Altered capillary filtration coefficient in parathion- and paraoxon-induced edema in isolated and perfused rabbit lungs

Abstract

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 ( R t) into four components: arterial, precapillary, postcapillary, and venous. The capillary filtration coefficient ( K fc) 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 K fc value increased progressively, reaching a maximum ( E max) 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 K fc was similar to that obtained with Pth. The concentration-response curve ( E max) expressed as a percentage of the baseline value versus the logarithm of the malor Pth concentration, ranging from 2 × 10 −5 to 4 × 10 −4 m) was linear ( y = 1661.1 + 327.3 x, r = 0.89, p < 0.001, n = 14). Piperonyl butoxide (4 × 10 −4 m), an inhibitor of cytochrome P450, had a strong protective effect against Pth (4 × 10 −4 m)-induced alterations of endothelium permeability ( n = 5, p < 0.001). The effects of Pox (4 × 10 −4 m) on K fc were completely abolished by pretreatment with 10 −5 m atropine, as shown by the significantly lower E max 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 E max 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 and 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. It can be explained by an increase in endothelium permeability. This effect is mediated principally by muscarinic receptors.