THE EFFECT OF INTRAVENOUSLY ADMINISTERED 6063, THE CARBONIC ANHYDRASE INHIBITOR, 2-ACETYLAMINO-1,3,4-THIADIAZOLE-5-SULFONAMIDE, ON FLUID AND ELECTROLYTES IN NORMAL SUBJECTS AND PATIENTS WITH CONGESTIVE HEART FAILURE

Abstract

Many of the clinical features of congestive heart failure are determined by the abnormal accumulation of water in the extracellular space, an event largely dependent upon the abnormal renal retention of sodium. Although there is a lack of knowledge of the exact mechanism responsible for this abnormality in renal excretion, it is well known that agents that enhance the excretion of sodium are valuable in the treatment of heart failure. The normal kidney plays an important part in preventing the sodium depletion of body fluids and maintaining the normal range of pH of the blood. This is accomplished by the tubular reabsorption of almost all the sodium which is filtered through the glomerulus and the conversion of the alkaline glomerular filtrate into an acid urine (1). The enzyme, carbonic anhydrase, found to be present in the renal cortex as well as other tissues such as gastric mucosa and erythrocytes of mammals (2), is regarded as an important element in the mechanism for the acidification of the urine (3) and the reabsorption of sodium. The inhibition of carbonic anhydrase and the prevention of the formation of an acid urine may serve as a method for reducing the abnormal sodium retention which is a feature of congestive heart failure. Following the observation that sulfanilamide induced acidosis (4) with an alkaline urine (5) and an increased excretion of sodium and potassium (6, 7) and the demonstration that sulfonamide compounds were specific carbonic anhydrase inhibitors (8), Hober suggested that the alkalinization of the urine was due to the inhibition of carbonic anhydrase in the renal tubules (9). Subsequently, Pitts and Alexander showed that sulfanilamide reduced the capacity of the kidney to eliminate acid under maximal stimulation by a