Activation of brain neurons by circulating angiotensin II: Direct effects and baroreceptor-mediated secondary effects

Circulating angiotensin II acts on neurons in circumventricular organs, lea ding to activation of central pathways involved in blood pressure regulatio n and body fluid homeostasis. Apart from this primary effect, an increase i n the level of circulating angiotensin II may also activate brain neurons a s a secondary consequence of the associated increase in blood pressure, whi ch will stimulate arterial baroreceptors and thus activate central neurons that are part of the central baroreceptor reflex pathway. The aim of this s tudy was to identify the population of neurons that are activated as a cons equence of the direct actions of circulating angiotensin II on the brain, i ndependent of secondary bare receptor-mediated effects. For this put-pose, we have mapped the distribution of neurons in the brainstem and forebrain t hat are immunoreactive for Fos (a marker of neuronal activation) following intravenous infusion of angiotensin II in conscious rabbits with chronicall y denervated carotid sinus and aortic baroreceptors. The distribution was c ompared with that evoked by the same procedure in two separate groups of ba rointact rabbits, in which angiotensin II was infused either at a rate simi lar to that in the barodenervated group, or at a rate approximately five ti mes greater. In barodenervated rabbits, angiotensin II infusion evoked a si gnificant increase in Fos expression, compared to control animals infused w ith the vehicle solution alone, in several forebrain nuclei (organum vascul osum of the lamina terminalis, subfornical organ, median preoptic nucleus, supraoptic nucleus, paraventricular nucleus, bed nucleus of the stria termi nalis and suprachiasmatic nucleus), but little or no increase in Fos expres sion in any lower brainstem region. In barointact rabbits infused with angi otensin II at a similar rate to that in barodenervated rabbits, a similar d egree of Fos expression was evoked in all of the above forebrain regions, b ut in addition a significantly greater degree of Fos expression was evoked in several medullary regions (nucleus tractus solitarius, area postrema, an d ventrolateral medulla), even though the angiotensin II-evoked increase in mean arterial pressure (17 +/- 3 mmHg) was less than that evoked in the ba rodenervated rabbits (26 +/- 2 mmHg). In barointact rabbits infused with an giotensin II at the higher rate, the increase in mean arterial pressure was 29 +/- 3 mmHg. In these animals, the pattern of Fos expression was similar to that evoked in barointact rabbits infused at the lower rate, but the de gree of Fos expression in all medullary regions and in some forebrain regio ns was significantly greater. The results of the present study, together with those of previous studies f rom our laboratory in which we determined the effects of phenylephrine-indu ced hypertension on brain Fos expression [Li and Dampney (1994) Neuroscienc e 61, 613-634; Potts et al. (1997) Neuroscience 77, 503-520], indicate that in conscious rabbits circulating angiotensin II activates primarily circum ventricular neurons within the organum vasculosum of the lamina terminalis and subfornical organ, but not the area postrema, and this in turn leads to activation of neurons in other forebrain regions, including the median pre optic, supraoptic, paraventricular and suprachiasmatic nucleus as well as t he bed nucleus of the stria terminalis. In contrast, the activation of neur ons in medullary regions evoked by an increase in the level of circulating angiotensin II is primarily a secondary effect resulting from stimulation o f arterial baroreceptors. (C) 1999 IBRO. Published by Elsevier Science Ltd.