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Biomedical subjects

N Chand

Publications and source records attributed to N Chand.

At least 37 records · Page 2Linked to original sources

Effect of azelastine on activation and release stages of allergic histamine secretion in rabbit basophils.

In this study the effect of azelastine on the activation (antigen-dependent, Ca(2+)-dependent, Stage I) and release (antigen-independent, Ca(2+)-dependent, Stage II) phases of allergen-induced histamine secretion in rabbit mixed leukocytes (basophils) was investigated. Azelastine (5 microM, 10-min) and diltiazem (5 microM: a Ca2+ antagonist, 10 min) inhibited ragweed extract-induced histamine secretion during the Stage II (release) phase. Theophylline (100 microM), a phosphodiesterase inhibitor, added immediately before antigen challenge, inhibited allergic histamine secretion during the Stage I (activation) phase. The data obtained in this study suggest that diltiazem and azelastine act on the Ca(2+)-dependent and antigen-independent phase (Stage II) of allergic histamine secretion in rabbit basophils.

Animals↗

Induction of non-specific airway hyperreactivity by potassium channel blockade in rat isolated trachea.

1. The exposure of rat isolated tracheal segment to the K(+)-channel inhibitor tetraethylammonium (TEA, 10 mM) for a period of 10-15 min generally produced little or no contractile response. 2. Cooling (10 C) provocation alone usually produced small (10 +/- 3% acetylcholine maximum) contractile responses. 3. In the presence of TEA (10 mM, 10-15 min exposure), rat trachea exhibited airway hyperreactivity to acetylcholine, 5-hydroxytryptamine (5-HT) and cooling. It also increased the peak tension induced by 5-HT. 4. TEA-induced airway hyperreactivity to cooling was significantly inhibited in Ca2(+)-free Krebs solution suggesting an important role for extracellular Ca2+ influx. 5. We conclude that the blockade of potassium channels with TEA induces non-specific airway hyperreactivity to cooling, 5-HT and acetylcholine in rat isolated tracheal segments.

Acetylcholine↗

Aeroallergen-induced immediate asthmatic responses and late-phase associated pulmonary eosinophilia in the guinea pig: effect of methylprednisolone and mepyramine.

Guinea pigs were sensitized by intraperitoneal injection of ovalbumin, 10 micrograms mixed with 100 mg A1(OH)3 in saline. On days 15-30 sensitized guinea pigs were challenged with ovalbumin aerosol (0.5 mg/ml, 30 s, 15 psi) which produced immediate asthmatic responses characterized by dyspnea, convulsions, and some deaths during the first 14 min. Twenty to 24 h later the animals were sacrificed with an overdose of pentobarbital, and lungs, bronchi, and lower trachea were dissected and fixed in 10% neutral buffered formalin. Histopathological examination of randomly coded tissues of the respiratory tract revealed a pulmonary eosinophilic cellular infiltrate in the epithelium/subepithelium of trachea, bronchi, and bronchioles as well as the peribronchial, peribronchiolar, and perivascular areas of the lungs. Oral administration of mepyramine (10 mg/kg) 2 h before aeroallergen challenge provided complete protection against immediate asthmatic responses and prevented deaths during the first 14 min without influencing the late phase associated lung eosinophilic cellular infiltrate. The immediate asthmatic responses were not influenced by methylprednisolone (30 mg/kg) administered orally 24 and 2 h before aeroallergen challenge. Following an additional dose of methylprednisolone 4 h after challenge, there was a significant inhibition of pulmonary eosinophilia (30 mg/kg; -24 h, -2 h, and +4 h). These observations suggest that histamine is the principal mediator of immediate asthma attacks in guinea pigs. Methylprednisolone may be acting by inhibiting the production of eosinophil chemotactic factor of anaphylaxis (platelet-activating factor or leukotriene B4) from the alveolar macrophages, T lymphocytes, and perhaps other cells, thus preventing pulmonary eosinophilia.

Administration, Oral↗

Inhibition of 5-HETE, LTB4, and LTC4 formation by azelastine in rat mixed peritoneal cells.

Azelastine produced a concentration-dependent inhibition of calcium ionophore A23187 (0.2 microM) stimulated generation of 5-HETE, leukotriene B4, and leukotriene C4 in rat mixed peritoneal cells, yielding IC50 values of 35.5, 47.4, and 31.7 microM, respectively. Nordihydroguaiaretic acid (a potent 5-lipoxygenase inhibitor) also exerted a strong and concentration-dependent inhibition of 5-HETE and leukotriene B4 and C4 formation with IC50 values of 0.15, 0.09, and 0.1 microM, respectively. The inhibition of the formation of the products of the lipoxygenase pathway of arachidonic acid metabolism by azelastine may contribute to its overall antiallergic, antiasthmatic, and pulmonary anti-inflammatory activities.

Animals↗

Inhibition of PAF-induced histamine secretion and bronchoconstriction by WEB 2086.

Platelet activating factor (PAF) stimulates histamine secretion from rabbit mixed leukocytes in a concentration-dependent fashion (EC50 10 ng/ml). The PAF (10 ng/ml)-induced histamine secretion was inhibited by WEB 2086 (IC50 = 20 nM). Furthermore, PAF (10 ng/kg, i.v.)-induced bronchoconstriction in guinea pig was also inhibited by WEB 2086 (ID50 = 5.3 micrograms/kg, i.v., 5 minutes). These data showed the existence of PAF-receptors on rabbit basophils and in guinea pig airways which are highly sensitive to blockade by WEB 2086.

Animals↗

Changes in aeroallergen-induced pulmonary mechanics in actively sensitized guinea pig: inhibition by azelastine.

The influence of orally administered azelastine and selected H1-receptor antagonists on aeroallergen-induced acute lung anaphylactic responses in actively sensitized guinea pigs (experimental asthma model) was studied. Azelastine (1 mg/kg, PO, two hours) exerted significant inhibition of the aeroallergen-induced decline in dynamic lung compliance and an elevation in pulmonary airway resistance. Terfenadine, pyrilamine, and diphenhydramine given as oral doses of 1 mg/kg two hours before aeroallergen challenge exerted weak or no inhibition of acute lung anaphylactic responses. In conclusion, the data obtained in this study showed that azelastine administered orally is capable of exerting antiasthmatic effects in both the central and peripheral airways of guinea pigs. This effect may be attributed to its ability to inhibit the formation or secretion of pharmacologic mediators (ie, histamine, LTC4/D4, .O2-) from inflammatory cells.

Air Pollution↗

Pharmacologic modulation of endothelin-induced contraction in isolated rat tracheal segments.

Porcine endothelin was found to be the most potent of the tested bronchoconstrictor agents on isolated rat tracheal segments. The calculated EC50S were as follows: endothelin = 106 nM, 5-HT = 1.45 microM, acetylcholine = 6 microM, KCl = 26.3 mM, and CaCl2 = 0.4 mM. Rat trachea is insensitive to histamine, neurokinin-A, and LTC4/LTD4. PAF (5.1 +/- 2.2 microM) produced strong contractile responses (1076 + 91 mg). Verapamil (1 microM, 60 min) antagonized CaCl2 but did not influence endothelin-induced contractile responses. In Ca2(+)-free Krebs solution, endothelin-induced responses were inhibited significantly. Relatively high concentrations of nifedipine and cadmium chloride (10 microM) attenuated endothelin-induced contractile responses. Indomethacin (5 microM, 60 min) slightly enhanced the endothelin-induced concentration-effect curve. These data show that endothelin induces slowly developing and sustained stimulus-contraction coupling in rat tracheal smooth muscle cells mainly by utilizing receptor-operated Ca2+ channels which are resistant to verapamil.

Animals↗

An investigation into the possible involvement of platelet activating factor in experimental allergic encephalomyelitis in rats.

Rats developing experimental allergic encephalomyelitis have been treated with intra-venous injections of Platelet-Activating Factor on days 5, 6 and 7 post adjuvant injection. Other rats have been treated with one of two different PAF antagonists or vehicle. The animals injected with PAF on day 5 post adjuvant developed a more severe form of the disease at an earlier time point than did control animals. Animals treated with the PAF antagonists did not develop the disease to any great extent. Treatment with the vehicle had no effect compared to control. These results implicate PAF in the aetiology of this model of multiple sclerosis and may suggest a role for PAF antagonists in the treatment of this disease.

Animals↗

Inhibition of allergic and nonallergic leukotriene C4 formation and histamine secretion by azelastine: implication for its mechanism of action.

Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C4/D4 synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC4 formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC4 formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC4 synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC4 generation may contribute to its mode of action and its therapeutic efficacy.

Animals↗

Allergic responses and subsequent development of airway hyperreactivity to cold provocation in the rat trachea: pharmacological modulation.

An in vitro model of airway hyperreactivity to cold provocation was developed. Cold provocation (10 degrees C) alone was not sufficient to cause contraction of rat isolated tracheal smooth muscle preparations. However, following recovery from antigen-induced responses in sensitized rat tracheal segments, cold provocation resulted in marked contractile responses. L-652,731 (a Paf-acether antagonist) and atropine significantly attenuated antigen-induced responses and subsequent development of airway hyperreactivity to cold provocation. Indomethacin augmented allergic responses and subsequent development of airway hyperreactivity to cold challenge. Nordihydroguaiaretic acid, FPL 55712 and theophylline did not exert any effect. The data obtained in this study showed that (i) Paf-acether and acetylcholine may play an important role in the mediation of allergic responses and subsequent development of airway hyperreactivity to cold provocation; (ii) the significant attenuation of antigen-induced airway hyperreactivity to cold provocation by Ca2+ channel blockers (nifedipine, bepridil and TMB-8) suggests an increase in Ca2+ influx/permeability following antigen challenge which appears to be responsible for the development of airway hyperreactivity to cold provocation; and (iii) 5-HT, prostaglandins or thromboxanes and leukotrienes play little or no role in the mediation of allergic responses and subsequent development of airway hyperreactivity to cold exposure in rat trachea.

Acetylcholine↗

Phospholipase A2 induced airway hyperreactivity to cooling and acetylcholine in rat trachea: pharmacological modulation.

1. Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10-30 min, exhibit airway hyperreactivity (AH) to cooling (10 degrees C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling. 2. PLA2-induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution. 3. Verapamil, azelastine, diltiazem and TMB-8 (each 10 microM) significantly attenuated PLA2-induced AH. This effect was not shared by nifedipine (10 microM). 4. Bepridil (10 microM), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2. 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling. 6. Atropine significantly attenuated PLA2-induced AH suggesting the participation of acetylcholine. 7. Nordihydroguaiaretic acid (an antioxidant; 5-lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase) significantly attenuated PLA2-induced AH to cooling. 8. In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf-acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug).

Acetylcholine↗

Inhibition of allergic histamine release from rat peritoneal mast cells by azelastine. Interaction with selected antiasthmatic drugs.

The in vitro interaction of azelastine (a new antiallergic/antiasthmatic drug) with albuterol (a beta 2 bronchodilator), theophylline (a phosphodiesterase inhibitor), disodium cromoglycate (DSCG, a mast cell-stabilizing agent) and prednisolone (a steroid) was studied for effects on allergic histamine release from rat peritoneal mast cells (RPMCs). The RPMCs preincubated with albuterol, theophylline, DSGC (10 min) and prednisolone (2h) caused a 2- to 18-fold decrease in the IC30 for azelastine. Significant potentiation (synergism) was seen only with albuterol (0.01, 0.1 and 1.0 microM, 10 min) and theophylline (1.0 microM, 10 min). The pre-exposure of RPMCs with DSCG (0.1, 1.0 and 10 microM) for a period of 10 min produced a slight leftward shift of azelastine's concentration-effect curve (0.01, 0.1 and 10 microM added immediately before antigen challenge). This effect was not dependent on the concentration of DSCG. These data demonstrated (1) the lack of cross-tachyphylaxis between DSCG and azelastine, and (2) the synergistic interaction between azelastine and albuterol or theophylline.

Albuterol↗

Pharmacological modulation of bradykinin-, acetylcholine- and calcium ionophore A23187-induced relaxation of rabbit pulmonary arterial segments.

Bradykinin (BK; 10(-10)-10(-7) M) relaxes phenylephrine-contracted rabbit isolated pulmonary arterial rings. The mechanical destruction of the endothelial layer obliterates acetylcholine (ACh) and A23187-induced relaxation without influencing BK-, isoproterenol-, sodium nitroprusside- and papaverine-induced relaxations. Atropine and propranolol selectively antagonized ACh- and isoproterenol-induced relaxation, respectively, without influencing BK-induced relaxation. Indomethacin (1.4 X 10(-5) M, a potent cyclooxygenase inhibitor, 30-60 min) and p-bromophenacylbromide (5 X 10(-6) M, p-BPB, a potent phospholipase A2 inhibitor, 30-60 min) selectively inhibited BK-induced relaxation without influencing relaxation to isoproterenol, sodium nitroprusside and papaverine. These data suggest that BK stimulates PLA2 and releases arachidonic acid (AA), which is further metabolized via cyclooxygenase and prostaglandin synthetase to prostacyclin (PGI2), causing relaxation of rabbit pulmonary arterial segments. The inhibition of ACh- and A23187-induced relaxation by p-BPB, but not by indomethacin, suggest that initial activation of PLA2 causes the release of AA, which is subsequently metabolized to endothelial-derived relaxant factor (EDRF; lipid peroxides, ROOH, ROO-?).

Acetylcholine↗

Capsicum--production, technology, chemistry, and quality. Part IV. Evaluation of quality.

Capsicum fruits are popular worldwide and are used in the cuisines of both the developing and the developed countries. With its different varieties, forms, and uses, the spice capsicum contributes to the entire gamut of sensory experience--color as finely ground paprika powder or extract in sausages, goulash, cheese, and snacks; both pungency and color as the many varieties of chillies used in Mexican, African, Indian, and southeast Asian cuisines; color, aroma, and mild pungency as the fresh green chillies used in many of the growing countries; and appearance, color, aroma, and texture as fresh fruit in salads and as a pickled and canned product. In three earlier parts in this series, the varieties, cultivation, and primary processing; the processed products, world production, and trade; and the chemistry of the color, aroma, and pungency stimuli have been reviewed. In this part, the evaluation of quality through instrumental determination of the causal components and the sensory evaluation of color, aroma, and pungency are discussed. Several methods for quantitative determination of the stimuli and the sensory evaluation of the responses to the stimuli are reviewed. The problems of sensory evaluation of color, aroma, and pungency, the dominant attributes for validation of the instrumentally determined values for carotenoids, volatiles, or particular fractions, and total and individual capsaicinoids are specifically discussed. Summarized details of selected instrumental methods for evaluating the stimuli, which are either validated by correlation to sensorily perceived responses or to adopted standards, are given along with representative data obtained for discussing the adequacy and reliability of the methods. Pungency as a specific gustatory perception and the many methods proposed to evaluate this quality are discussed. A recommended objective procedure for obtaining reproducible values is discussed, and a method for relating different panel results is shown. With such a method, highly significant correlations have been shown between estimated total capsaicinoids and the determined pungency. The estimation of total capsaicinoids by any simple, reliable method is shown to be adequate for quality control of pungency of Capsicum fruits.

Capsicum↗

The obligatory role of calcium in the development of antigen-induced airway hyperreactivity to cold provocation in the rat isolated trachea.

The effect of antigen challenge on cold provocation (30-10 degrees C) in isolated tracheal segments from control (normal) and ovalbumin-sensitized rats was studied. Sensitization alone or acute cold provocation (10 degrees C) alone was not sufficient to cause contraction of tracheal smooth muscle preparation. Following recovery from antigen-induced responses (Schultz-Dale phenomenon) in sensitized rat segments, cold provocation induced strong contractile responses. Both the antigen-induced contractions and the subsequent development of airway hyperreactivity to cold were dependent on extracellular Ca2+ and inhibited by verapamil. The data in this study indicate that extracellular Ca2+ plays an obligatory role in the mediation of antigen-induced contractile responses as well as the subsequent development of hyperreactivity to cold provocation in rat tracheal smooth muscle.

Animals↗

Inhibition of histamine secretion from rat peritoneal mast cells and rabbit leukocytes by p-bromophenacyl bromide, a phospholipase A2 inhibitor.

The present investigation was undertaken to explore the role of phospholipase A2 (PLA2) activation in histamine secretion from rabbit leukocytes and rat peritoneal mast cells (RPMC) by using p-bromophenacyl bromide (p-BPB), a potent inhibitor of PLA2. p-BPB exerted concentration dependent inhibition of allergic histamine release from RPMC and rabbit leukocytes as well as calcium ionophore A23187-stimulated histamine release from RPMC with IC50s of 36.2, 1.3 and 80.0 nM, respectively. pBPB exerted a bell-shaped (biphasic) concentration-effect (inhibition) curve on ragweed antigen-induced histamine secretion from rabbit leukocytes. The data obtained in this study suggest that PLA2 activation plays an essential role in histamine secretion from rabbit leukocytes and RPMC.

Acetophenones↗