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PubMed1999

Effect of inflammatory mediators on the electrophysiology of the human oviduct.

The effects of histamine and other inflammatory mediators on the electrophysiology and intracellular free calcium ([Ca(2+)](i)) of human oviductal epithelial cells, grown as a polarized layer in primary culture, were studied. Transepithelial potential difference (PD) and short-circuit current (I(scc)) were recorded using a modified Ussing chamber. Resistance (R) was calculated from the measurements of PD and I(scc). Basally applied histamine produced transient increases in PD and I(scc) with a small decrease in R. The histamine effect was reduced by triprolidine (H(1) receptor antagonist) but was unaffected by H(2) (ranitidine) or H(3) (thioperamide) receptor antagonists. Blockers of Na(+), K(+), or Na(+)/K(+)/2Cl(-) channels did not affect histamine action. Blockers of Cl(-)/HCO(3)(-) channels or Ca(2+) channels reduced the histamine effect. Platelet activating factor (PAF), applied apically, increased PD and I(scc). Histamine produced a transient increase in fluorescence of Fura 2-AM dye, indicating an increase in [Ca(2+)](i). Triprolidine pretreatment inhibited histamine-stimulated [Ca(2+)](i) increase. Cimetidine, (H(2) receptor antagonist), ranitidine, or thioperamide reduced the histamine effect. Histamine increased contractions of both circular and longitudinal smooth muscles in oviduct segments, an effect that was antagonized by triprolidine or thioperamide but not by ranitidine. Histamine's action on Ca(2+) and Cl(-) movements may adversely affect oviductal fluid production and decrease fertility. PAF's effects on Cl(-) movements may be important for normal embryo transport.

Alprostadil↗
PubMed1993

Agonist-induced Ca2+ mobilization in cultured bovine and human corneal endothelial cells.

We investigated the possibility that cultured corneal endothelial cells express receptors that are coupled to the phosphoinositide cycle/intracellular Ca2+ signaling pathway. Agonist-stimulated changes in intracellular calcium ([Ca2+]i) in single bovine and human corneal endothelial cells (BCEC and HCEC, respectively) derived from confluent cultures were measured by microspectrofluorimetry using the Ca(2+)-sensitive probe, fura-2. Total inositol phosphates accumulated during a 30 min incubation in the presence or absence of agonists was determined in Li+ containing medium with cells pre-labelled for 48 hrs with 10 microCi/ml 3H-myoinositol. Histamine (HA), ADP and ATP induced a rapid increase in [Ca2+]i. Subsequently, [Ca2+]i decreased to either a stable, agonist-dependent sustained elevation, or fell back to baseline to begin oscillatory fluctuations. The initial rise in [Ca2+]i was insensitive to removal of extracellular calcium (Ca2+o), whereas the stable elevations in [Ca2+]i and the [Ca2+]i oscillations required Ca2+o. In contrast, bradykinin (BK) and endothelin-1 (ET-1) elicited an initial rise in [Ca2+]i that returned to prestimulatory levels within 2 min despite the continued presence of agonist. The Ca(2+)-mobilizing agonists carbachol, phenylephrine, adenosine and substance P were all ineffective in elevating [Ca2+]i. Histamine-induced Ca2+ mobilization was inhibited by the H1-receptor antagonist triprolidine, but triprolidine had no effect on either BK or ATP stimulation of Ca2+ mobilization. In BCEC, 100 microM HA significantly increased total inositol phosphate accumulation (18.8-fold over unstimulated controls) and was 90% inhibited by 0.5 microM triprolidine. BK and ATP also significantly increased formation of inositol phosphates in BCEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Distribution of antihistamines into the CSF following intranasal delivery.

The preferential absorption of certain drug compounds from the nasal cavity into the cerebrospinal fluid (CSF) raises questions regarding the transport processes controlling drug disposition following intranasal delivery. The disposition characteristics of several structurally similar antihistamine compounds, hydroxyzine, chlorpheniramine, triprolidine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femoral artery, respectively. The drug levels in CSF and plasma were assayed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption following nasal administration. Interestingly, the hydroxyzine levels in CSF following intranasal administration were significantly higher than those following intra-arterial administration. The AUC ratios between CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4.0 and 0.4, respectively. The AUC ratios for triprolidine, the other antihistamine with measurable CSF concentrations, were 0.5 and 0.7, respectively. The distribution of antihistamines from the nasal membrane into the CSF appears to be controlled by a combination of their molecular properties. It also appears that the intranasal delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved from an equivalent parenteral dose.

Administration, Intranasal↗
PubMed1991

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine.

The active conformation of several histamine H1-antagonists is investigated. As a template molecule we used the antagonist cyproheptadine, which consists of a piperidylene ring connected to a tricyclic system. The piperidylene moiety is shown to be flexible. The global minimum is a chair conformation but, additionally, a second chair and various boat conformations have to be considered, as their energies are less than 5 kcal/mol above the energy of the global minimum. Two semi-rigid histamine H1-antagonists, phenindamine and triprolidine, were fitted onto the various conformations of cyproheptadine in order to derive the pharmacologically active conformation of cyproheptadine. At the same time, the active conformation of both phenindamine and triprolidine was derived. It is demonstrated that, within the receptor-bound conformation of cyproheptadine, the piperidylene ring most probably exists in a boat form.

Binding Sites↗
PubMed1983

The H1-antagonist mequitazine: studies on performance and visual function.

The effects of single oral doses of mequitazine (5 and 10 mg), terfenadine (60 mg) and triprolidine (10 mg) as active controls, and placebo were evaluated on visuo-motor coordination, digit symbol substitution, critical flicker fusion and dynamic visual acuity, and on subjective assessments of mood and well-being in six normal female volunteers. The study was double-blind. Mequitazine (5 mg) impaired visuo-motor coordination 7.5 h after ingestion (considered to be a chance result), but there was no effect on digit symbol substitution, critical flicker fusion threshold or dynamic visual acuity. Mequitazine (10 mg) impaired visuo-motor coordination and reduced the number of substitutions on the digit symbol substitution test. Terfenadine (60 mg) had no effect on performance or on subjective feelings. Triprolidine (10 mg) impaired visuo-motor coordination, reduced the number of substitutions on the digit symbol test, lowered the critical flicker fusion threshold and reduced dynamic visual acuity. Mequitazine (5 mg) and terfenadine (60 mg) are likely to prove acceptable H1 antagonists when sedation must be avoided.

Adult↗
PubMed1984

The H2-antagonists, cimetidine and ranitidine: studies on performance.

The effects of single oral doses of cimetidine (200 and 400 mg) and ranitidine (150 and 300 mg) were evaluated on visuo-motor coordination, dynamic visual acuity, digit symbol substitution, symbol copying, and critical flicker fusion, and on subjective assessments of mood and well-being in seven healthy female volunteers. The study was double blind and placebo controlled, and triprolidine (10 mg) was used as an active control. With cimetidine and ranitidine there were no adverse changes in performance, central nervous function or subjective assessment of mood. Triprolidine impaired visuo-motor coordination, reduced the number of substitutions on the digit symbol substitution test and the number of symbols copied, lowered the critical flicker fusion threshold and reduced dynamic visual acuity. Cimetidine (200-400 mg) and ranitidine (150-300 mg) are highly unlikely to impair performance, and may be used in individuals involved in skilled activity.

Adult↗
PubMed1985

Histaminergic systems and sleep. Studies in man with H1 and H2 antagonists.

Effects of H1 (mepyramine, mequitazine, triprolidine and brompheniramine) and H2 (cimetidine and ranitidine) antagonists on sleep were studied in healthy man. There were no effects of mepyramine (50 and 100 mg), and the only effect of mequitazine (5 and 10 mg) was a reduction in the number of awakenings. Triprolidine (10 and 20 mg) and brompheniramine (4 and 8 mg) did not alter wakefulness during sleep or the total sleep time, but rapid eye movement sleep was reduced. There were no effects of ranitidine (150 and 300 mg), but slow wave sleep was increased by cimetidine (200 and 400 mg). It is tentatively suggested that the histaminergic system is concerned with the mechanisms which favour vigilance during the wakeful state, and the balance between wakefulness and slow wave activity during sleep. Effects of some H1 antihistamines on rapid eye movement sleep are believed to be due to their monoaminergic rather than their histaminergic activity.

Adolescent↗
PubMed1996

Efficacy of acrivastine plus pseudoephedrine for symptomatic relief of seasonal allergic rhinitis due to mountain cedar.

BACKGROUND: Acrivastine is a second-generation H1-antagonist chemically related to triprolidine, but more polar and with less central nervous system penetration than triprolidine. OBJECTIVE: The efficacy of the antihistamine-decongestant combination product (Semprex-D capsules) containing acrivastine 8 mg plus pseudoephedrine HCl 60 mg was evaluated for the treatment of seasonal allergic rhinitis symptoms. METHODS: A total of 676 patients sensitive to mountain cedar pollen was enrolled into a 6-center, randomized, double-blind, placebo-controlled, parallel, 4-group study designed to compare acrivastine + pseudoephedrine, acrivastine, pseudoephedrine, and placebo. Patients with demonstrable diary symptom scores at baseline took study medication (4 doses/day) and recorded symptom scores twice daily for 2 weeks. The effectiveness of the acrivastine + pseudoephedrine combination was examined relative to the individual components and placebo in terms of changes in diary symptom scores. RESULTS: Over the 2-week period, the combination of acrivastine plus pseudoephedrine was significantly more effective than (1) acrivastine, pseudoephedrine, and placebo (P < .001) for relief of all symptoms; (2) pseudoephedrine (P < .001) for relieving allergy symptoms, ie, running nose, sneezing, itchy nose/throat and tearing; and (3) acrivastine (P < .001) for reducing nasal congestion. Relative to placebo, small increases in adverse experience rates were observed with acrivastine + pseudoephedrine for dry mouth, insomnia, somnolence, and headache. CONCLUSION: These findings in a large clinical trial demonstrate (1) the efficacy of acrivastine and (2) that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Adolescent↗
PubMed1991

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Adult↗
PubMed1980

N,N-Diethyl-2-(1-pyridyl)ethylamine, a partial agonist for the histamine receptor in guinea pig ileum.

N,N-Diethyl-2-(1-pyridyl)ethylamine (E-2-P) produced 59 +/- 7% of the maximal response to histamine in guinea pig ileal longitudinal smooth muscle and antagonized the responses of this tissue to histamine. The estimated binding constant of E-2-P for the histamine receptor predicted a binding curve nearly coincident with the agonist concentration-response curve indicating no receptor reserve for this partial agonist. Diphenhydramine (30 nM) produced competitive antagonism of response to E-2-P (pKB = 8.3 +/- 0.13). Triprolidine (0.3 nM), a slower acting antihistamine, produced a depression of the maximal responses to E-2-P. This effect was analyzed in terms of a "hemi-equilibrium" hypothesis which approximates a pseudoirreversible antagonism of histamine receptors by triprolidine with respect to E-2-P. All data are consistent with the classification of E-2-P as a simple partial agonist for the histamine receptor of guinea pig ileum.

Animals↗
PubMedDate not supplied

Effects of a single dose of loratadine on flying ability under conditions of simulated cabin pressure.

Pilots with allergic diseases, who need antihistaminic drug therapy, have to be grounded temporarily because this therapy is considered to interfere with flight safety due to its sedative effects. There is evidence that loratadine is practically void of these sedative effects, and therefore might be prescribed to pilots. A study was conducted to determine the effects of loratadine on performance and alertness. In a randomized, double-blind, within subjects design, 18 male subjects were studied, employing loratadine 10 mg, triprolidine hydrochloride 5 mg, and placebo. Objective (vigilance, complex tasks) and subjective tests, tailored to the specific tasks of aircrew, were applied under hypobaric conditions that prevail in an intact cockpit. With respect to alertness and performance, the results of this study showed no significant differences between loratadine and placebo during a period of 1 to 6 hours after drug ingestion. Triprolidine, used as a positive control, showed significant detrimental effects on both subjective and objective measures. It is anticipated that a single dose of loratadine 10 mg will not affect flying performance. This finding might also have implications for the treatment of allergic disorders of personnel involved in other highly skilled jobs.

Adult↗
PubMed1986

H1-histamine receptors on human astrocytoma cells.

The H1-histamine receptor antagonist [3H]mepyramine bound with high affinity (Kd = 3-5 nM) to membranes derived from 1321N1 human astrocytoma cells. The H1-receptor antagonists triprolidine and diphenhydramine inhibited [3H]mepyramine binding with Kj values of 1-5 nM, whereas the Kj of the H2-histamine receptor antagonist cimetidine was greater than 100 microM. Histamine also inhibited [3H]mepyramine binding to 1321N1 cell membranes, and the histamine inhibition curve was shifted to the right and steepened in the presence of 1 microM guanosine 5'-O-(3-thiotriphosphate). Treatment of 1321N1 cells with pertussis toxin had no effect on the capacity of histamine to inhibit [3H]mepyramine binding either in the absence or presence of guanosine 5'-O-(3-thiotriphosphate). Therefore, agonist-occupied histamine receptors in these cells apparently interact with a guanine nucleotide regulatory protein that is not the inhibitory guanine nucleotide regulatory protein of adenylate cyclase. Although adenylate cyclase activity was not affected by histamine in a cell-free preparation, incubation of 1321N1 cells with histamine resulted in an attenuation of cyclic AMP accumulation. Analysis of cyclic AMP degradation in the presence of histamine indicated that the effects of histamine on cyclic AMP accumulation are mediated through activation of phosphodiesterase. This idea was supported by the fact that the phosphodiesterase inhibitor 1-isobutyl 3-methylxanthine blocked attenuation of cyclic AMP accumulation by histamine in a noncompetitive manner. Histamine also markedly increased phosphoinositide breakdown and 45Ca2+ efflux in 1321N1 cells. These histamine-induced effects apparently are mediated through H1-receptors, since triprolidine, but not cimetidine, potently inhibited histamine action. As for histamine interaction with its receptor, pertussis toxin had no effect on histamine-induced phosphoinositide breakdown, 45Ca2+ efflux, or attenuation of cyclic AMP accumulation. Taken together, these data indicate that 1321N1 human astrocytoma cells are a useful model system for the study of H1-histamine receptors and the biochemical responses mediated through these receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids.

Animals↗
PubMed2003

Histaminergic receptors modulate the coronary vascular response in isolated guinea pig hearts. Role of nitric oxide.

OBJECTIVE: The effects of histamine and of histamine receptor agonists and antagonists on the coronary outflow and on the generation of nitric oxide (NO) were evaluated on isolated guinea pig hearts. METHODS: Isolated guinea pig hearts were perfused for 50 min in a Langendorff apparatus with histamine (10(-7)- 10(-8) M), in the absence or in the presence of N(G)-monomethyl-L-arginine (L-NMMA, 10(-4) M), a NO synthase inhibitor and of triprolidine (3.10(-8) M) and cimetidine (10(-7) M), H(1) receptor and H(2) receptor antagonists, and with trifluoromethyl-phenylhistamine (TFMPH, 10(-7) M) and dimaprit (10(-7) M), H(1) and H(2) receptor agonists. The effects of (R)-alpha-methylhistamine (10(-7) M), a H(3) receptor agonist and of FUB 181 (10(-7) M), a H(3) receptor antagonist, were studied in the presence of bradykinin (10(-7) M). RESULTS: Histamine increases the coronary outflow and the generation of NO in a concentration-dependent fashion. The effects were completely abolished by blocking NO-synthase (NOS) with L-NMMA (10 (-4 ) M). The effects were also abolished by cimetidine (10 (-7 ) M), H (2 ) receptor antagonist, and only scarcely affected by triprolidine (3.10 (-8 ) M), H (1 ) receptor antagonist. The effects were reproduced by dimaprit (10 (-7 ) M), H (2 ) receptor agonist, and only scarcely by TFMPH (10 (-7 ) M), a selective H (1 ) receptor agonist. Bradykinin (10 (-7 ) M) produces a sustained coronary dilation paralleled by a marked increase in the generation of NO; the effects were significantly reduced by L-NMMA. The stimulation of H (3 ) receptors by (R)-alpha-methylhistamine (10 (-7 ) M) significantly reduced both effects, which reverted to normal with FUB 181 (10 (-7 ) M), an H (3 ) receptor antagonist. CONCLUSION: These results suggest that, in isolated guinea pig hearts, histamine produces coronary dilation through an H (2 )/H (3 )-dependent mechanism involving the generation of nitric oxide.

Animals↗
PubMed1999

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H1 and H2 histamine receptors.

To investigate whether H1 and H2 histamine receptors are implicated in the modulation of acetylcholine release by endogenous histamine, the ventral striatum of the conscious, freely moving rat was superfused by the push-pull superfusion technique with drugs and the release of acetylcholine was determined in the superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA, 50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect of triprolidine was not influenced either on simultaneous superfusion with 10 micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist) and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced acetylcholine release rate in the ventral striatum. Presuperfusion with alpha-fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of histamine, abolished the famotidine-induced release of acetylcholine. The releasing effect of famotidine was also abolished on simultaneous superfusion with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of acetylcholine elicited by famotidine was reversed to a decreased acetylcholine outflow when the striatum was superfused with the GABA(A) receptor antagonist bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2 agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the presence of bicuculline the release of acetylcholine by dimaprit was enhanced and prolonged. It seems possible that dimaprit and impromidine stimulate different subtypes of H2 receptors. The findings suggest that the release of acetylcholine in the striatum is modulated by neighbouring histaminergic neurons in a complex way. Stimulation of H1 histamine receptors, probably located on cholinergic neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors located on cholinergic or GABAergic neurons enhances the release of acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons exerts the opposite effect.

Acetylcholine↗
PubMed1995

Blockers for excitatory effects of achatin-I, a tetrapeptide having a D-phenylalanine residue, on a snail neurone.

Some histamine H1 receptor antagonists suppressed the inward current (Iin) of an Achatina identifiable neurone type, PON (periodically oscillating neurone), caused by an Achatina endogenous tetrapeptide having a D-phenylalanine residue, achatin-I (Gly-D-Phe-Ala-Asp), under voltage clamp. Achatin-I was applied locally to the neurone by brief pneumatic pressure ejection and antagonists were administered by perfusion. The dose-response curves of the effective histamine H1 antagonists indicated their potency order to suppress the Iin as follows: chlorcyclizine, promethazine, triprolidine and homochlorcyclizine > trimeprazine and clemastine > diphenylpyraline. The potent drugs were mostly piperazine and phenothiazine types. The effects of chlorcyclizine, promethazine and triprolidine on the dose (the duration of the pressure ejection)-response curve of achatin-I indicated that these drugs affected the Iin caused by achatin-I in a non-competitive manner. The antagonists for the receptors of the small-molecule neurotransmitters other than histamine H1, such as histamine H2, acetylcholine, gamma-aminobutyric acid (GABA), L-glutamic acid, dopamine, alpha- and beta-adrenalin and 5-hydroxytryptamine, had no effect on the Iin caused by achatin-I.

Amino Acid Sequence↗
PubMed2005

Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H2 receptors in vitro.

Previous studies have revealed distribution of histaminergic fibers and presence of histamine receptors in globus pallidus (GP). In this study, the brain slice preparation of adult rats was used to examine the effect of histamine on the spontaneous unitary discharge of GP neurons and the underlying receptor mechanism. Ninety-five GP neurons were extracellularly recorded from 42 slices containing the GP, of which 87 (91.6%) were excited by the stimulation of histamine. The histamine-induced excitation was concentration-dependent and persisted in low Ca2+/high Mg2+ medium (n = 9), demonstrating that the action of histamine on the GP neurons was postsynaptic. The excitatory effect of histamine on the GP neurons was not blocked by selective histamine H1 receptor antagonist triprolidine (n = 16) or chlorpheniramine (n = 6), but was effectively suppressed by ranitidine, a highly selective histamine H2 receptor antagonist (n = 21). On the other hand, highly selective histamine H2 receptor agonist dimaprit mimicked the excitatory effect of histamine on the GP neurons (n = 23), while histamine H1 receptor agonists, including 2-pyridylethylamine (n = 22), 2-thiazolyethylamine (n = 9) and betahistine (n = 9), did not cause GP neurons any response. The dimaprit-induced GP neuronal excitation was effectively antagonized by selective histamine H2 receptor antagonist ranitidine (n = 14) but not influenced by selective histamine H1 receptor antagonist triprolidine (n = 12). Moreover, adenylate cyclase (AC) activator forskolin (n = 7) was observed to evoke GP neurons an excitatory response, whereas the histamine-induced excitation was effectively reduced by H-89 (n = 9), a selective and potent inhibitor of protein kinase A (PK(A)). Finally, it was noted that neurons of both subdivisions of the GP, the internal (GPi, n = 35) and external (GPe, n = 60) segment, showed no differences in their responses to stimulations of the tested histaminergic reagents. These results demonstrated that histamine excited GP (including GPi and GPe) neurons via histamine H2 receptors and H2 receptors linked intracellular G-protein-AC-PK(A) signaling pathway, suggesting that the hypothalamic histaminergic afferent fibers innervating GP may play an important modulatory role in motor control through its excitatory effect on GP neurons.

Action Potentials↗
PubMed2000

Histamine excites rat cerebellar Purkinje cells via H2 receptors in vitro.

Recent neuroanatomical studies have revealed a direct hypothalamocerebellar histaminergic pathway. However, the functional significance of the histaminergic fibers in the cerebellum is not yet clear. In this study, the effects of histamine on the firing of cerebellar Purkinje cells (PCs) were investigated in vitro. Histamine predominantly produced excitatory (106/111, 95.5%) and in a few cases inhibitory (5/111, 4.5%) responses in PCs. The histamine-induced excitation was not blocked by perfusing the slice with low Ca2+ high/Mg2+ medium (n = 8), supporting a direct postsynaptic action of histamine. The histamine H2 receptor antagonist ranitidine effectively blocked the excitatory response of PCs to histamine (n = 20), but triprolidine, an H1 receptor antagonist, could not significantly block the histamine-induced excitation, or only very slightly decreased the excitatory effect of histamine on the cells (n = 13). On the other hand, the highly selective H2 receptor agonist dimaprit mimicked the excitatory effect of histamine on PCs and this dimaprit-induced excitation was also blocked by ranitidine (n = 20), but not triprolidine (n = 8). However, the H1 receptor agonists betahistine and 2-thiazolylethylamine did not show any effect on the PCs (n = 9 and 14). These results reveal that histamine excites cerebellar PCs via H2 receptors and suggest that the hypothalamocerebellar histaminergic fibers may play an important role in functional activities of the cerebellum.

Action Potentials↗