Pharmacological effects in animals and normal human subjects of the diuretic amiloride hydrochloride (MK-870>

The effects of vasopressin, theophylline and cyclic AMP on sodium transport across isolated frog skin have been studied using 24Na for the measurement of sodium fluxes. Both vasopressin and theophylline produced consistent increases in short-circuit current, sodium influx and efflux, with a reduction in partial resistance of the skin. The same results were obtained with cyclic AMP only when it was combined with small (loses of theophylline which were by themselves ineffective. The similarity of effect of these three compounds on sodium transport mechanisms strengthens the hypothesis that the physiological activity of vasopressin may be mediated by cyclic AIMIP.THE work of Orloff and Handler [1962] has shown that vasopressin (ADH). theophylline and cyclic adenosine 3'-5'-monophosphate (cyclic AMP) increase both the short-circuit current across isolated toad bladder and the permeability to water. More recently Handler, Butcher, Sutherland and Orloff [1965] have demonstrated an increase in the cyclic AMP content of toad bladder treated with vasopressin. They have suggested, therefore, that the antidiuretic action of ADH may be mediated by an increase in the production of cyclic AMP in receptor cells. Theophylline, which mimics the effect of ADH, is thought to inhibit the inactivation of cyclic AMP by tissue phospho-diesterases.From measurements of short-circuit current alone it is impossible to establish the similarity of effect of ADH, theophylline and cyclic AMP on sodium transport mechanisms. Ussing and Zerahn [1951] found that vasopressin increases both the short-circuit current and the net influx of sodium ions through isolated frog skin and that a decrease in resistance to the passage of sodium ions was responsible for this effect.We have extended this work to include measurements of sodium fluxes across isolated frog skin treated with ADH, theophylline and cyclic AMP. METHODThe isolated frog skin preparation [Ussing and Zerahn, 1951] was used. Ventral frog skin was mounted between two Perspex half-cells each filled with 50 ml. frog Ringer solution. With the potential difference across the skin reduced to zero, the current generated by the skin (the short-circuit current) was measured.After a control period of observation, the substances to be tested were added to the bath fluid on either the inside or the outside of the skin and the changes in shortcircuit current recorded.The influx and efflux of 24sodium were measured for each compound. For this purpose approximately 100 ,e. 24sodium as sodium chloride were introduced into the bath fluid on one side of the skin and samples withdrawn from the opposite side to 416

A standardized technique suitable for clinical evaluation of diuretic drugs in hospitalized patients with fiuid retention is described. The sensitivity and reliability of the method have been explored. Urinary excretion of sodium, potassum, and fiuid, as well as acute weight loss have been employed as response parameters. The assay has been applied to yield data on the absolute and comparative efficacies of a newly introduced phthalimidine diuretic, clorexolone, in a group of fifty patients. Clorexolone was found to be a potent diuretic producing a pattern of water and electrolyte excretion similar to that caused by the benzothiadiazine group of diuretics. Its natriuretic action persisted for at least 48 hours after oral administration. A comparison of maximally effective doses of clorexolone and a standard benzothiadiazine derivative, hydrofiumethiazide, showed the two drugs to be essentially eqUipotent. Except for a rise in serum uric acid levels, no potentially adverse effects were observed during prolonged therapy with clorexolone and potassium supplements.

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SUMMARY Microgram quantities of tritiated aldosterone or cortisol were injected into the aorta of rats. The kidneys were removed at various times after injection, and examined by light and electron microscope autoradiography. The mineralocorticoids or their metabolites were bound to kidney cells in amounts sufficient to give autoradiographs. Radioactivity occurred mainly in the proximal and distal convoluted tubules. Within these cells it was bound mainly to mitochondria and plasma membranes. The results are discussed in relation to the current theories of mineralocorticoid action.