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ERIBERTO S. LOZADA, JUNE GOUAUX, NICHOLAS FRANKI, GERALD B. APPEL, RICHARD M. HAYS, Studies of the Mode of Action of the Sulfonylureas and Phenylacetamides in Enhancing the Effect of Vasopressin, The Journal of Clinical Endocrinology & Metabolism, Volume 34, Issue 4, 1 April 1972, Pages 704–712, https://doi.org/10.1210/jcem-34-4-704
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Abstract
Chlorpropamide and acetaminophen are effective antidiuretic agents in diabetes insipidus. They appear to act by sensitizing the kidney to the low levels of vasopressin that may continue to circulate in many patients with this disease. To determine the mechanism of action of these agents, a series of studies of their effects on water flow was carried out in the isolated urinary bladder of the toad. The patterns of action of chlorpropamide and the phenylacetamides (phenacetin, acetaminophen and structurally related compounds) were compared to that of theophylline, a potent phosphodiesterase inhibitor. Theophylline enhanced the effect of low and saturating concentrations of vasopressin, enhanced the effect of cyclic AMP, had no effect on the inhibitory action of prostaglandin E1 (PGE1) and (at 3 × 10−3m) greatly increased water flow in the absence of vasopressin. Chlorpropamide differed from theophylline in all major respects, enhancing only low concentrations of vasopressin, inhibiting the effect of cyclic AMP, significantly increasing the inhibitory action of PGE1 and showing little effect on water flow in the absence of vasopressin. The phenylacetamides exhibited both theophylline-like and chlorpropamide-like actions. These observations can best be explained by a primary effect of chlorpropamide on adenyl cyclase, in which the enzyme is rendered more sensitive both to stimulation by vasopressin and inhibition by PGE1. Inhibition of phosphodiesterase does not appear to be a significant part of the chlorpropamide effect. The phenylacetamides, on the other hand, appear to have a dual action, modifying adenvl cyclase and inhibiting phosphodiesterase.