Neurobiology-Respiratory, Schering-Plough Research Institute, Kenilworth, N.J. 07033-0539, USA.
Pharmacology. 2010;85(5):311-8. doi: 10.1159/000299792. Epub 2010 May 10.
Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation.
For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats.
Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg).
Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.
组织胺和半胱氨酰白三烯是肥大细胞介质的关键，对过敏性鼻炎的症状有很大的影响，而且可能是互补的。目前，我们试图探索组织胺和白三烯 D（4）（半胱氨酰白三烯）对猪鼻动静脉的直接作用。我们还在过敏介导的鼻炎症的体内模型中使用氯雷他定和孟鲁司特钠研究了组织胺和半胱氨酰白三烯的联合阻断作用。
为了评估组织胺和 LTD（4）对动脉和静脉的作用，将猪鼻黏膜分离并切成薄片（100-300μm 厚）。记录鼻动静脉的实时图像，并通过测试药物前后的横截面面积变化来估计血管活动。对于体内研究，检查了单独给予和联合给予氯雷他定和孟鲁司特钠对卵清蛋白致敏和攻击的褐家鼠上呼吸道炎症的影响。
组织胺（0.001-10μmol/L）和 LTD（4）（0.001-10μmol/L）均产生浓度依赖性的鼻黏膜动静脉管腔面积增加。组织胺（0.01μmol/L）单独作用可使动脉和静脉的横截面积分别增加 24%和 12%。LTD（4）（0.001μmol/L）单独作用可使动脉和静脉扩张约 17%和 9%。用组织胺（0.01μmol/L）和 LTD（4）（0.001μmol/L）联合处理可使血管扩张增加 65%（动脉）和 26%（静脉）。在我们的体内褐家鼠研究中，口服氯雷他定（0.01-10mg/kg）和孟鲁司特钠（0.01-10mg/kg）可显著地剂量依赖性地减少抗原诱导的总鼻炎性细胞浸润。当与孟鲁司特钠（0.01mg/kg）联合研究时，氯雷他定的抗炎剂量反应曲线向左移动。同样，当存在氯雷他定（0.01mg/kg）时，孟鲁司特钠（0.01-10mg/kg）的剂量反应特征也发生了变化。
我们的研究支持这样的观点，即组织胺和半胱氨酰白三烯可能协同作用，引起过敏性鼻病理，如上呼吸道炎症和鼻血管扩张（这可能转化为增加的鼻黏膜充血）。此外，目前的结果支持这样的假设，即联合治疗过敏性鼻炎用 H（1）受体拮抗剂和 CysLT（1）受体拮抗剂可能比单独使用这些药物有更大的益处。
