Effect of a nonpeptide angiotensin II receptor antagonist, DuP 753, on angiotensin-related water intake in rats.

The effect of peripheral administration of the nonpeptide angiotensin II-1 (AII) receptor blocker, DuP 753, on the dipsogenic responses to peripherally administered angiotensins I, II, and III was tested. In all cases, DuP 753 significantly inhibited the drinking response, whether administered 15 or 45 minutes prior to administration of the dipsogen. These results suggest that the drinking responses to angiotensins I, II, and III are mediated by AII-1 receptors. They also suggest that either AIII acts via the AII-1 receptor or that DuP 753 competes at an AIII-sensitive receptor. These studies also showed that when both AII and DuP 753 were given cerebroventricularly (ICV), potent inhibition of the drinking response occurred. Further, when DuP 753 was administered peripherally and AII ICV, drinking was also inhibited. Hence, DuP 753 must penetrate the brain, at least at the circumventricular sites implicated in angiotensin-related drinking. However, centrally administered DuP 753 failed to inhibit the drinking response to peripherally administered AII. This observation is presently unexplained, but may be related to the possibility that centrally administered DuP 753 is inactivated more quickly than when it is administered peripherally. Additional studies will be required to assess this.