Der Einfluß von Hydrochlorothiazid und anderen sulfonamidierten Diuretica auf die 3′,5′-AMP-Phosphodiesterase-Aktivität in der Rattenniere

Summary

Vasopressin has been reported to accelerate the conversion of adenosine triphosphate to cyclic 3′,5′-AMP by stimulating the activity of the adenyl cyclase. According to the view of Orloff and Handler cyclic 3′,5′-AMP is responsible for the augmentation of osmotic water flow. The cyclic nucleotide ist degraded by the enzyme 3′,5′-AMP phosphodiesterase (PDE) to 5′-AMP. Inhibition of this enzyme by theophylline results in an increase in the concentration of 3′,5′-AMP and a concomittant increase in osmotic water flow, as shown in the urinary bladder of the toad (Bufo marinus).

The experiments presented in this paper derived from a previous observation that furosemide and hydrochlorothiazide inhibit PDE. Both diuretics have been shown to reduce renal PDE activity when injected i.v. to rats in a dose of 25 mg/kg. Following injection of furosemide PDE activity has been found reduced only in the cortex, the effect of hydrochlorothiazide has been shown to be restricted to the inner medulla.

Studies on the subcellular distribution of renal PDE revealed two fractions, one third of total activity bound to large particles, probably cell membranes, two third soluble in the hyaloplasm. The two fractions of the enzyme differ in their k _m-value for 3′,5′-AMP. Subcellular distribution and k _m-values of PDE in the liver have been found to be identical with those in the kidney.

Hydrochlorothiazide has been shown to affect both fractions of renal PDE. Because of the restriction of the action of furosemide to the renal cortex no attempt was made to differentiate the effect of the compound with respect to its subcellular localization. Accumulation of 3′,5′-AMP caused by an impaired degradation of the nucleotide in this region could lead to an increase in the permeability of the distal convoluted tubules to water. As the difference in the osmotic pressure between distal tubular fluid and the surrounding interstitial fluid is relatively small, the increase in water permeability can only result in a small increase in tubular water reabsorption. In view of hydrochlorothiazide reducing PDE activity in the inner medulla and the high difference in the osmotic pressure between the fluid in the collecting tubules and the interstitial fluid it is suggested that a hydrochlorothiazide induced increase in water permeability results in a high increase in water rea-absorption, especially in diabetes insipidus where there is a low osmolarity of the tubular fluid in the collecting duct with an unimpaired cortico-papillary osmotic gradient. This corresponds to the paradoxical antidiuretic effect of diuretics in the treatment of diabetes insipidus centralis and renalis, especially after diuretic induced sodium depletion and reduction of the osmolarity of tubular fluid resulting in an increased osmotic difference between fluids within collecting ducts and interstitium.