Interactions of the systemic and brain renin-angiotensin systems in the control of drinking and the central mediation of pressor responses

Abstract

Most of the biological actions of the circulating (a.k.a., the systemic or blood-borne) renin-angiotensin system require the generation of the octapeptide angiotensin (ANG) II from the decapeptide ANG I. In the case of circulating ANG I, the lungs are generally considered the major site for this conversion. The present experiments explored the possibility that under conditions of marked elevations of blood-borne ANG I, the generation of ANG II takes place within brain-associated target tissues, most notably circumventricular organs (CVOs) that lack a blood-brain barrier. The first important result of these experiments demonstrates that intracerebroventricular (i.c.v.) infusion of the converting enzyme inhibitor, captopril, completely blocks the drinking response and significantly attenuates the pressor response produced by systemically infused ANG I. This result indicates that under physiological/pathophysiological conditions associated with large elevations of circulating ANG I, an important part of the biological responses derived from blood-borne ANG may result from local conversion of ANG I to ANG II within specific brain target tissues which have high concentrations of converting enzyme. This local conversion process provides an important mechanism that would act to reinforce the "classic" conversion process which takes place in the lungs thereby delivering more ANG II immediately to central target receptors. The second important finding from these studies showed that drinking produced by systemically infused ANG II was not attenuated by an i.c.v. dose of captopril which was effective in blocking a comparable dipsogenic response induced by i.v. ANG I. This observation suggests that drinking induced by systemic ANG II does not require an intact metabolic cascade within the brain for the formation of ANG II (or ANG II-like effector peptide) from ANG I.