OBJECTIVETo 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 microl of normal saline and different concentrations of exET-1 in saline (ranged from 2 x 10(-6) mol/L to 10 x 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 microl of normal saline as control and 4 x 10(-6) mol/L exET-1 via tracheal dripping. Twenty microl of exCGRP (concentrations ranged from 6.7 x 10(-8) mol/L to 6.7 x 10(-6) mol/L) were given 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 x 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 x 10(-6) mol/L, and the incidence of PH was reduced to 20% (focal PH 10%, spotty PH 10%).

CONCLUSIONA 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.