Influence of aminopeptidase inhibitors on brain angiotensin metabolism and drinking in rats.

The metabolism of [125I]angiotensin II (AII, octopeptide) and [125I]angiotensin III (AIII, heptapeptide) was determined in the cerebroventricular compartment following intracerebroventricular (i.c.v.) pretreatment with artificial cerebrospinal fluid (aCSF) or the aminopeptidase B inhibitor, bestatin (BE). Microwave fixation was used to stop brain aminopeptidase activity followed by high-performance liquid chromatography methods to measure degradation. The resulting mean t 1/2 values were: aCSF/AII = 23.5 s, BE/AII = 32.0 s; aCSF/AIII = 8.2 s, BE/AIII = 16.0 s. A second experiment indicated that i.c.v. administered BE induced considerable water consumption, while amastatin (AM, an aminopeptidase A inhibitor) did not. Combined i.c.v. treatment with BE/AII or BE/AIII produced water consumptions that were equivalent with the sum of the water intakes due to independent treatments. Unexpectedly, combined treatment with AM/AII also significantly facilitated water consumption as compared with the independent treatments. These results suggest that i.c.v. BE-induced drinking is due to the extension of the half-life of endogenous AIII, and that both AM and BE facilitate drinking to i.c.v. AII and AIII by inhibiting the degradation of AII and AIII. This delay in degradation prolongs the action of AIII at central angiotensin receptors while also slowing the conversion of AII to AIII, thus providing a depot of available AII to be converted to AIII in an obligatory manner.