Effects of tachykinin NK1 or PAF receptor blockade on the lung injury induced by scorpion venom in rats

In cases of severe human scorpion envenoming, lung injury is a common findi ng and frequently the cause of death. In the rat, two distinct mechanisms a ccount for oedema following the intravenous injection of the venom - acute left ventricular failure resulting from a massive release of catecholamines and an increase in pulmonary vascular permeability. In the present work, w e investigated the effects of a tachykinin NK1 receptor antagonist (CP96,34 5, the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxy -phenyl)methyl)-1-azabicycol[2.2.2]octan-3-amine) and its 2R-3R inactive en antiomer (CP96,344) on the acute lung injury induced by the i.v. injection of Tityus serrulatus venom in rats. Lung injury was assessed by evaluating the extravasation of Evans blue dye in the bronchoalveolar lavage fluid and in the lung of venom-treated and control animals. The effects of the plate let-activating factor (PAF) receptor antagonist WEB2170 (2-methyl-1-phenyli midazol[4,5c]pyridine were evaluated for comparison. The i.v. injection of the venom induced the extravasation of Evans blue in the bronchoalveolar la vage fluid and into the left lung. Pretreament with the tachykinin NK1 rece ptor antagonist CP96,345, but not CP96,344, inhibited Evans blue dye extrav asation in the bronchoalveolar lavage fluid and in the lung by 96% and 86%, respectively. The PAF receptor antagonist WEB2170 inhibited the increase i n vascular permeability in the bronchoalveolar lavage fluid by 60% and had no effect on the extravasation to the lung parenchyma of venom-injected ani mals. In addition to abrogating lung injury, pretreatment of rats with CP96 ,345, but not CP96,344 or WEB2170, decreased by 70% the mortality induced b y the venom. This is the first study to show the relevance of the tachykini n NK1 receptor in mediating lung injury and mortality in animals injected w ith the neurotoxic T. serrulatus venom. Blockade of the tachykinin NK1 rece ptor may represent an important strategy in the treatment of patients with signs of severe envenoming and clearly deserves further studies. (C) 1999 E lsevier Science B.V. All rights reserved.