内皮素致肺出血及降钙素基因相关肽拮抗内皮素作用的研究

Exogenous endothelin-1 induced pulmonary hemorrhage in newborn rats and the antagonizing effect of calcitonin gene-related peptide

目的 观察外源性内皮素 1(exET 1)致肺出血作用及外源性降钙素基因相关肽(exCGRP)对ET 1的拮抗作用。方法 实验① :新生Wistar大鼠 10 0只 ,随机分对照组A组 10只 ,实验组B、C、D、E 4组各 2 0只、F组 10只 ,经气管插管于气管内滴入生理盐水 (对照组 )及不同浓度exET 1(实验组 )各 30 μl。实验② :Wistar大鼠 5 0只 ,随机分对照组D1组 10只 ,实验组D2 、D3 、D4、D5组各 10只。于气管内滴入生理盐水 (D1组 )及 4× 10 -6mol/LexET 1(D2 ～D5组 )各 30 μl,30min后D3 ～D5组再滴入不同浓度exCGRP 2 0 μl。③各组滴药 3h后处死动物 ,观察肺组织大体病理及HE染色改变。结果 ①不同浓度exET 1气管内滴入 ,可引起不同程度肺出血 ,其中D组 4× 10 -6mol/LexET 1致肺出血率高达 80 % ,死亡率 2 0 %。②气管内滴入exET 1后 ,再滴入不同浓度exCGRP ,均可减轻exET 1所致肺出血 ,其中 6 7× 10 -6mol/LexCGRP效果最佳 ,肺出血率降至 2 0 % ,死亡率 0 %。结论 exET 1气管内滴入可致肺出血 ,推测肺组织内源性ET 1异常升高 ,是导致肺出血发病机制之一。exCGRP气管内滴入 ,能有效拮抗exET

Objective To observe the phenomenon of pulmonary hemorrhage(PH)induced by exogenous endothelin 1 (exET 1) and the antagonizing effect of exogenous calcitonin gene related peptide (exCGRP) in newborn rats Methods ① To study the exET 1 induced PH: 100 newborn Wistar rats were randomly assigned into control group (group A, n =10) and experiment groups (20 rats in each of groups B, C, D and E and 10 in group F) Thirty μl of normal saline and different concentrations of exET 1 in saline (ranged from 2×10 -6 mol/L to 10×10 -6 mol/L)were dripped into the rats′ trachea through intubation for control group and the experiment groups, respectively ② To study the antagonizing effect of calcitonin gene related peptide against endothelin:50 rats were randomly assigned into control group (group D 1, n =10) and experiment groups D 2、D 3、D 4 and D 5 (10 rats in each group), and were treated with 30 μl of normal saline as control and 4×10 -6 mol/L exET 1 via tracheal dripping Twenty μl of exCGRP (concentrations ranged from 6 7×10 -8 mol/L to 6 7×10 -6 mol/L) were geiven by dripping to rats in groups D 3 to D 5 30 minutes after the administration of exET 1 ③ The rats were sacrificed 3 hours after the first tracheal dripping and the gross anatomical and histological (HE staining) changes in lungs were observed Results ① Following the treatment with exET 1,the rats showed cyanosis and dyspnea rapidly The severity of respiratory symptoms varied in a dose dependent fashion with the concentrations of exET 1. The symptoms were relieved in the survived rats in about 30 minutes The rats of all exET 1 treated groups presented with different degree of PH and group D (treated with 4×10 -6 mol/L of exET 1) had the highest incidence (diffuse PH 30%, focal PH 25%, spotty PH 25% and 80% in total), with a mortality of 20% Rats in group E and F had lower incidence of PH (50% and 20%) but higher mortality (35% and 60%). ② After the administration of different concentrations of exCGRP, the skin of the exET 1 treated rats turned ruddy rapidly with a significantly decreased incidence of PH and all the rats survived The best protective effect was observed with the concentration of 6 7×10 -6 mol/L, and the incidence of PH was reduced to 20% (focal PH 10%, spotty PH 10%) Conclusion A significant increase of the endogenous ET 1 in hemorrhagic lung tissue caused by rewarming and reoxygenation following hypothermia and hypoxia had been confirmed Administration of intratracheal exET 1 could induce pulmonary hemorrhage This suggests that a significant increase of endogenous ET 1 in lung tissue may be one of the mechanisms in pathogenesis of PH caused by rewarming and reoxygenation following hypothermia and hypoxia Endotracheal administration of exCGRP showed protective antagonizing effect against PH induced by exET 1 The authors speculate that the exCGRP has the potential to treat or even prevent PH caused by a significant increase of the endogenous ET 1.