A POTENTIAL ROLE FOR ENDOGENOUS ADENOSINE IN CONTROL OF HUMAN GLOMERULAR AND TUBULAR FUNCTION

Adenosine has profound effects on renal function in experimental animals, but little is known about its role in human subjects. The recent advent of specific adenosine agonists and antagonists suitable for human use, however, now makes it possible to evaluate the influence of this potent vasoactive compound in both normal and pathological states. In this study we assessed the effects of FK-453, a nonxanthine, selective adenosine A1-receptor antagonist, on normal renal hemodynamics, tubular function, and plasma renin release. Eight healthy, male subjects each received three single oral doses of FK-453 (50, 100, and 200 mg) in ascending dose order with random allocation of one matched placebo dose, each on a separate study day. Renal hemodynamics, tubular function, and plasma renin concentrations (PRC) were assessed at baseline and postdose on each study day. Glomerular filtration rate (clearance of Cr-51-labeled EDTA) rose by 18.0%, 3 h after the administration of 100 mg of FK-453 and by 18.3% and 23.5%, 2 and 3 h, respectively, after the 200-mg dose, which was significantly different from the changes following placebo. There were no significant changes in mean arterial blood pressure or effective renal plasma flow (clearance of I-125-Hippuran). In contrast there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional excretions of sodium, phosphate, bicarbonate, chloride, magnesium, and uric acid in response to FK-453. No glycosuria or aminoaciduria was detected on urinalysis. There was, in addition, a marked increase in PRC in response to FK-453. These data are consistent with a physiological role for adenosine in the control of human glomerular and tubular function, especially in the proximal segment, as well as plasma renin release acting via the A1 receptor.