Ueno A, Naraba H, Ikeda Y, Ushikubi F, Murata T, Narumiya S, Oh-ishi S
Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Life Sci. 2000 Feb 11;66(12):PL155-60. doi: 10.1016/s0024-3205(00)00420-3.
To prove that prostaglandin I2 (PGI2) is a major prostaglandin involved in bradykinin-induced exudation, we examined carrageenin- or bradykinin-induced paw edema in prostacyclin receptor-deficient mice (IPKO). Paw volume of wild-type mice (IPWT) increased gradually 5-6 hr after the carrageenin injection in a similar manner as in ICR mice, but the swelling in IPKO mice was significantly smaller (about 60% of the IPWT volume). Indomethacin, at 10 mg/kg, suppressed the swelling of the IPWT paw to the level of the non-pretreated IPKO, which was not affected by indomethacin, confirming the previous result that PGI2 is a major prostaglandin involved in the swelling. The paw edema of IPWT and IPKO was significantly attenuated by the nonpeptide bradykinin B2-receptor antagonist FR173657, at 30 mg/kg, to the same level of swelling, indicating kinin involvement. Injection of bradykinin (1.2 nmole) into the paw caused rapid edema, which peaked around 15 min in both mice. However, the edema induced in IPKO was smaller and almost at the same level as that elicited in the indomethacin-treated IPWT, suggesting that edema induced by bradykinin includes the intrinsic effect of PGI2. Concomitant injection of carbacyclin with bradykinin caused enhancement of edema in IPWT mice but not in IPKO mice, indicating that intrinsic PGI2 could cause enhancement of bradykinin- or even carrageenin-induced edema formation. These results clearly demonstrate that bradykinin released by carrageenin may be a key mediator to induce PGI2 formation, and both autacoids work together to induce enhanced inflammatory exudation.
为了证明前列腺素I2（PGI2）是参与缓激肽诱导渗出的主要前列腺素，我们研究了前列环素受体缺陷小鼠（IPKO）中角叉菜胶或缓激肽诱导的爪肿胀。野生型小鼠（IPWT）在注射角叉菜胶后5 - 6小时爪体积逐渐增加，与ICR小鼠的方式相似，但IPKO小鼠的肿胀明显较小（约为IPWT体积的60%）。10mg/kg的吲哚美辛将IPWT爪的肿胀抑制到未预处理的IPKO的水平，而IPKO不受吲哚美辛影响，这证实了先前的结果，即PGI2是参与肿胀的主要前列腺素。30mg/kg的非肽缓激肽B2受体拮抗剂FR173657可使IPWT和IPKO的爪肿胀显著减轻至相同水平，表明激肽参与其中。向爪内注射缓激肽（1.2纳摩尔）会引起快速肿胀，在两种小鼠中均在约15分钟时达到峰值。然而，IPKO中诱导的肿胀较小，几乎与吲哚美辛处理的IPWT中引起的肿胀处于同一水平，这表明缓激肽诱导的肿胀包括PGI2的内在作用。卡巴前列素与缓激肽同时注射导致IPWT小鼠的肿胀增强，但IPKO小鼠中未出现这种情况，表明内源性PGI2可导致缓激肽甚至角叉菜胶诱导的水肿形成增强。这些结果清楚地表明，角叉菜胶释放的缓激肽可能是诱导PGI2形成的关键介质，并且这两种自分泌物质共同作用以诱导增强的炎症渗出。
