Dissociation of effects of xanthine analogs on renal prostaglandins and renal excretory function in the awake rat

PG Baer, EL Armstrong and LM Cagen

In awake, male rats, oral theophylline (TH) or enprofylline (EN; 3- propyl xanthine), 10 to 50 mg/kg b.wt., similarly increased urinary prostaglandin (PG)E2 excretion, by 2- to 3-fold; urinary PGF2 alpha excretion was increased to a lesser extent (50%), while excretion of a PGI2 metabolite, 6-keto-PGF1 alpha, was not altered. In rat renal high- speed supernatant, neither TH nor EN inhibited activity of 15- hydroxyprostaglandin dehydrogenase, an intrarenal PG catabolizing enzyme, suggesting that the increased urinary PG excretion was due to increased synthesis. TH, at all doses that increased urinary PGE2 excretion, also caused dose-related 2-to 4-fold increases in urine volume and urinary excretion of sodium and potassium. In contrast, at low doses EN increased urinary PGE2 excretion without altering urine volume or electrolyte excretion; at the highest dose tested, EN produced a modest diuresis and natriuresis. Pretreatment of rats with indomethacin or meclofenamate (10 mg/kg b.wt., p.o.), chemically dissimilar PG synthesis inhibitors, prevented effects of TH and EN on urinary PG excretion, and also blocked their diuretic and natriuretic effects. Thus, increased renal PGs may be permissive and requisite for the diuretic and natriuretic effects of xanthines, but not sufficient to cause those effects. Enprofylline has been reported (Persson et al., Life Sci. 30: 2181, 1982) to be more active than theophylline as a phosphodiesterase inhibitor, but inactive as an adenosine antagonist, suggesting that the latter action is not required for xanthine stimulation of urinary PG excretion but may be a factor in the diuretic and natriuretic effects.

Volume 227, Issue 3, pp. 600-604, 12/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics