triprolidine and emedastine

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

LY188695 was evaluated both in vitro and in vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea with pKB values of 9.9, 9.9, and 9.2 respectively. In the lung parenchymal strip, LY188695 caused a rightward shift of the histamine concentration-response curve with a reduction in the maximal response at all antagonist concentrations tested. The reason for this effect is unknown, but it was not due to a nonspecific depressant action of the compound on the parenchyma. Selectivity was shown by its inactivity against leukotriene D4, bradykinin, prostaglandin F2 alpha, acetylcholine, norepinephrine, and serotonin on various guinea pig and rat smooth muscles. Similarly, H2 receptor-mediated relaxation of the rat uterus was unaltered by LY188695. Increases in total pulmonary impedance caused by i.v. histamine to anesthetized guinea pigs were reduced by as little as 3 micrograms/kg given orally 1 hour prior to histamine challenge. In this system, LY188695 was 15 times more potent than chlorpheniramine and 100 times more potent than terfenadine. Similar responses elicited by acetylcholine were not antagonized by LY188695. A duration of action greater than 4 hours was observed in this model. Ovalbumin given i.v. to sensitized guinea pigs increased total pulmonary impedance which was markedly decreased after oral administration of 30 or 100 micrograms/kg LY188695. These results indicate that LY188695 is a very potent antagonist of H1-mediated responses and suggest that this agent might be useful in disease states characterized by an overproduction of histamine.

Topics: Animals; Benzhydryl Compounds; Benzimidazoles; Bronchial Provocation Tests; Chlorpheniramine; Diphenhydramine; Guinea Pigs; Histamine H1 Antagonists; Lung; Male; Muscle, Smooth; Promethazine; Pyrilamine; Terfenadine; Triprolidine