Daenas Christos, Hatziefthimiou Apostolia A, Gourgoulianis Konstantinos I, Molyvdas Paschalis Adam
Department of Physiology, Medical School, University of Thessaly, Larissa, Greece.
Eur J Pharmacol. 2006 Dec 28;553(1-3):280-7. doi: 10.1016/j.ejphar.2006.09.041. Epub 2006 Sep 27.
Macrolides have been proven to have beneficial bacteriostatic and anti-inflammatory properties, but very little is known about the potential value of their bronchodilatory effect. Therefore, in the present study we investigated the effect of azithromycin on contractile responses of isolated rabbit tracheal strips to carbachol or KCl. Azithromycin has a relaxant, concentration-dependent effect on tracheal strips precontracted with carbachol (300 nM), significant from the concentration of 1 muM. The mechanical removal of epithelium did not alter the effect of azithromycin. Azithromycin (100 microM) also relaxed tracheal strips precontracted with KCl (80 mM) even in the presence of atropine (100 microM). Moreover, azithromycin (100 microM) decreased contractions induced by 300 nM and 10 microM carbachol to 55.4% and 80.5% of initial contraction, respectively. The relaxant effect of azithromycin persisted in both calcium free solution and in the presence of the calcium channel antagonist, verapamil. The relaxant effect of azithromycin was not altered by the pre-treatment of preparations with the inhibitors of Ca(2+)-ATPase (cyclopiazonic acid), Na(+)-K(+) ATPase (ouabain), Rho-associated kinase [(R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] (Y-27632) or the non-specific cAMP and cGMP phosphodiesterases inhibitor 3-isobutyl-1-methyl-2,6(1H,3H)-purinedione (IBMX). These results suggest that azithromycin has a concentration-dependent, epithelium-independent, direct relaxant effect on precontracted tracheal strips that is not mediated via inhibition of Ca(2+) influx or Ca(2+) release from intracellular stores. Also, it is not due to alteration of the function of Na(+)-K(+) ATPase and does not depend on the formation of cAMP/cGMP or the Rho/Rho-activated kinase pathway.
大环内酯类药物已被证明具有有益的抑菌和抗炎特性，但关于其支气管扩张作用的潜在价值却知之甚少。因此，在本研究中，我们研究了阿奇霉素对离体兔气管条对卡巴胆碱或氯化钾收缩反应的影响。阿奇霉素对用卡巴胆碱（300 nM）预收缩的气管条具有舒张作用，且呈浓度依赖性，从1 μM浓度起作用显著。机械去除上皮细胞并未改变阿奇霉素的作用。即使在存在阿托品（100 μM）的情况下，阿奇霉素（100 μM）也能舒张用氯化钾（80 mM）预收缩的气管条。此外，阿奇霉素（100 μM）分别将300 nM和10 μM卡巴胆碱诱导的收缩降低至初始收缩的55.4%和80.5%。阿奇霉素的舒张作用在无钙溶液和存在钙通道拮抗剂维拉帕米的情况下均持续存在。用Ca(2+)-ATP酶抑制剂（环匹阿尼酸）、Na(+)-K(+)ATP酶抑制剂（哇巴因）、Rho相关激酶[（R）-(+)-反式-4-(1-氨基乙基)-N-(4-吡啶基)环己烷甲酰胺二盐酸盐]（Y-27632）或非特异性cAMP和cGMP磷酸二酯酶抑制剂3-异丁基-1-甲基-2,6(1H,3H)-嘌呤二酮（IBMX）预处理制剂，并未改变阿奇霉素的舒张作用。这些结果表明，阿奇霉素对预收缩的气管条具有浓度依赖性、不依赖上皮细胞的直接舒张作用，该作用不是通过抑制Ca(2+)内流或细胞内钙库释放Ca(2+)介导的。此外，它也不是由于Na(+)-K(+)ATP酶功能改变所致，并且不依赖于cAMP/cGMP的形成或Rho/Rho激活激酶途径。
