Leite-Avalca Mariane C G, Lomba Luis A, Bastos-Pereira Amanda L, Brito Haissa O, Fraga Daniel, Zampronio Aleksander R
*Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil †Veterinary Sciences Centre, State University of Santa Catarina, Lages, SC, Brazil ‡Department of Nursing, Federal University of Mato Grosso do Sul, Coxim, MS, Brazil.
Shock. 2016 Sep;46(3):290-6. doi: 10.1097/SHK.0000000000000598.
We previously reported that endothelin-1 (ET-1) reduced the frequency of spontaneous excitatory currents in vasopressinergic magnocellular cells through the activation of endothelin ETA receptors in rat brain slices. This effect was abolished by a cannabinoid CB1 receptor antagonist, suggesting the involvement of endocannabinoids. The present study investigated whether the blockade of ETA or CB1 receptors during the phase of increased levels of ET-1 after severe sepsis increases the survival rate of animals concomitantly with an increase in plasma arginine vasopressin (AVP) levels. Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). Treatment with the CB1 receptor antagonist rimonabant (Rim; 10 and 20 mg/kg, orally) 4 h after CLP (three punctures) significantly increased the survival rate compared with the CLP per vehicle group. Intracerebroventricular treatment with the ETA receptor antagonist BQ123 (100 pmol) or with Rim (2 μg) 4 and 8 h after CLP but not the ETB receptor antagonist BQ788 (100 pmol), also significantly improved the survival rate. Sham-operated and CLP animals that were treated with Rim had significantly lower core temperature than CLP animals. However, oral treatment with Rim did not change bacterial count in the peritoneal exudate, neutrophil migration to the peritoneal cavity, leucopenia or increased plasma interleukin-6 levels induced by CLP. Both Rim and BQ123 also increased AVP levels 12 h after CLP. The blockade of central CB1 and ETA receptors in the late phase of sepsis increased the survival rate, reduced body temperature and increased the circulating AVP levels.
我们之前报道过，内皮素-1（ET-1）通过激活大鼠脑片内的内皮素ETA受体，降低了加压素能大细胞中自发兴奋性电流的频率。大麻素CB1受体拮抗剂可消除这种效应，提示内源性大麻素参与其中。本研究调查了在严重脓毒症后ET-1水平升高阶段，阻断ETA或CB1受体是否会伴随血浆精氨酸加压素（AVP）水平升高而提高动物存活率。通过盲肠结扎和穿刺（CLP）诱导雄性Wistar大鼠发生脓毒症。CLP（三次穿刺）后4小时口服CB1受体拮抗剂利莫那班（Rim；10和20mg/kg）治疗，与CLP生理盐水组相比，显著提高了存活率。CLP后4小时和8小时脑室内注射ETA受体拮抗剂BQ123（100pmol）或Rim（2μg），而非ETB受体拮抗剂BQ788（100pmol），也显著提高了存活率。接受Rim治疗的假手术和CLP动物的核心体温显著低于CLP动物。然而，口服Rim并未改变CLP诱导的腹腔渗出液中的细菌计数、中性粒细胞向腹腔的迁移、白细胞减少或血浆白细胞介素-6水平升高。Rim和BQ123在CLP后12小时也均提高了AVP水平。脓毒症后期阻断中枢CB1和ETA受体可提高存活率、降低体温并提高循环AVP水平。
