The Chronically Reserpinized Rat as an Animal Model for Cystic Fibrosis: I. Acute Effect of Isoproterenol and Pilocarpine upon Pulmonary Lavage Fluid

Summary: Lung lavage samples from rats treated in a chronic fashion with reserpine had mean increases of 133, 170, and 120% in the total protein, lipid, and carbohydrate contents, respectively, when compared with those of untreated control animals, when these values were expressed in terms of body weight. An acute single ip injection of the β-adrenergic agent isoproterenol (10 mg) increased the glycoprotein content of pulmonary lavage fluid from control rats approximately 15–19%, but only 9–10% in those from reserpine treated rats. By contrast, pilocarpine (10 mg), administered in the same manner, caused a 15% increase in the total protein, carbohydrate, and lipid content of lavage samples from control rats and increased these same constituents in the lavage samples of reserpine treated rats 98, 102, and 80%, respectively. The increased total carbohydrate content in the lavage samples of the treated animals was not associated with changes in the percent distribution of neutral sugars, amino sugars, or sialic acid. The ratio of these various sugar components did not change in the lavage samples of control or reserpine treated rats upon stimulation with either pilocarpine or isoproterenol. The increased total lipid content fround in the lavage samples from the treated rats probably results from an increase in phospholipids. A decrease in phospholipid content occurred in the lavage samples of reserpine treated rats upon stimulation, while the opposite was observed in those of control animals. Chronic treatment of rats with reserpine, thus, appears to induce an enhanced production of glycoproteins in the airways and to interfere with phospholipid metabolism in the lung. In addition, the drug treatment enhances the secretory response to pilocarpine in comparison with the responses of control animals. The enhanced response or hypersecretion of glycoproteins is a quantitative one and does not seem to involve alterations in the ratios or distribution of the various sugar components. This disturbance in the secretory function of the respiratory tract, a target organ which is prominently involved in cystic fibrosis (CF) together with alterations in other exocrine glands which resemble those of CF patients, makes the reserpine treated rat a useful model for the further study of possible pathogenetic mechanisms in CF.Speculation: The experimental animal model for CF developed by the chronic administration of reserpine to rats has been found to have changes in the protein content of lung lavage samples, in addition to morphologic and secretory alterations in the salivary glands and the pancreas. Further analysis of the organic composition of lung lavage samples shows that the protein, carbohydrate, and lipid contents are significantly increased after chronic reserpine administration and that the response to stimulation with pilocarpine is enhanced in the treated animals when compared to that of untreated control rats. It therefore appears that chronic reserpine administration causes a hypersecretion of glycoproteins and changes in lipid metabolism in the respiratory tract of the rat and that, in conjunction with previous findings in other exocrine glands, these effects on lung function make the reserpine treated rat a useful tool for the study of the pathologic disturbance seen in the major exocrine glands affected in CF.