A role for endothelin in bicuculline‐induced neurogenic pulmonary oedema in rats

Abstract

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 y-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg-'). 2 Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg-'), arterial 02 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 (Paco2) 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 (Paw) 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', 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. PaCo2 did not increase and Pa02 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 Paw by 76.7 ± 12.4% (P <0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.

Postictal neurogenic pulmonary edema: Case report and brief literature review

“…Treatment of NPE centers on resolution of CNS injury and ventilation support. Specific treatments have been proposed like endothelin converting enzyme inhibitors or sympathectomy which has been successfully tested in rats [6] , [7] ; however, the evidence is insufficient for its use as a human treatment [2] , and seizure control is essential as the only preventable treatment.…”

The Endothelins in the Pulmonary System

“…224 pertension, reduced pulmonary artery pressure, right ventricular hypertrophy as well as alveolar duct and alveolar wall pulmonary artery muscularization. 285 In a Cryptogenic fibrosing alveolitis and pulmonary similar model, BQ-123 administered by osmotic mifibrosis (CFA) nipumps over the period of exposure to hypoxia also largely attenuated the key features associated with this CFA is a condition characterized by inflammation, model of pulmonary hypertension.…”

“…ET may also play a role in seizure-associated data in different species may be due to the sum of neurogenic pulmonary oedema. 224 differing effects in a variety of airway cell types. Indeed, Shimura and co-workers 237 have reported that, Mitogenesis although ET-1 produced a significant increase in muThe mitogenic actions of ET-1 and related peptides cous glycoprotein production from isolated subhave been investigated in vascular smooth muscle mucosal glands, this increase was abolished by the cell cultures derived from human, 225 bovine 226 and presence of cultured epithelial cells or if the exporcine 226,227 pulmonary artery.…”

“…ET-1 induced a dose-dependent increase increased in rat models of respiratory distress. 224,295 in cytosolic free Ca 2+ concentration and stimulated the proliferation of quiescent cells. 301 Taken together, Importantly, BQ-123 partly inhibits deterioration in these data suggest a role for ET-1 as an autocrine/ REFERENCES paracrine growth factor in human lung cancers.…”

Molecular Pharmacology and Pathophysiological Significance of Endothelin

“…The enhanced production of endothelin-1 and the effectiveness of endothelin receptor antagonists have been demonstrated in a number of other diseases, such as acute myocardial infarction (216,217), neurogenic pulmonary edema (218), and peptic ulcer (219,220). In addition to its acute vasoconstrictor effects, as already mentioned in the section on pulmonary hypertension, endothelin-1 is considered to exert chronic effects and to be deeply implicated in the proliferative responses associated with vascular diseases (221,222).…”