Altered capillary filtration coefficient in parathion- and paraoxon-induced edema in isolated and perfused rabbit lungs.
Changes in pulmonary endothelium permeability and in microvascular hemodynamics induced by parathion (Pth) and paraoxon (Pox), its active metabolite, were investigated in isolated, perfused rabbit lungs. Blood-free perfusate was recirculated through isolated and ventilated lungs in an isogravimetric state and in zone III conditions. The arterial/venous/double occlusion technique was used to divide the total vascular resistance (Rt) into four components: arterial, precapillary, postcapillary, and venous. The capillary filtration coefficient (Kfc) was evaluated by measuring the amount of fluid filtering through the endothelium when the arterial and venous pressures were suddenly increased. Pth and Pox induced pulmonary edema by increasing endothelium permeability without changing the hemodynamic parameters at any level of the vascular bed. The Kfc value increased progressively, reaching a maximum (Emax) 60 min after administration of organophosphate (558 +/- 65% (n = 5) and 707 +/- 109% (n = 5) of baseline values, for Pth and Pox, respectively). During the next 60 min, it decreased. The time course of Pox-induced changes in Kfc was similar to that obtained with Pth. The concentration-response curve (Emax) expressed as a percentage of the baseline value versus the logarithm of the molar Pth concentration, ranging from 2 x 10(-5) to 4 x 10(-4) M) was linear (y = 1661.1 + 327.3x, r = 0.89, p < 0.001, n = 14). Piperonyl butoxide (4 x 10(-4) M), an inhibitor of cytochrome P450, had a strong protective effect against Pth (4 x 10(-4) M)-induced alterations of endothelium permeability (n = 5, p < 0.001). The effects of Pox (4 x 10(-4) M) on Kfc were completely abolished by pretreatment with 10(-5) M atropine, as shown by the significantly lower Emax value recorded in atropine-pretreated lungs (129 +/- 33%, n = 4) than in Pox-treated lungs (707 +/- 109%, n = 5, p < 0.001). The effects of Pth, on the other hand, were only partially inhibited, since the Emax value recorded in atropine-pretreated lungs (196 +/- 20%, n = 4) remained significantly higher than that recorded for control lungs (129 +/- 15%; n = 5; p < 0.05). These results show that isolated and perfused rabbit lungs constitute an appropriate model for studying the direct pulmonary effects of organophosphates. The edema-inducing action of Pth depends on its activation by conversion to Pox in the lung tissue.(ABSTRACT TRUNCATED AT 400 WORDS)
Delaunois
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Department of Pharmacology-Pharmacotherapy-Toxicology, Faculty of Veterinary Medicine, University of Liège, Belgium.
Gustin
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Ansay
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D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001711:Biotransformation; D002199:Capillary Permeability / Q000187:drug effects*; D002200:Capillary Resistance / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000033:anatomy & histology / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010261:Paraoxon / Q000493:pharmacokinetics / Q000494:pharmacology*; D010278:Parathion / Q000493:pharmacokinetics / Q000494:pharmacology*; D010477:Perfusion; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000503:physiopathology; D011817:Rabbits
D009596:Nitrophenols; D010278:Parathion; D001285:Atropine; D010882:Piperonyl Butoxide; D010261:Paraoxon; C024836:4-nitrophenol