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unina.it
In the present study, the effect of the blockade of membrane calcium channels activated by intracellular Ca(2+) store depletion on basal and depolarization-induced [3H]norepinephrine ([3H]NE) release from SH-SY5Y human neuroblastoma cells was examined. The second-generation H(1) receptor blockers astemizole, terfenadine, and loratadine, as well as the first-generation compound hydroxyzine, inhibited [3H]NE release induced by high extracellular K(+) concentration ([K(+)](e)) depolarization in a concentration-dependent manner (the IC(50)s were 2.3, 1.7, 4.8, and 9.4 microM, respectively). In contrast, the more hydrophilic second-generation H(1) receptor blocker cetirizine was completely ineffective (0.1-30 microM). The inhibition of high [K(+)](e)-induced [3H]NE release by H(1) receptor blockers seems to be related to their ability to inhibit Ca(2+) channels activated by Ca(i)(2+) store depletion (SOCs). In fact, astemizole, terfenadine, loratadine, and hydroxyzine, but not cetirizine, displayed a dose-dependent inhibitory action on the increase in intracellular Ca(2+) concentrations ([Ca(2+)](i)) obtained with extracellular Ca(2+) reintroduction after Ca(i)(2+) store depletion with thapsigargin (1 microM), an inhibitor of the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) pump. The rank order of potency for SOC inhibition by these compounds closely correlated with their inhibitory properties on depolarization-induced [3H]NE release from SH-SY5Y human neuroblastoma cells. Nimodipine (1 microM) plus omega-conotoxin (100 nM) did not interfere with the present model for SOC activation. In addition, the inhibition of depolarization-induced [3H]NE release does not seem to be attributable to the blockade of the K(+) currents carried by the K(+) channels encoded by the human Ether-a-Gogo Related Gene (I(HERG)) by these antihistamines. In fact, whole-cell voltage-clamp experiments revealed that the IC(50) for astemizole-induced hERG blockade is about 300-fold lower than that for the inhibition of high K(+)-induced [3H]NE release. Furthermore, current-clamp experiments in SH-SY5Y cells showed that concentrations of astemizole (3 microM) which were effective in preventing depolarization-induced [3H]NE release were unable to interfere with the cell membrane potential under depolarizing conditions (100 mM [K(+)](e)), suggesting that hERG K(+) channels do not contribute to membrane potential control during exposure to elevated [K(+)](e). Collectively, the results of the present study suggest that, in SH-SY5Y human neuroblastoma cells, the inhibition of SOCs by some second-generation antihistamines can prevent depolarization-induced neurotransmitter release.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705456&dopt=Abstract
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uniroma1.it
PURPOSE: A specific reaction against several kinds of inhalant allergens characterizes allergic rhinitis. Mast cells play a crucial role in the allergic inflammation releasing histamine and other mediators. Tryptase is considered to be a specific marker of mast cell activation. This study was devoted to evaluate the serum tryptase in allergic rhinitis and to evaluate the effect of cetirizine and fluticasone propionate on mast cell activation. 13 subjects, suffering from perennial allergic rhinitis induced by Dermatophagoides pteronyssinus, were studied. MATERIALS AND METHODS: Tryptase serum levels were detected by the fluoroenzymeimmunoassay (Pharmacia & Upjohn AB, Uppsala, Sweden). Blood samples were taken four times: before starting the study, after two weeks of 10 mg cetirizine treatment once a day, after two weeks of wash-out, and again after 15 days of 100 micrograms intranasal fluticasone propionate therapy twice a day. RESULTS: In allergic rhinitis, the basal values of serum tryptase (M +/- SD: 6.1 +/- 2.4 micrograms/l) were significantly higher than in controls (M +/- SD: 3.0 +/- 1.2 micrograms/l). After the antihistamine treatment, tryptase values (M +/- SD: 4.4 +/- 1.8 micrograms/l) decreased significantly (p < 0.001). After the stop of antihistamine treatment, tryptase levels increased (M +/- SD: 5.5 +/- 2.6 micrograms/l, p < 0.001). After the topical corticosteroid treatment, tryptase values decreased again significantly (M +/- SD: 4.5 +/- 3.1 micrograms/l, p < 0.04). CONCLUSIONS: All these data seem to confirm the effective action of cetirizine and fluticasone propionate on tryptase serum levels. While the action of corticosteroid is well known, the action of cetirizine is still to define, considering the recent reports on anti-inflammatory effect of the second generation of H1 receptor antagonists. Further studies are necessary to understand if the pharmacological effect on tryptase is a specific one of cetirizine, or if it is common to other anti-H1 molecules.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11794849&dopt=Abstract
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ucb-group.com
Competition experiments with [(3)H]mepyramine showed that cetirizine and its enantiomers, levocetirizine and (S)-cetirizine, bound with high affinity and stereoselectivity to human H(1) histamine receptors (K(i) values of 6, 3, and 100 nM, respectively). Cetirizine and levocetirizine were 600-fold more selective for H(1) receptors compared with a panel of receptors and channels. Binding results indicated that the interaction between cetirizine, its enantiomers, and histamine is compatible with a competitive behavior, in contrast with the noncompetitive profile of cetirizine and levocetirizine observed in isolated organs. Binding kinetics provided a suitable explanation for this observation, because levocetirizine dissociated from H(1) receptors with a half-time of 142 min; that of (S)-cetirizine was only 6 min, implying that the former could act as a pseudo-irreversible antagonist in functional studies. The carboxylic function of levocetirizine seemed responsible for its long dissociation time. Indeed, hydroxyl or methyl ester analogs dissociated more rapidly from H(1) receptors, with half-times of 31 min and 7 min, respectively. The importance of the carboxylic function of levocetirizine for the interaction with the H(1) receptor was further supported by the results from the mutation of Lys(191) to Ala(191). This mutation decreased the dissociation half-time of levocetirizine from 142 to 13 min and reduced its affinity from 3 to 12 nM, whereas the affinity and dissociation kinetics of hydroxyl and methyl ester analogs were hardly affected. The mutation of Thr(194) reduced the binding stereoselectivity by selectively enhancing the affinity of the distomer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11809864&dopt=Abstract
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