Dissociation of the Natriuretic and Antikaliuretic Properties of Triamterene Derivatives by Dose–Response Experiments

Abstract

Several derivatives of triamterene were synthesized with the aim of obtaining physicochemical properties superior to those of triamterene. Their effects on electrolyte excretion were tested with dose–response curves in rats: a dissociation of ED₅₀ values of Na⁺ excretion from those of K⁺ retention was found; while the ED₅₀ values of natriuresis were structure independent, the ED₅₀ values for potassium retention depended highly on the charge of the side chain of the triamterene derivatives. Acidic compounds displayed low and amines high K⁺-retaining potencies. Hence we postulate that there are at least two sites of action of the tested compounds in the kidney, (i) The first is the Na⁺ conductance. Its blockade is responsible for the reduction in the lumen-negative electrical potential difference; this is the main driving force for K⁺ secretion. The affinity to the Na⁺ conductance is not correlated with the basic/acidic properties of the compounds, (ii) The second site is the finite K⁺ conductance of the luminal membrane of the distal tubule. The affinity of the drugs to this K⁺ conductance depends strongly on the charge of the molecule. Only pteridine derivatives with a basic side chain, i.e., with a high pK _a value, block the membrane K⁺ conductance and are therefore potent potassium-retaining drugs.