Effect of peptide and nonpeptide antagonists of angiotensin II receptors on noradrenaline release in hypothalamus of rats with angiotensin II-induced increase of water intake.

Angiotensin II (Ang II) administered intracerebroventriculary (icv) at a dose that induces drinking behavior in rats significantly increased K(+)-stimulated release of [(3)H] noradrenaline (NA) in hypothalamus without affecting basal [(3)H] NA release. The observed difference between the effects of Ang II on basal and K(+)-stimulated [(3)H]NA release may possibly be due to the fact that peptides are released after increased neuronal activity. It can be suggested that Ang II is important primarily in pathological states and that NA plays a substantial role in the brain Ang II-induced drinking response. The imidazolic nonpeptidic compound 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazole potassium salt (DuP 753, losartan), its active metabolite 2-n-butyl-4-chloro-1-{[2-(1H-tetrazol-5-yl)- biphenyl-4-yl]methyl}imidazole-5-carboxylic acid (EXP 3174) and peptide Ang II analogue, sarmesin, antagonized the Ang II-induced effect on [(3)H]NA release, in spite of the differences in their chemical structures. Thus, the drugs tested inhibited K(+)-stimulated [(3)H]NA release in hypothalamus, acting via the angiotensin (AT)(1) receptor subtype. We could not reject the possibility of a non-receptor mechanism of action for DuP753, EXP3174 and sarmesin. This research allows us to suggest a neurochemical mechanism for the modulatory role of these drugs on the NA-ergic system. The Ang II receptor antagonists studied may become important therapeutic agents, which act preferentially on pathologically activated systems. These agents may be of use for the prevention of excessive ingestion of water in some neuropsychotic diseases.