Inhibition Of Histamine-induced Contraction Research Articles

Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice

To explore whether intestinal microflora plays a role in anti-pruritic activity of baicalin, a main constituent of the rhizome of Scutellaria baicalensis (SB). Baicalin was anaerobically incubated with human fecal microflora, and its metabolites, baicalein and oroxylin A, were isolated. The inhibitory effect of baicalin and its metabolites was accessed in histamine- or compound 48/80-induced scratching behavior in mice. Baicalin was metabolized to baicalein and oroxylin A, with metabolic activities of 40.2+/-26.2 and 1.2+/-1.1 nmol.h(-1).mg(-1) wet weight of human fecal microflora, respectively. Baicalin (20, 50 mg/kg) showed more potent inhibitory effect on histamine-induced scratching behavior when orally administered than intraperitoneally. In contrast, baicalein and oroxylin A had more potent inhibitory effect when the intraperitoneally administered. The anti-scratching behavior activity of oral baicalin and its metabolites was in proportion to their inhibition on histamine-induced increase of vascular permeability with oroxylin A more potent than baicalein and baicalin. In Magnus test using guinea pig ileum, oroxylin A is more potent than baicalein and baicalin in inhibition of histamine-induced contraction. The anti-scratching behavioral effect of oral baicalin was significantly reduced when oral antibiotics were simultaneously administered, whereas the effect of baicalein and oroxylin A were not affected. Oral baicalin may be metabolized by intestinal microflora into baicalein and oroxylin A, which ameliorate pruritic reactions through anti-histamine action.

Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent

These studies aimed to outline the in vitro and in vivo histamine H(1) receptor antagonistic activity and safety pharmacology of SUN-1334H, a new potent antihistamine agent under clinical development. In vitro antihistamine activity and selectivity of SUN-1334H was evaluated in a panel of receptor and enzyme assays and functional assays using isolated tissues. In vivo antihistamine and antiallergy efficacy were assessed following oral administration of SUN-1334H in histamine-induced bronchoconstriction in guinea pigs, skin wheal in beagle dogs and ovalbumin-induced rhinitis (sneezing, vascular permeability and intranasal pressure) in guinea pigs. Cardiovascular safety was assessed by CHO-K1/human ether-à-go-go related gene (hERG) K(+) current assay, dog telemetry and guinea-pig ECG. CNS safety was assessed by functional observational battery in rats and pentobarbital-induced sedation and pentylenetetrazol-induced convulsions in mice. The effect on intestinal motility was assessed in rats. In vitro receptor binding assays showed that SUN-1334H had high histamine H(1) receptor binding affinity with an inhibition constant value of 9.7 nmol/L and either no or insignificant affinity with a panel of receptors and enzymes. In functional assays, SUN-1334H caused potent inhibition of histamine-induced contractions of isolated guinea-pig ileum with an IC(50) (half the maximal inhibitory concentration) of 0.198 micromol/L. In contrast, SUN-1334H had no significant effect on isolated tissue contractions induced by cholinergic, H(2)-histaminergic, serotonergic, adrenergic receptor agonists or BaCl(2). In studies of animal models of histamine-mediated disorders, SUN-1334H potently inhibited histamine-induced bronchospasm over 24 hours following oral administration and completely suppressed histamine-induced skin wheal in beagle dogs and ovalbumin-induced rhinitis in guinea pigs. In CHO-K1/hERG cells, SUN-1334H did not modulate hERG K(+)-currents at concentrations as high as 100 micromol/L. Cardiovascular and CNS function and intestinal motility were not altered at doses several-fold greater than those required for efficacy, indicating a good safety profile of the drug. SUN-1334H is a potent, orally active, highly selective H(1) receptor antagonist with a long duration of action in its preclinical profile. It has potential for the treatment of disorders involving histamine as a mediator.

Demonstration of antihistamine properties with AST-1: a bioactive extract from garden slugs (Diplosolenodes occidentalis)

Parched and ground whole garden slugs are claimed in rural Jamaican folklore practices to have useful effects in the treatment of bronchial asthma. Since this claim may be associated with respiratory dysfunction due to histamine from allergic sensitization, the authors investigated the effects of a semi-pure alcoholic extract (AST-1) on histamine-induced contraction of the guinea pig in vitro tracheal muscle preparation and cutaneous allergic responses in ovalbumin sensitized guinea pigs. Chemical analysis of AST-1 by column chromatography and thin layer chromatography indicated two compounds in the composition, but the molecular structures were not determined Pharmacological evaluation of AST-1 produced a concentration-dependent inhibition of histamine-induced contraction of the guinea pig tracheal muscle preparation. AST-1 also inhibited contraction of the tracheal muscle produced by selective H1 receptor stimulation with HTMT dimaleate. H2 receptors were not involved, as indicated by the absence of contraction with dimaprit hydrochloride, a selective H2 agonist. Also, in ovalbumin sensitized guinea pigs, AST-1 and diphenhydramine, a selective H1 antagonist, inhibited the cutaneous responses due to intradermal injection of histamine and ovalbumin. These results suggest that AST-1 has H1 anti-histamine properties which can inhibit histamine-induced tracheobronchial muscle contraction and cutaneous responses due to allergy.

Pharmacological Differences between Liu-Jun-Zi-Tang, a Traditional Chinese Herbal Medicine, and Domperidone on Isolated Guinea-Pig Ileum

The different characteristics of Liu-Jun-Zi-Tang, a spray-dried powdered extract from 8 Chinese herbs, and domperidone, a D2 antagonist, both of which are used clinically for the treatment of gastritis, were validated in isolated guinea pig ileal longitudinal muscle. Liu-Jun-Zi-Tang at 0.05 mg/ml did not affect the twitch response by electrical field stimulation, but it concentration-dependently inhibited the twitch response at concentrations of 0.1 and 1.0 mg/ml, and maximum inhibition occurred 5 min after application of Liu-Jun-Zi-Tang. In the presence of Liu-Jun-Zi-Tang, the concentration-response curve for ACh-contraction showed inhibition in a non-competitive manner, which is the same as domperidone. In the presence of Liu-Jun-Zi-Tang (1.0 mg/ml), ACh (10(-7) M)-, histamine (5x10(-7) M)- and barium chloride (10(-4) M)-induced basal contractions were inhibited by 24, 19 and 54 %, respectively. On the other hand, in the presence of domperidone (2x10(-5) M), ACh- and barium chloride-induced basal contractions were inhibited by 28 and 63%, respectively, similar to that in the presence of Liu-Jun-Zi-Tang. However, the inhibition of histamine-induced contraction in the presence of domperidone was significantly increased (81%) compared with that in the presence of Liu-Jun-Zi-Tang. These findings suggest that Liu-Jun-Zi-Tang has milder effects on histamine-induced disorders than domperidone. In other words, domperidone has a more potent effect on histamine-induced disorders.

Inhibition of histamine-induced contraction during a long exposure to low [Cl]o condition of the rabbit basilar artery

Inhibition of histamine-induced contraction during a long exposure to low [Cl]o condition of the rabbit basilar artery

P-303 - Inhibition of histamine-induced contraction by a novel anti-diabetics, troglitazone in the porcine coronary artery

P-303 - Inhibition of histamine-induced contraction by a novel anti-diabetics, troglitazone in the porcine coronary artery

Prostaglandin E 2, but not prostacyclin inhibits histamine-induced contraction of human bronchial smooth muscle

The effects of exogenous prostaglandin E 2 and prostacyclin on the function of epithelium-intact and epithelium-denuded human bronchial smooth muscle and the role of these mediators in the inhibition of histamine-induced contraction was examined using bronchi obtained from 22 patients undergoing thoracotomy. Under resting tension, a variable biphasic contraction-relaxation or monophasic relaxation was observed following the cumulative addition of exogenous prostaglandin E 2 or prostacyclin. Cumulative addition of these mediators to pre-contracted bronchi produced incomplete relaxation, irrespective of the presence of epithelium. Addition of prostaglandin E 2, at a concentration equating to that produced after histamine stimulation (1.2 × 10 −9 M), produced a reduction (24%) in the maximum contractile response ( E max) to a subsequent histamine challenge ( P < 0.03). However, a similar response was not observed after the addition of prostacyclin at a concentration similar to that produced endogenously (6.5 × 10 −10 M). The combined addition of both mediators resulted in a significant reduction (26%) in the E max to histamine ( P < 0.02) but this effect was not statistically different to that of prostaglandin E 2 alone. The addition of supramaximal concentrations (1 μM) of each prostanoid, either alone or in combination, did not inhibit responses to histamine. These data suggest that whilst prostaglandin E 2 does not act as a direct acting relaxant agonist, it may inhibit histamine-induced muscle contraction and thereby contribute to the observed tachyphylaxis to this mediator. In contrast, prostacyclin appears to be of little importance in modulating human bronchial smooth muscle responses to histamine either directly or by enhancing responses to prostaglandin E 2. The inhibitory effect of prostaglandin E 2 appears to be concentration-dependent and suggests a bimodal action of this mediator in human airways.

Sympathetic inhibition of histamine-induced contraction of canine trachealis in vivo.

The effect of sympathetic stimulation on histamine-induced tracheal contraction was studied in 42 dogs in situ. After cholinergic blockade with atropine, dose-response curves to intra-arterial (ia) histamine (10(-10)-10(-6) mol) were performed in 11 adrenal-intact (ADi) and 5 adrenalectomized (ADx) dogs receiving steady-state sympathetic stimulation from continuous intravenous infusion (62.5-312 micrograms . kg-1 . min-1) of 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). In ADi dogs receiving maximal sympathetic prestimulation (312 micrograms . kg-1 . min-1 DMPP), tracheal tension barely exceeded base-line resting tension after 10(-6) mol ia histamine. In five dogs, tracheal tension after maximal sympathetic prestimulation exceeded base line for greater than or equal to 10(-8) mol ia histamine. In 12 other dogs, reversal of histamine-induced contraction by maximal sympathetic prestimulation was studied. Tracheal tension decreased 45.6 +/- 4.4 g/cm in four ADi dogs (P less than 0.001), 12.4 +/- 2.8 g/cm in four ADx dogs (P less than 0.02), and 2.2 +/- 2.5 g/cm in four control dogs receiving sham infusions (P greater than 0.90). No evidence was found for nonadrenergic relaxation of canine airway smooth muscle. We conclude that tracheal sympathetic nerves cause significant antagonism of histamine-induced contraction, which is augmented by adrenal secretion. We also report a pharmacological method for dose-related steady-state sympathetic stimulation of canine airways.