Abstract-The aim of this work was to evaluate the potential of liposomes as a tool for the sustained release of the short half-life peptides of the renin-angiotensin system in a specific site of the brain. Angiotensin (Ang)-(1-7) was selected for this study because of its known cardiovascular effects at the level of the rostral ventrolateral medulla (RVLM) and because of the considerable interests in elucidating its physiopathological role as a neuromodulator. Ang-(1-7)-containing liposomes (LAng) were microinjected unilaterally in the RVLM of Wistar rats, and the effects on blood pressure (MAP) and heart rate were evaluated by telemetry. Empty liposomes (Lemp) were used as control. LAng elicited a significant pressor effect during daytime and bradycardia during nighttime that lasted for 5 and 3 days, respectively. These cardiovascular effects resulted in a significant attenuation of the circadian variations of MAP and heart rate. In the case of MAP, a significant inversion of the circadian rhythm was observed on day 2 after LAng microinjection. None of these effects were observed following microinjection of Lemp. Using this novel technique, it was possible to establish, in chronic conditions, the pressor effect of Ang-(1-7) at the RVLM. Moreover, our data unmasks a new physiological role for Ang-(1-7) at the level of the RVLM: modulation of the circadian rhythms of MAP and heart rate. Key Words: liposomes Ⅲ angiotensin-(1-7) Ⅲ cardiovascular effects Ⅲ rostral ventrolateral medulla Ⅲ Blood pressure Ⅲ heart rate S everal recent studies indicate that peptides of the reninangiotensin system (RAS) may act as important neuromodulators, especially in the brain medullary areas related to the tonic and reflex control of arterial pressure. 1 Experimental evidence was obtained following site-specific microinjections of these peptides; however, because of their very short in vivo half-life, only their acute cardiovascular effects could be observed. 2-6 Therefore, information is still lacking on the long-term effects of these peptides, which should allow a better understanding of their physiopathological role. To address this question, injectable microreservoirs, which could act as sustained release systems in specific sites of the brain, have to be developed. Liposomes appear to be good candidates because of their biocompatibility and their recognized potential for the encapsulation and delivery of polypeptides in vivo. 7 Moreover, liposome encapsulation was previously shown to produce a marked prolongation of the peripheral effect of some vasoactive peptides, including angiotensin (Ang) II, 8 vasopressin, 9 and vasoactive intestinal peptide. 10 In this work, we evaluated the potential of liposomes for the sustained release of RAS peptides in a specific site of the brain. Ang-(1-7) was selected for this study because of its known cardiovascular effects at the level of the rostral ventrolateral medulla (RVLM) 2-5 and because of the considerable interests in its long-term physiopharmacological effects. 11 More specifically, ...