Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin II receptor antagonist.

Abstract

The purpose of these studies was to quantitatively assess the role of endogenous angiotensin II activity in controlling transport in the proximal convoluted tubule (PCT) and whole nephron. We used the nonpeptide angiotensin II receptor antagonist DuP 753, which lacks the agonist and kinin/prostaglandin-inducing properties of saralasin and captopril, respectively. During in vivo microperfusion in the Munich-Wistar rat, we found that DuP 753 had a powerful inhibitory effect on bicarbonate (370 +/- 3 to 200 +/- 9 pEq/mm.min, P less than 0.001), chloride (214 +/- 3 to 105 +/- 9 pEq/mm.min, P less than 0.001), and water (5.2 +/- 0.1 to 2.8 +/- 0.2 nl/mm.min, P less than 0.001) absorption in the S1 subsegment of the PCT. At maximally effective doses, DuP 753 (10 mg/kg i.v.) was significantly more effective than was captopril (3 mg/kg i.v.) in inhibiting sodium chloride transport in the S1 PCT. DuP 753 is the most potent diuretic ever described in this segment. Consistent with the axial decline of angiotensin II receptor density in the PCT, DuP 753 was a less effective transport inhibitor in the S2 subsegment of the PCT, similar to captopril. Though downstream reabsorptive elements partially compensate for the action in the earliest segment of the nephron, we also showed using free-flow micropuncture and clearance techniques that DuP 753 induces a substantial diuresis, natriuresis and chloruresis. In conclusion, the marked decrease in S1 PCT fluid and electrolyte absorption induced by DuP 753 indicates that endogenous angiotensin II exerts significant tonic support of proximal transport in vivo.