ENDOTHELIN-1 IS NOT INVOLVED IN PULMONARY-HYPERTENSION AFTER LUNG EMBOLISM IN ISOLATED-PERFUSED RABBIT LUNGS

Aim of the study was to evaluate, whether endothelin-1 (ET-1) is invol ved in pulmonary vascular reactions after lung embolism in a model of an isolated perfused and ventilated rabbit lung. Methods: The experime nts were performed on 36 isolated and ventilated rabbit lungs which we re perfused with a cell-and plasma-free buffer solution. The arterial pressure and the lung weight gain were continuously registered. Interm ittently perfusate samples were taken to determine ET-1 and thromboxan e A(2) concentrations. Lung embolism was induced by an injection of 0. 75 ml air (n=6) into the pulmonary artery. To investigate the putative role of ET-1 during lung embolism, the ETA receptor antagonists LU135 252 (10(-6) m, n=6) and the ETB receptor antagonist BQ788 (10(-6) m, n =6) were added to the perfusate before air injection. The potential in volvement of thromboxane A(2) in embolism-induced vascular reactions w as investigated by pretreatment with the cyclooxygenase inhibitor dicl ofenac (10 mu g/ml, n=6). Furthermore, the combination of LU135252 and diclofenac (10(-6) m, 10 mu g/ml, n=6) was tested. Results: Air injec tion resulted in a massive generation of TXA(2) (>860 pg/ml) which was paralleled by an immediate increase of pulmonary arterial pressure up to 24.6+/-4.2 mmHg, which decreased during 10 minutes to baseline lev el. There was a delayed onset of edema formation starting 60 minutes a fter air injection resulting in a mean weight gain of 8.3+/-5.6 g afte r 120 minutes. ET-1 was not detectable at any time in the perfusate (E LISA). Neither pretreatment with LU135252 nor the addition of BQ788 at tenuated the embolism-induced pressure increase and edema formation, w hile diclofenac as well as the combination of diclofenac and LU135252 significantly reduced the increase of PAP (p<0.01). Edema formation wa s unaffected by diclofenac. Conclusions: The results suggest that ET-1 is not essentially involved as mediator of vascular reaction followin g lung embolism, whereas thromboxane A(2) seems to be an important med iator of the acute PAP-increase.