A ROLE FOR ENDOTHELIN IN BICUCULLINE-INDUCED NEUROGENIC PULMONARY-EDEMA IN RATS

1 The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure-associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the gamma-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg(-1)). 2 Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg(-1)), arterial O-2 partial pressure (PaO2) significantly dropped from 17.49 +/- 1.20 kPa to 7.51 +/- 2.21 kPa (P < 0.01) and arterial CO2 partial pressure (P(a)co(2)) significantly increased from 4.64 +/- 0.56 kPa to 8.15 +/- 0.99 kPa (P < 0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end-inspiratory airway pressure (P-aw) rapidly increased. 3 Concomitantly there was a time-dependent increase of big ET-1 and ET-1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicuculline. injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not; contain detectable amounts of ET. 4 Pretreatment with the endothelin-converting enzyme inhibitor, phosphoramidon (5.4 mg kg(-1), i.v.) for 5 min significantly (P < 0.001) reduced peak ET-1 levels in BAL fluid by 65.4 +/- 9.9% at 8 min after bicuculline injection. Simultaneously it afforded protection from hypoxia. P(a)co(2) did not increase and PaO2 decreased only slightly from 14.63 +/- 1.00 kPa to 12.97 +/- 0.61 kPa (P > 0.05) after phosphoramidon pretreatment. In contrast, vehicle-treated animals that received bicuculline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in P-aw by 76.7 +/- 12.4% (P < 0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis. 5 Pretreatment with the ET(A) receptor antagonist, BQ-123 (1 mg kg(-1), i.v.), for 5 min did not affect the levels of ET-1 in the BAL fluid at 8 min after bicuculline injection but did ameliorate the development of hypoxia. No hypercapnia developed and PaO2 decreased only moderately from 16.65 +/- 0.25 kPa to 14.19 +/- 2.15 kPa (P > 0.05) in BQ-123-treated animals. In contrast, vehicle-treated animals that received bicuculline exhibited significant hypercapnia as well as profound hypoxia. BQ-123 significantly reduced the increase in P-aw by 51.3 +/- 12.8% (P < 0.01). It affected MABP only slightly and had no effect on the acidosis. 6 These results suggest that ET peptides play a significant role in this model of neurogenic pulmonary oedema and may act as mediators of respiratory distress. The deleterious effects of endogenous ET in this model are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, BQ-123. ETA receptor antagonists may therefore be of potential therapeutic value in respiratory distress.