DuP 753, a nonpeptide angiotensin II-1 receptor antagonist, alters dopaminergic function in rat striatum

The purpose of this study was to determine if the nonpeptide angiotensin II-1 receptor antagonist DuP 753 after, acute or chronic administration in vivo or after in vitro exposure, altered indices of dopaminergic function in rat striatum. In vivo studies examined the effect of acute and chronic 21-day administration of DuP 753 (10 mg/kg, s.c.) on levels of dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC). To determine if chronic treatment with DuP 753 was able to inhibit the pressor response to angiotensin II, a single i.v. dose of angiotensin II (0.1 μg/kg) was administered 18 hours after the last dose of DuP 753. Acute DuP 753 resulted in significantly decreased (14%) levels of DA. Chronic DuP 753 resulted in increased (1.64 fold) levels of DOPAC, although DA levels were not altered. The single i.v. administration of angiotensin II resulted in increased (88%) DOPAC levels regardless of chronic DuP 753. The in vitro effect of DuP 753 (0.1 nM-1.0 μM) on basal and field stimulation-evoked release of DA and DOPAC was determined in superfused striatal slices from drug naive rats. DA was not detected in these experiments. DuP 753 did not alter basal outflow of DOPAC. At low concentrations (1.0-10 nM), DuP 753 decreased (53%) stimulation-evoked DOPAC overflow; however, at concentrations greater than 10 nM, the inhibitory effect was diminished. Nomifensine (10 μM; a DA uptake inhibitor) was included in the superfusion buffer in order to measure the effect of DuP 753 on the concentration of DA in superfusate. DuP 753 had no effect on basal DA and DOPAC outflow. Nomifensine markedly potentiated the DuP 753-induced decrease in stimulation-evoked DOPAC and DA overflow. Pargyline (10 μM; a monoamine oxidase (MAO) inhibitor) was included with nomifensine in the superfusion buffer to examine the contribution of MAO to the DuP 753-induced decrease in dopaminergic neurotransmission. The effect of DuP 753 on DA overflow was not altered by the presence of pargyline. Additionally, angiotensin II (1 and 10 μM) increased the overflow of DOPAC from striatal slices under control conditions. Therefore, the results in vitro suggest that acutely the agonist increases DA neurotransmission and the antagonist decreases DA neurotransmission. In contrast, chronic in vivo adminitration of DuP 753 resulted in increased striatal DOPAC levels indicative of an increased dopaminergic neurotransmission. Therefore, chronic in vivo administration of DuP 753 appears to result in a compensatory response of the dopaminergic system in striatum.