AJP - Heart and Circulatory Physiology, Vol 265, Issue 1 226-H231, Copyright © 1993 by American Physiological Society

ARTICLES

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

R. E. Widdop, S. M. Gardiner, P. A. Kemp and T. Bennett
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, United Kingdom.

In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) 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 micrograms) 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 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), 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.

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