The rostral ventrolateral medulla mediates sympathetic baroreflex responses to intraventricular angiotensin II in rabbits Takeshi Saigusa a , Naomi S. Granger b , Shirley J. Godwin b , Geoffrey A. Head b, * a Department of Physiology, Faculty of Medicine, University of Yamanashi, Tamaho, Nakakoma, Yamanashi 409-3898, Japan b Neuropharmacology Laboratory, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia Received 21 October 2002; received in revised form 7 April 2003; accepted 17 April 2003 Abstract The present study examined the role of the rostral ventrolateral medulla (RVLM) in mediating the pressor and renal sympathetic baroreflex effects of intraventricularly administered angiotensin II (Ang II) in urethane anaesthetised rabbits. Microinjection of Ang II over a wide range of medullary sites showed that pressor responses were observed only in the RVLM. Ang II was particularly potent in producing a transient pressor response at this site with a half maximal dose of 9 fmol. The administration of the Ang II antagonist Sar 1 -Ile 8 -Ang II (10 pmol) bilaterally into the RVLM inhibited the pressor response to local and fourth ventricular Ang II, but not the pressor response to RVLM applied glutamate. To determine the contribution of the RVLM to the renal sympathetic baroreflex effects of Ang II, blood pressure –renal sympathetic nerve activity (RSNA) curves were constructed with intravenous infusion of phenylephrine or nitroprusside before and after Ang II, vehicle or glutamate infusions into the RVLM. Ang II infusion of 4 pmol/min into the RVLM increased blood pressure by 8 F 3 mm Hg and shifted the renal sympathetic baroreflex curve to the right. The maximum RSNA evoked by lowering blood pressure increased by 36 F 6%, similar to the effect seen with fourth ventricular Ang II and RVLM glutamate. These studies suggest that the major medullary pressor site of action of Ang II when injected into the hindbrain cerebro-spinal fluid of anaesthetized rabbits is the RVLM where it facilitates baroreflex control of RSNA. D 2003 Elsevier B.V. All rights reserved. Keywords: Renal nerve activity; RVLM; Intracerebral microinfusion; Glutamate; Angiotensin; Baroreflex 1. Introduction Angiotensin II (Ang II) plays an important role in the regulation of the cardiovascular system at many levels including the kidney, vasculature and importantly in the central nervous system (Phillips, 1987). Since circulating Ang II does not normally penetrate the blood–brain barrier (Schelling et al., 1976), the central effects of circulating Ang II are assumed to be mediated by stimulation of receptors in particular regions of the brain which lack this barrier (Phillips, 1987). Autoradiographic studies have revealed that Ang II receptors are also distributed in a number of regions which lie behind the blood–brain barrier (Mendel- sohn et al., 1988). In the medulla these include the rostral ventrolateral medulla (RVLM), the caudal ventrolateral medulla (CVLM) and the nucleus tractus solitarius (NTS), all of which are known to play essential roles in the tonic and reflex control of the sympathetic vasomotor tone (Casto and Phillips, 1986). There has been much interest in determining not only the effect of activating or inhibiting the Ang II receptors but trying to formulate a picture of the role of these receptors in the framework of the regulation of the cardiovascular system. Ang II applied locally is generally excitatory (Chan et al., 1991) and produces sympathetically mediated pressor responses when applied to the RVLM of a number of species (Allen et al., 1988; Andreatta et al., 1988; Muratani et al., 1991; Saigusa and Head, 1993; Saigusa et al., 1996; Sasaki and Dampney, 1990) and sympatho-inhibition when applied to the CVLM (Muratani et al., 1993; Saigusa et al., 1996; Sasaki and Dampney, 1990). Administration of Ang II into the cerebrospinal fluid generally induces pressor responses which are, in part, mediated through sympathetic vasocon- striction (Elghozi and Head, 1990; Head and Williams, 1992; Severs et al., 1966). Experiments in our laboratory have demonstrated that very small quantities of Ang II applied close to the surface of the brainstem through a fourth ventricle (4 V) catheter produce significant pressor responses 1566-0702/03/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S1566-0702(03)00104-8 * Corresponding author. Tel.: +61-3-8532-1332; fax: +61-3-8532-1100. E-mail address: Geoff.Head@baker.edu.au (G.A. Head). www.elsevier.com/locate/autneu Autonomic Neuroscience: Basic and Clinical 107 (2003) 20 – 31