DIFFERENTIAL BLOCKADE OF CENTRAL EFFECTS OF ANGIOTENSIN-II BY AT(2)-RECEPTOR ANTAGONISTS

In conscious, chronically instrumented, male Long-Evans rats, we showe d previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 mug) caused a rapid-onset mark ed, but transient, blockade of the regional hemodynamic responses to i ntracerebroventricular angiotensin II (ANG II). In contrast, the AT2-r eceptor antagonist PD-123319 (80 mug) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular A NG II. In the present study we attempted to mimic the actions of PD-12 3319 by giving a supramaximal dose of EXP-3174 (10 mug), and we also a ssessed the effects of PD-123177 (80 mug), 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 respo nses to intracerebroventricular ANG II, and PD-123177 was without inhi bitory effects in this model. The results indicate important functiona l differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.