thiourea and 4-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

The diverse physiological functions of histamine are mediated through distinct histamine receptors. In this study we investigated the role of H2R and H4R in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood.. Changes in reactive oxygen species (ROS) production by whole blood phagocytes after treatment with histamine, H4R agonists (4-methylhistamine, VUF8430), H2R agonist (dimaprit) and their combinations with H4R antagonist (JNJ10191584) and H2R antagonist (ranitidine) were determined using the chemiluminescence (CL) assay. To exclude the direct scavenging effects of the studied compounds on the CL response, the antioxidant properties of all compounds were measured using several methods (TRAP, ORAC, and luminol-HRP-H2O2 based CL).. Histamine, 4-methylhistamine, VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner. On the other hand, only VUF8430 was able to inhibit PMA-activated whole blood CL. Ranitidine, but not JNJ10191584, completely reduced the effects of histamine, 4-methylhistamine and dimaprit. The direct scavenging ability of tested compounds was negligible.. Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by H2R. Our results also suggest that H4R agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to H2R.

Topics: Benzimidazoles; Dimaprit; Guanidines; Histamine; Histamine Agonists; Humans; Male; Methylhistamines; Phagocytes; Reactive Oxygen Species; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H2; Receptors, Histamine H4; Thiourea

Histamine influences T-cell reactions via histamine receptors 1 and 2. The histamine receptor 4 (H(4)R) is the most recently identified histamine receptor and is also expressed on human CD4(+) T cells; however, its regulation and function are unclear.. To investigate expression, regulation, and function of the H(4)R on human CD4(+) T cells.. Histamine receptor 4 expression was studied by real-time quantitative RT-PCR and by flow cytometry. Effects of H(4)R stimulation on induction of the signal transduction molecules activator protein 1 (AP-1) and nuclear factor-kappaB (NF-kappaB) were determined by electrophoretic mobility shift assay and on cytokine production by RT-PCR and ELISA.. Histamine receptor 4 mRNA and protein were expressed by CD4(+) T cells and upregulated by IL-4. Its expression was higher on T(H)2 cells than T(H)1 cells and naive T-cells. H(4)R agonists (clobenpropit and 4-methylhistamine) induced AP-1 in T(H)2 cells but not in T(H)1 cells. This effect was blocked by the H(4)R antagonist JNJ7777120. H(4)R agonists upregulated IL-31 mRNA in PBMCs and T(H)2 cells, a cytokine that has been associated with T(H)2 cells and the induction of pruritus. IL-31 mRNA induction by H(4)R stimulation was pronounced in PBMCs from patients with atopic dermatitis. Expression of IL-4, IL-5, and IL-13 was not altered by the H(4)R.. Human CD4(+) T cells express a functional H(4)R. The receptor is upregulated under T(H)2 conditions, and its stimulation leads to induction of AP-1 and IL-31.

Topics: Cells, Cultured; Dermatitis, Atopic; Histamine H3 Antagonists; Humans; Imidazoles; Interleukin-4; Interleukins; Methylhistamines; NF-kappa B; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Th1 Cells; Th2 Cells; Thiourea; Transcription Factor AP-1

We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine.. Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity.. Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430.. Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors.

Topics: Agmatine; Animals; Cell Line; Chemotaxis; Chlorocebus aethiops; Dendritic Cells; Gastric Acid; Guanidines; Histamine Agonists; Humans; Male; Methylhistamines; Mice; Radioligand Assay; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H2; Receptors, Histamine H3; Receptors, Histamine H4; Thiourea

The expression of the recently cloned histamine H(4) receptor (H(4)R) by leukocytes suggests a role in immunomodulation.. The expression and function of the H(4)R on human monocytes obtained from peripheral blood was investigated.. H(4)R expression was studied by using flow cytometry. Effects of H(4)R stimulation on Ca(2+) mobilization was determined fluorometrically, CCL2 production was determined by means of ELISA, intracellular CCL2 staining was measured with flow cytometry, and CCL2 mRNA was measured by using real-time quantitative LightCycler PCR. The relevance of CCL2 production was determined in chemotaxis transmigration assays.. H(4)R protein was expressed by monocytes and upregulated by IFN-gamma. H(4)R agonists (clobenpropit and 4-methylhistamine) induce a Ca(2+) mobilization in monocytes, which could be blocked with the selective H(4)R antagonist JNJ7,777,120. Furthermore, H(4)R agonists downregulated CCL2 protein production. This effect could also be blocked by JNJ7,777,120. Supernatants of H(4)R agonist-stimulated monocytes attracted less monocytes in transmigration assays. The downregulation of CCL2 production was regulated at different levels. First, the synthesis of CCL2 mRNA was significantly decreased. Second, intracellular staining suggested an inhibition of CCL2 secretion after stimulation with H(4)R agonists.. Human monocytes express the H(4)R, and its stimulation leads to a Ca(2+) influx and an inhibition of CCL2 production, resulting in a reduction of monocyte recruitment.. The H(4)R could represent an important anti-inflammatory receptor on monocytes and could be an interesting target for drug development.

Topics: Calcium; Cells, Cultured; Chemokine CCL2; Chemotaxis, Leukocyte; Down-Regulation; Histamine; Histamine Agonists; Humans; Imidazoles; Indoles; Interferon-gamma; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Matrix Metalloproteinase 8; Methylhistamines; Monocytes; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Thiourea; Up-Regulation

Activation of histaminergic and noradrenergic/adrenergic neurons in the brain stimulates the release of the neurohypophysial hormones arginine vasopressin (AVP) and oxytocin (OT) and are involved the mediation of the hormone responses to physiological stimuli such as dehydration and suckling. We therefore investigated whether the two neuronal systems interact in their regulation of AVP and OT secretion in conscious male rats. When administered intracerebroventricularly (i.c.v.), histamine (HA) as well as the H1 receptor agonist 2-thiazolylethylamine or the H2 receptor agonist 4-methylHA stimulated AVP and OT secretion. Prior i.c.v. infusion of antagonists specific to alpha or beta adrenergic receptors or their subtypes did not significantly affect the hormone response to HA or the histaminergic agonists. Infused i.c.v. norepinephrine (NE) or epinephrine (E) increased AVP and OT secretion. Prior i.c.v. infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the AVP and OT responses to NE and the AVP response to E, whereas only cimetidine inhibited the OT response to E significantly. Systemic pretreatment with imetit, which by activation of presynaptic H3 receptors inhibits neuronal synthesis and release of HA, decreased the AVP and OT responses to NE and E significantly. In the doses used, HA and E had no significant effect on mean arterial blood pressure. NE increased mean arterial blood pressure 10% at 1 and 2.5 min, whereafter the blood pressure returned to basal level within 10 min. The results indicate that noradrenergic and adrenergic neurons stimulate AVP and OT secretion via an involvement of histaminergic neurons, which may occur at magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The stimulatory effect of the amines on neurohypophysial hormone secretion seems to be independent of a central action on blood pressure. In contrast, a functionally intact noradrenergic and adrenergic neuronal system seems not to be a prerequisite for a HA-induced release of AVP and OT. The present findings further substantiate the role of histaminergic neurons in the central regulation of neurohypophysial hormone secretion.

Topics: Animals; Arginine Vasopressin; Blood Pressure; Cerebral Ventricles; Cimetidine; Epinephrine; Histamine; Histamine Agonists; Hypothalamus; Imidazoles; Infusions, Parenteral; Male; Methylhistamines; Norepinephrine; Oxytocin; Pituitary Gland, Posterior; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H2; Thiazoles; 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

We used intracellular microelectrodes to study the effects of histamine on both normal and abnormal automaticity in sheep Purkinje fibers. Histamine, dimaprit and 4-methylhistamine caused a similar reduction of the action potential duration in driven Purkinje fibers. Histamine (10-6 M) induced spontaneous activity in p previously quiescent preparations more often than did equimolar concentrations of dimaprit and 4-methylhistamine. The effects of histamine on automaticity were enhanced in the presence of barium In fact histamine, at concentrations which were unable to induce automaticity in normal preparations, induced it in the presence of barium. In Purkinje fibers manifesting barium-induced automatic activity, histamine (10-7--10-6M) significantly increased the average number of spontaneous action potentials and shortened the time of their appearance. In the same range of concentrations, histamine dose-dependently increased the iological manifestation of calcium overload. Histamine (10-6--10-4M) increased the OAP amplitude of strophanthidin -treated Purkinje fibers, eventually inducing triggered extrabeats. All these previously described effects were selectively blocked by cimetidine (10-5 M). It is concluded that histamine may induce cardiac arrhythmias under conditions of calcium overload and that this effect may be due to induction or enhancement of oscillatory afterpotentials.

Topics: Animals; Barium; Dimaprit; Electrophysiology; Heart; Histamine; Histamine H2 Antagonists; In Vitro Techniques; Membrane Potentials; Methylhistamines; Purkinje Fibers; Sheep; Strophanthidin; Thiourea

In rats under a mild stress of restraint the interaction between central opioid receptors and histaminergic stimulation of the pituitary-adrenocortical activity was investigated indirectly through corticosterone secretion. In order to avoid a possible direct action on adrenal glands, all the tested drugs were administered intracerebroventricularly (icv). Naloxone an opioid antagonist and cimetidine, a H2- and mepyramine a H1-receptor antagonists were given 15 min before histamine and histamine agonists. One hour after histaminergic drug injection the rats were restrained for 10 min and decapitated. Histamine, 2-pyridylethylamine (PEA), a histamine H1-receptor agonist, and 4-methylhistamine (MeHA) and dimaprit, H2-receptor agonists, significantly intensified the stress-induced increase in serum corticosterone levels. Naloxone, given alone icv or ip, did not substantially alter the stress-induced corticosterone response. Like mepyramine naloxone abolished the corticosterone response to PEA in stressed rats. Naloxone also decreased significantly, though not totally, the corticosterone response to MeHA, dimaprit and histamine, its efficiency being similar to that of cimetidine, a H2-receptor antagonist. These results suggest that in stressed rats central opioid receptors are considerably involved in the histamine H1-receptor - and, to a lesser degree, in the H2-receptor stimulation of the hypothalamo-pituitary-adrenocortical axis.

Topics: Animals; Cimetidine; Corticosterone; Dimaprit; Histamine; Male; Methylhistamines; Naloxone; Pituitary-Adrenal System; Pyridines; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Restraint, Physical; Stress, Physiological; Thiourea

Histamine produces concentration-dependent contractions of lung parenchyma strips obtained from normal and sensitized guinea-pigs. The responsiveness of the sensitized lung strips to histamine was significantly increased compared to normal tissues. Clemizole (0.1 microM) was equally effective as an H1-antagonist in normal (dose-ratio 9.12) and sensitized (dose-ratio 9.77) tissues. The concentration-response curves to histamine were displaced to the left by cimetidine (0.1 microM to 0.1 mM) with similar dose-ratios in normal and sensitized tissues. Cimetidine enhanced maximal responses to histamine only in normal lung strips. The effects of submaximal equieffective concentrations of histamine were augmented to the same extent by cimetidine (0.1 mM) in normal and sensitized tissues. The responses to histamine were not modified by indomethacin (5 microM). The responsiveness and sensitivity of sensitized lung strips to isoprenaline, impromidine, 4-methyl-histamine and dimaprit were not different from those of normal tissues. Cimetidine yielded, as antagonist of dimaprit, similar pA2 values in normal and sensitized tissues. In conclusion, there is no experimental evidence in favour of the existence of an impairment of H2-receptor activity in sensitized airways. Hyperreactivity to histamine is probably due to differences between normal and sensitized tissues with respect to Ca2+ entry and/or intracellular Ca2+ release in response to H1-receptor activation.

Topics: Animals; Benzimidazoles; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Guanidines; Guinea Pigs; Histamine; Imidazoles; Impromidine; Isoproterenol; Lung; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Receptors, Histamine H2; Thiourea

The effects of intracerebroventricular injection of histamine H2-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H2-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4-0.8 mumol/rat) and 4-MeH (0.4-0.8 mumol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mumol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H2-antagonists CIM (0.8 mumol/rat) and RAN (0.6 mumol/rat) also enhanced the pain threshold, while FAM (0.03 mumol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H2-receptors and that the activation of HA-H2-receptors is inhibitory to nociception.

Topics: Animals; Dimaprit; Histamine H2 Antagonists; Male; Methylhistamines; Nociceptors; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Thiourea

The effects of administration into the brain ventricle of H2 receptor agonists (4-methylhistamine, 0.8 mumol/rat; dimaprit, 0.4-0.8 mumol/rat), H2 antagonists (cimetidine, 0.8 mumol/rat; ranitidine, 0.4-0.8 mumol/rat; famotidine, 0.03 mumol/rat) and of the dimaprit chemical analogue SK&F 91487 (0.4 mumol/rat) on unstimulated and histamine-stimulated prolactin secretion in normal male rats were studied. The H2 agonist 4-methylhistamine caused a significant increase in unstimulated blood PRL, whereas dimaprit, SK&F 91487, and the H2 antagonists tested did not change PRL levels. 4-Methylhistamine significantly enhanced the stimulatory effects of histamine on prolactin, whereas all the H2 antagonists inhibited histamine-induced prolactin release. The inhibition of histamine-induced prolactin secretion by the H2 agonist dimaprit is nonspecific, since its chemical analogue SK&F 91487, which has no H2 agonist activity, also inhibits it. These results indicate that stimulation of the H2 receptors in the central nervous system is facilitatory for PRL secretion, suggesting that the activation of H2 receptors may contribute to the PRL-releasing effects of histamine.

Topics: Animals; Brain; Cimetidine; Dimaprit; Famotidine; Histamine H2 Antagonists; Injections, Intraventricular; Male; Methylhistamines; Prolactin; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Thiazoles; Thiourea

From measurements of chronotropy in the guinea-pig isolated right atrium, a compound (E1309) was found which behaved as an irreversible antagonist at the histamine H2 receptor. E1309 was used to block irreversibly a proportion of the H2 receptors and the dissociation constants, relative efficacies and receptor reserves of four H2-agonists were determined. The calculated dissociation constants were similar to the Ki values reported from H2-radioligand binding studies but different from the observed EC50 values. The order of potency for the four H2-agonists was impromidine much greater than histamine greater than dimaprit greater than 4-methylhistamine. The order of relative efficacy was 4-methylhistamine greater than dimaprit greater than histamine greater than impromidine, the natural agonist not being the most efficacious. This atypical finding is discussed in relation to other receptor classes.

Topics: Animals; Dimaprit; Dose-Response Relationship, Drug; Female; Guanidines; Guinea Pigs; Heart Rate; Histamine; Histamine H2 Antagonists; Imidazoles; Impromidine; In Vitro Techniques; Male; Methylhistamines; Receptors, Adrenergic, beta; Receptors, Histamine; Receptors, Histamine H2; Thiazoles; Thiourea

Controversy exists regarding the involvement of H1- or H2-receptors in the PRL-releasing activity of histamine (HA). This could be due to differences in the route of administration of HA and histaminergic compounds. Therefore, we studied the effect on PRL secretion of HA and HA-agonists infused intracerebroventricularly (ICV) or systemically (IA) either alone or in combination with HA-antagonists in male rats. HA administered ICV as well as IA stimulated PRL secretion dose dependently. The stimulatory effect of ICV-infused HA was blocked by the H2-receptor antagonist cimetidine (CIM) and mimicked by the H2-receptor agonists 4-methylhistamine (4-MeHA) and dimaprit (DIM). In contrast, the H1-receptor antagonist mepyramine (MEP) enhanced the PRL-releasing effect of HA while the H1-receptor agonist 2-thiazolylethylamine (2-TEA) had no significant effect. The stimulatory effect of IA-infused HA was blocked by the H1-receptor antagonist MEP and mimicked by the H1-receptor agonist 2-TEA, whereas the H2-receptor antagonist CIM enhanced the PRL-stimulatory effect of HA and the H2-receptor agonist DIM was without effect. 4-MeHA stimulated PRL secretion, but this effect was unrelated to stimulation of H2-receptors. The effect of ICV administered HA was unaffected by IA infused antagonists and the effect of IA administered HA was not altered by ICV infused antagonists. HA had no effect on the PRL release from isolated adenohypophyses, and HA did not stimulate PRL secretion in pituitary stalk-sectioned rats following IA infusion. The findings indicate that HA administered ICV exerts its PRL releasing activity via H2-receptors while HA administered IA stimulates PRL secretion via H1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cimetidine; Dimaprit; Histamine; Histamine H1 Antagonists; Male; Methylhistamines; Pituitary Gland, Anterior; Prolactin; Pyrilamine; Pyrimidinones; Rats; Receptors, Histamine; Thiazoles; 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

In the rats subjected to a mild stress of immobilization impromidine, and H2-receptor agonist, given 60 min prior to the stress, intensified the stress-induced increase in hypophyseal-adrenocortical response, evaluated indirectly through the corticosterone concentration in the blood serum. Impromidine was far more potent but only about half as efficient as histamine, 4-methyl histamine (4-MH) and dimaprit. The effect of impromidine was abolished by pretreatment of the rats with cimetidine. The alpha-adrenergic blockers phenoxybenzamine, phentolamine and yohimbine, almost totally antagonized the corticosterone response to impromidine in stressed rats. Propranolol, a beta-adrenergic blocker, abolished the corticosterone response to impromidine but did not antagonize the response to 4-MH and dimaprit. The effect of impromidine was not modified by i.c.v. pretreatment of the rats with atropine. The results obtained show that impromidine is far more potent but less efficient than histamine and the previously known selective H2-receptor agonists in inducing the pituitary-adrenocortical response in stressed rats. These results also suggest that impromidine may release norepinephrine but not interact with cholinergic receptors while stimulating the corticosterone response in stressed rats.

Topics: Adrenal Cortex; Animals; Atropine; Cimetidine; Corticosterone; Dimaprit; Imidazoles; Impromidine; Injections, Intraventricular; Male; Methylhistamines; Pituitary Gland; Propranolol; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Restraint, Physical; Stress, Physiological; Sympatholytics; Thiourea

Topics: Animals; Dimaprit; Guinea Pigs; Histamine H2 Antagonists; Ileum; Imidazoles; Impromidine; In Vitro Techniques; Methylhistamines; Muscle Contraction; Muscle, Smooth; Pyrimidinones; Receptors, Histamine; Receptors, Histamine H2; Thiourea

Responses to histamine agonists administered intraventricularly under ether anesthesia were analyzed to evaluate receptor mediation in histamine stimulation of prolactin and LH release in ovariectomized, estradiol-progesterone-treated rats (OVX-E2P-treated rats). Prolactin release was markedly increased by the H2-histamine agonists, 4-methyl histamine and Dimaprit. These effects were antagonized by metiamide, an H2-blocking agent. The H1-histamine agonist, 2-(2-pyridyl)ethylamine (PEA) in high doses released prolactin and its effect was partially prevented by metiamide. Mepyramine, and H1-antagonist, did not exert any effect on the release of prolactin enhanced by the histamine agonists. LH release was significantly increased after 4-methyl histamine administration. Its effect was weak and was blocked by metiamide. Neither Dimaprit nor PEA exhibited action on plasma LH levels. The results obtained with histamine agonists suggest that histamine evokes prolactin release in OVX,E2P-treated rats through H2-receptors. At present, conclusions on H2-receptor mediation in LH release induced by histamine cannot be drawn from these results. The above-mentioned data, however, conclusively discard a significant participation of H1-receptors.

Topics: Animals; Castration; Dimaprit; Female; Histamine; Histamine H1 Antagonists; Luteinizing Hormone; Methylhistamines; Metiamide; Pituitary Gland, Anterior; Prolactin; Pyridines; Pyrilamine; Rats; Thiourea

In rats subjected to a mild stress of immobilization histamine, H1-receptor agonist 2-pyridylethylamine (PEA), and H2-receptor agonists, 4-methylhistamine (4-MHA) and dimaprit, given intraventricularly 60 min prior to stress, intensified the stress-induced increase of hypophyseal-adrenocortical response, evaluated indirectly through corticosterone concentration in blood serum. The effects were dose dependent and on a molar basis histamine and PEA were the most potent and 4-MHA and dimaprit were less effective, in this respect. The effect of histamine was almost totally blocked by both H1-receptor antagonists, mepyramine or chloropyramine, and by H2-receptor antagonists, metiamide or cimetidine. The corticosterone response to PEA was abolished by mepyramine, and the responses to 4-MHA or dimaprit were antagonized by cimetidine and metiamide. The response to the H1 agonist was not substantially altered by pretreatment with cimetidine, and the responses to the H2 agonists were not changed by mepyramine. These results suggest that in stressed rats the corticosterone response to histamine is mediated by both H1 and H2 central histamine receptors.

Topics: Animals; Corticosterone; Dimaprit; Histamine; Histamine Antagonists; Male; Methylhistamines; Pituitary-Adrenal System; Pyridines; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Stress, Physiological; Thiourea

The selectivity of 4-methylhistamine (4-MH) as an agonist at histamine H1- and H2-receptors has been evaluated in the guinea-pig isolated ileum. The EC50 values of 4-MH on H1- and H2-receptors that mediate contractile responses were determined. The EC50 at H1-receptors was estimated after selective blockade of H2-receptors by tiotidine and the EC50 at H2-receptors estimated after selective blockade of H1-receptors by mepyramine. The -log EC50 values at H1- and at H2-receptors were 4.57 and 5.23, respectively. The dissociation constants for the interaction of 4-MH with H1- and H2-receptors were determined. The -log KD values at H1- and H2-receptors were 3.55 and 4.27, respectively. These results suggest that 4-MH is only about 5 times as potent at H2- as it is at H1-receptors in the guinea-pig ileum and that 4-MH should be used with caution to discriminate between H1- and H2-receptors.

Topics: Animals; Dibenzylchlorethamine; Dimaprit; Drug Interactions; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle, Smooth; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Thiourea

The effects of histamine H2-receptor agonists and antagonists on isolated guinea-pig lung parenchymal and tracheal strips were investigated. Dimaprit, 10(-7) to 10(-3) M, produced dose-dependent relaxation of parenchymal strips while at 10(-3) M, tracheal strips relaxed only partially. Pretreatment of parenchymal strips with cimetidine or YM-11170, H2-receptor antagonists, resulted in a parallel shift of the dimaprit dose-response curve to the right. 4-Methylhistamine produced relaxation of parenchymal strips in a bell-shaped dose-related manner; at high concentrations, it effected the contraction of tracheal strips. In mepyramine-pretreated parenchymal and tracheal strips, 4-methylhistamine induced dose-dependent relaxation, indicating that at high concentrations, it stimulates two functionally opposite receptors, H1 and H2. These results suggest that there are H2-receptors in guinea-pig airways, predominantly in the periphery.

Topics: Airway Resistance; Animals; Cimetidine; Dimaprit; Drug Interactions; Guinea Pigs; Histamine H2 Antagonists; In Vitro Techniques; Male; Methylhistamines; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Receptors, Histamine; Receptors, Histamine H2; Thiourea; Trachea

1 Airway responses were examined in isolated tissues and in whole animal preparation of female albino guinea-pigs of known age. 2 Tone induced with acetylcholine in tracheal and bronchial tissues from young and old female guinea-pigs was not reduced by dimaprit or 4-methyl histamine even in tissues pretreated with mepyramine maleate. 3 Antagonism of H2-receptors with cimetidine did not affect the potency or efficacy of histamine in tracheal tissues from animals of either age group. 4 After cimetidine treatment the potency of histamine was increased in bronchial tissues from old but not young animals. The sensitizing effect was still demonstrable in tissues incubated with indomethacin. 5 In vivo airway sensitivity to threshold concentrations of histamine in animals from either age group was unaffected by cimetidine treatment. 6 Propranolol enhanced airway responses to histamine aerosols in young but not old guinea-pigs. 7 Cimetidine was without effect on histamine sensitivity in young guinea-pigs after propranolol treatment but significantly reduced airway sensitivity to histamine in old guinea-pigs. 8 Our data show that (a) H2-receptors are of no physiological significance for airway responses to histamine in vitro or in vivo and (b) during development the modulating actions of catecholamines upon airway responses are significantly reduced.

Topics: Aging; Airway Resistance; Animals; Bronchi; Cimetidine; Dimaprit; Female; Guanidines; Guinea Pigs; Histamine; In Vitro Techniques; Methylhistamines; Muscle Contraction; Propranolol; Receptors, Histamine; Receptors, Histamine H2; Thiourea; Trachea

Histamine, 4-methylhistamine and dimaprit induced a dose-dependent increase in the cyclic AMP content of chopped canine parotid gland in the presence of 3-isobutyl-1-methylxanthine. Metiamide, but not mepyramine, inhibited the effect of these agonists dose-dependently. The cyclic AMP content was also increased by 2-(2-pyridyl)ethylamine. This effect was completely blocked by propranolol. These results indicate that the cyclic AMP response to histamine in canine parotid gland is mediated by H2-receptors. Mepyramine enhanced the effect of histamine. However, 2-(2-pyridyl)ethylamine had no significant inhibitory effect on the cyclic AMP response to 4-methylhistamine. A combination of aminoguanidine and quinacrine potentiated the effect of histamine, though no difference was observed in the histamine concentration of the media with or without these inhibitors when determined at the end of incubation. This suggests that there exist active histamine-metabolizing systems in canine parotid gland.

Topics: Animals; Cyclic AMP; Dimaprit; Dogs; Female; Histamine; Histamine Antagonists; In Vitro Techniques; Male; Methylhistamines; Parotid Gland; Pyridines; Receptors, Histamine; Receptors, Histamine H2; 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

Effects of dimaprit and 4-methylhistamine, two histamine H2-receptor agonists, on noradrenaline and serotonin systems in the rat brain were investigated. Administration of dimaprit into the lateral brain ventricle produced 30% decrease in hypothalamal noradrenaline. 2 h after administration of dimaprit the level of 3-methoxy-4-hydroxyphenylglycol was increased by 50%. 4-Methylhistamine and histamine produced qualitatively the same effects as dimaprit. Dimaprit and 4-methylhistamine increased locomotor activity in tranylcypromine-treated rats. The hyperkinetic action of both drugs was prevented by phenoxybenzamine. Dimaprit had negligible effect on the serotonin system while 4-methylhistamine and histamine decreased serotonin and simultaneously increased 5-hydroxyindolcacetic acid. 4-Methylhistamine and histamine, but not dimaprit, evoked head-twitches in tranylcypromine-treated rats. It is concluded that dimaprit and 4-methylhistamine act similarly on the noradrenaline system, probably releasing noradrenaline, but having different effects on the serotonin system. 4-Methylhistamine (and histamine) probably releases serotonin from rat hypothalamus while dimaprit does not. The results are discussed in relation to a possible interaction of histamine with both noradrenaline and serotonin systems in the rat brain.

Topics: Animals; Behavior, Animal; Brain; Dimaprit; Female; Histamine; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol; Methylhistamines; Norepinephrine; Rats; Receptors, Histamine; Receptors, Histamine H2; Serotonin; Thiourea; Tranylcypromine