Bazı bronkokonstriktör maddelerin etkilerinde epitelin rolü

Abstract

BAZI BRONKOKONSTRÎKTÖR MADDELERİN ETKİLERİNDE EP i TEL İN ROLÜ Bahar TUNÇTAN Doc- Dr. Nurettin ABACIOGLU (Tez Yöneticisi) Farmakoloji Anabilim Dalı (1992) ÖZET Bu çalışmada kobay trakeası ve SAK' tan oluşan ko-aksiyal biyoesey sisteminde 5-HT ve BK'nın etkilerinin epitelle ilişkisi ve kullanılan deneysel anaflaksi modelinde in vitro OA uygulamasından sonra bu ilişkide ne gibi bir derişiklik meydana geldiği incelenmiştir. Ko-aksiyal sistemde 5-HT düşük dozlarda gevşeme yüksek dozda kasılma seklinde bifazik cevap oluştururken, SAK tek basınayken ve epitelsizlestirilmis kobay trakeası içine yerleştirildiğinde doz-ba^ımlı kasılmalar oluşturması, oluşan deQisikliQin epitelden kaynaklandığını göstermektedir. Ko-aksiyal sistemde, imipramin ve parjilin muhtemelen 5-HT 'ye ait gevşemeleri, 5-HT'nin uptake ve parçalanmasını engelleyerek güçlendirmektedirler. Ko-aksiyal sistemde, ortamda İNDO bulunması halinde alınan sonuçlardan, trakea epi telinden SAK' ta inhibitor etkili bir SO ürününün yanısıra başka bir inhibitor maddenin de salmdiQi izlenimi edinilmiştir. Kullandığımız bir diŞer bronkokonstriktör madde olan BK SAK' ta doz-ba9ımlı gevşeme oluşturmuş, bu gevşemeler ko-aksiyal sistemde anlamlı olarak azalmış, epitelsizlestirmeden sonra ise yine anlamlı bir azalma görülmüştür. Bu olay epitelden salıverilen inhibitor maddelerin, gevşemelere katkıda bulunabilecek düzeyde olmadığını, ya da aksine BK tarafından epitel veya epitel-dısı dokulardan salıverilmesi stimüle edilen eksitatör maddeler nedeniyle gevşemelere katkısının maskelendiğini düşündürmektedir. îNDO ve kaptopril'in gevşemeleri anlamlı olarak etkilememesi ko-aksiyal 'sistemde BK'nın olusturduQu gevşemeleri prostanoid yapıda olmıyan eksitatör maddelerin azaltabileceğini ve BK'nın epitelde bulunan karboksipeptidaz dışındaki enzimler tarafından metabolize edildiğini göstermektedir. OA ile önceden aktif olarak duyarl ılastırı Imıs kobaylardan izole edilen kobay trakeaları ile hazırlanan ko-aksiyal sistemde, 5-HT ile oluşan bifazik cevap in vitro OA uygulanmasından sonra tamamen kasılmalara dönüşmesi, diQer yandan BK ile elde edilen gevşemelerin ise in vitro OA uygulaması sonrasında yalnızca düşük dozlarda anlamlı olarak artmasının OA uygulanmasından sonra epitelde oluştuğu saptanan morfolojik ve fonksiyonel derişikliklere baQli olabileceği anlaşılmıştır. Geliştirdiğimiz modifiye ko-aksiyal sistemde prekontrak ti 1 madde olarak kullandığımız FE ile oluşan kasılmaların platoyu sürdüremiyerek gevşemeye dönüşmesi, ayrıca bu gevşemelerin epitelsizlestirilmesinden sonra azalması FE'nin oluşturduğu kasılmaların azalmasının inhibitor f aktör ( ler )' in bazal salıverilmesi nedeniyle meydana gelebileceğini düşündürmektedir.SUMMARY In the present study, it has been investigated that the relationship between epithelium and the effects of 5-HT and BK, and whether there was a difference in this relationship after in vitro OA challenge in the experimental anaphylaxis model used. 5- HT produced dose-dependent contractions on the precontracted RAM which was mounted alone and when it was mounted co-axial ly within epithelium-denuded GPT, while in the co-axial system with epithelium-intact trachea 5-HT produced biphasic response. This showed that alteration depends on guinea-pig tracheal epithelium. In the co-axial system, imipramine and pargyline caused a potentiation on the relaxations of 5-HT possibly by preventing uptake and degradation of 5-HT. In the co-axial system, results in the presence of INDO meant that 5-HT caused an inhibitory CO product and another inhibitory factor release from the guinea-pig tracheal epithelium. Another bronchoconstrictor agent which we have used, BK, produced dose-dependent relaxations on the RAM and these relaxations decreased significantly in the co-axial system with epithelium-intact 6PT. These relaxations decreased again, after epithelium removal. These results suggested that inhibitory factors released from the guinea-pig tracheal epithelium did not contribute to the relaxations or, on the contrary, this contribution masked by excitatory factors which released from epithelial or nonepithelial tissue by BK. In the co-axial system INDO and captopril did not affect the relaxations caused by BK significantly. This situation implied that nonprostanoid excitatory factors might reduce the relaxations and enzymes different from carboxypeptidase might responsible from degradation of BK. In the co-axial assemlies with epithelium-intact 6PT isolated from sensitized guinea-pigs, biphasic response which produced by 5-HT reversed completely to the contractions after in vitro OA challenge. In addition BK-induced relaxations increased significantly (especially at the low doses of BK) after in vitro OA administration. These results suggested that epithelial alterations (morphological and functional) due to OA challenge might contribute to these alterations. In the modified co-axial system which we have developed, Phe-induced contractions did not produce plateau and conversion if these contractions to the relaxations and also, reduction of the precentage of fade after epithelium removal, implied that basal release of inhibitory factor(s) might responsible from the fade of Phe-induced contractions.

SUMMARY In the present study, it has been investigated that the relationship between epithelium and the effects of 5-HT and BK, and whether there was a difference in this relationship after in vitro OA challenge in the experimental anaphylaxis model used. 5- HT produced dose-dependent contractions on the precontracted RAM which was mounted alone and when it was mounted co-axial ly within epithelium-denuded GPT, while in the co-axial system with epithelium-intact trachea 5-HT produced biphasic response. This showed that alteration depends on guinea-pig tracheal epithelium. In the co-axial system, imipramine and pargyline caused a potentiation on the relaxations of 5-HT possibly by preventing uptake and degradation of 5-HT. In the co-axial system, results in the presence of INDO meant that 5-HT caused an inhibitory CO product and another inhibitory factor release from the guinea-pig tracheal epithelium. Another bronchoconstrictor agent which we have used, BK, produced dose-dependent relaxations on the RAM and these relaxations decreased significantly in the co-axial system with epithelium-intact 6PT. These relaxations decreased again, after epithelium removal. These results suggested that inhibitory factors released from the guinea-pig tracheal epithelium did not contribute to the relaxations or, on the contrary, this contribution masked by excitatory factors which released from epithelial or nonepithelial tissue by BK. In the co-axial system INDO and captopril did not affect the relaxations caused by BK significantly. This situation implied that nonprostanoid excitatory factors might reduce the relaxations and enzymes different from carboxypeptidase might responsible from degradation of BK. In the co-axial assemlies with epithelium-intact 6PT isolated from sensitized guinea-pigs, biphasic response which produced by 5-HT reversed completely to the contractions after in vitro OA challenge. In addition BK-induced relaxations increased significantly (especially at the low doses of BK) after in vitro OA administration. These results suggested that epithelial alterations (morphological and functional) due to OA challenge might contribute to these alterations. In the modified co-axial system which we have developed, Phe-induced contractions did not produce plateau and conversion if these contractions to the relaxations and also, reduction of the precentage of fade after epithelium removal, implied that basal release of inhibitory factor(s) might responsible from the fade of Phe-induced contractions.