) M. The potency of histamine on the bovine iris dilator was almost the same as that observed in guinea pig ileum. Histamine-induced contraction of the bovine iris dilator was antagonized by the H1 antagonists pyrilamine, diphenhydramine and chlorpheniramine, whereas pretreatment with the H2 antagonists cimetidine and ranitidine was most effective. In addition, histamine and the H1 agonist 2-methylhistamine caused a contraction of bovine iris dilator, but the H2 agonist 4-methylhistamine was not effective. An H3 antagonist, thioperamide, also had no contractive effects on the bovine iris dilator. The bovine iris dilator contained a considerable amount of histamine, which was not released by compound 48/80, substance P or by increasing K+ concentration in the medium. In conclusion, histamine caused a potent contraction of the bovine iris dilator via H1 receptor, and this muscle showed a high sensitivity to histamine similar to guinea pig ileum.

Topics: Analysis of Variance; Animals; Cattle; Chlorpheniramine; Cimetidine; Diphenhydramine; Dose-Response Relationship, Drug; Female; Guinea Pigs; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Ileum; Iris; Lethal Dose 50; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; p-Methoxy-N-methylphenethylamine; Piperidines; Potassium; Pyrilamine; Ranitidine; Receptors, Histamine H1; Substance P

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.

Topics: Amygdala; Animals; Brain; Cerebral Cortex; Histamine; Histamine Antagonists; Kinetics; Male; Methylhistamines; Mice; Pargyline; Piperidines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H3; Tissue Distribution