Differential blockade of central effects of angiotensin II by AT2- receptor antagonists

In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT₁- receptor antagonist EXP-3174 (1 μg) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT₂- receptor antagonist PD-123319 (80 μg) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 μg), and we also assessed the effects of PD-123177 (80 μg), an AT₂-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT₂-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.