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A role for endothelin in bicuculline‐induced neurogenic pulmonary oedema in rats
Author(s) -
Herbst C.,
Tippler B.,
Shams H.,
Simmet Th.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb14997.x
Subject(s) - bicuculline , phosphoramidon , anesthesia , endocrinology , medicine , endothelin 1 , blood pressure , bronchoalveolar lavage , chemistry , bolus (digestion) , arterial blood , endothelin receptor , antagonist , lung , receptor
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 γ‐aminobutyric acid (GABA) antagonist, bicucuiline (1.2 mg kg −1 ). 2 Recurrent seizure activity elicited by bicucuiline injection led to rapidly developing pulmonary oedema. Within 4 min after bicucuiline application (1.2mg kg _1 ), arterial O 2 partial pressure ( P a O 2 ) significantly dropped from 17.49±1.20 kPa to 7.51 ±2.21 kPa ( P <0.01) and arterial CO 2 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 bicucuiline 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 bicucuiline injection. Simultaneously it afforded protection from hypoxia. P a cO 2 did not increase and P a O 2 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 bicucuiline 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 bicucuiline injection but did ameliorate the development of hypoxia. No hypercapnia developed and P a o 2 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 ET A receptor, for they were inhibited by the ET A receptor antagonist, BQ‐123. ET A receptor antagonists may therefore be of potential therapeutic value in respiratory distress.