Angiotensin-(3–7) pressor effect at the rostral ventrolateral medulla

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Abstract

Ang-(3–7) is a fragment of the renin–angiotensin system that can be derived both from Ang II or Ang-(1–7). In the present study we determined the cardiovascular effects produced by angiotensin-(3–7) [Ang-(3–7)] microinjection into the rostral ventrolateral medulla (RVLM), a key region for the control of sympathetic drive to the periphery. RVLM microinjection of Ang-(3–7) (20, 40 or 80 ng) in male Wistar rats anesthetized with urethane produced significant increases in MAP (19 ± 3.8 mm Hg, n = 5; 16 ± 1.6 mm Hg, n = 15 and 11 ± 1.2 mm Hg, n = 4, respectively) as compared to saline (4 ± 0.7 mm Hg, n = 6). These alterations were similar to that induced by Ang-(1–7) (14 ± 1.3 mm Hg, 40 ng; n = 12) and Ang II (17 ± 2.3 mm Hg, 40 ng; n = 7). Microinjection of losartan (AT1 receptor antagonist, 100 pmol) or A779 (selective Mas receptor antagonist, 100 pmol) did not alter the pressor effect caused by Ang-(3–7). Microinjection of an Ang-(3–7) analogue, d-Ala7-Ang-(3–7) (100 pmol), completely abolished the pressor effect caused by Ang-(3–7). These results suggest that Ang-(3–7) may be an additional peptide of the RAS to act as neuromodulator, at least at the RVLM. Further, the Ang-(3–7) pressor effect is not mediated by the interaction with AT1 or the Ang-(1–7), Mas, receptors.

Introduction

Angiotensin (Ang) II is well accepted to be the main biological active end product of the renin–angiotensin system (RAS). However, it is increasingly clear that important central and peripheral actions of the RAS may be conveyed by other angiotensinogen metabolites, including Ang IV and Ang-(1–7) [1], [2], [3]. These peptides may possess unique pharmacological properties in the brain which are, at least in part, mediated by selective angiotensin receptor subtypes [2], [3]. While Ang II effects involve AT1 and AT2 receptors, Ang IV is mediated by a distinct receptor, named AT4, identified as the insulin regulated aminopeptidase (IRAP) [4]. More recently, we identified the G-protein coupled orphan receptor Mas as an Ang-(1–7) receptor [5]. In this study we showed that d-Ala7-Ang-(1–7) (A779), previously described as a selective Ang-(1–7) antagonist [6], was able to block the actions of Ang-(1–7) and to displace the Ang-(1–7) binding to Mas-transfected cells [5]. In addition, Mas-KO mice lack the anti-diuretic action of Ang-(1–7) after an acute water load, and kidney and aorta from these mice did not present Ang-(1–7) binding or Ang-(1–7)-induced vasorelaxation, respectively [5].

The rostral ventrolateral medulla (RVLM), an area that contains the major group of sympathoexcitatory neurons in the medulla for the tonic and phasic control of arterial pressure is a site for the action of angiotensin peptides [2], [7]. The microinjection of Ang-(1–7) and Ang II into the RVLM produces cardiovascular effects in different species [8], [9], [10], [11], probably through the interaction with different receptor subtypes. Several evidence suggest that Mas is the mediator of Ang-(1–7) effect at the VLM [2], [3], [5], [6], [12], whereas those of Ang II are due to interaction with AT1 receptor [2], [13].

There are many evidence that endogenously Ang-(1–7), Ang II or Ang IV can be converted to Ang-(3–7) through the action of aminopeptidases or carboxipeptidases [14], [15], [16], [17], [18], [19], [20]. Ang-(3–7) was shown to induce the release of dopamine in the rat striatum [21]. In addition, it was suggested that part of the central effects produced by Ang-(1–7) could be due to its conversion to Ang-(3–7) [21]. However, the central cardiovascular effects of Ang-(3–7) are not known.

The objective of the present study was to determine the cardiovascular effects produced by the microinjection of Ang-(3–7) into the RVLM of anesthetized rats. The involvement of the AT1 or Mas angiotensin receptor subtypes in the Ang-(3–7) effect was also investigated.

Section snippets

Surgical procedures

Experiments were performed in male Wistar rats (250–290 g) anesthetized with urethane (1.2 g/kg i.p., Sigma Chemical Co). Following tracheostomy, a catheter was inserted into the abdominal aorta, through the femoral artery for arterial pressure measurement. Next, the animals were placed in a stereotaxic frame (David Kopf instruments, CA) with the tooth bar − 11 mm below the level of the interaural line. The dorsal surface of the brainstem was exposed by a limited occipital craniotomy and

Cardiovascular effects produced by RVLM microinjections of Ang-(3–7)

Fig. 1 shows representative recordings of the PAP, MAP and HR to illustrate the typical effects produced by unilateral microinjection of Ang-(3–7), Ang-(1–7) and Ang II (40 ng each) into the RVLM of Wistar rats. Microinjection of Ang-(3–7), 20 ng, 40 ng or 80 ng induced significant and comparable pressor responses (19 ± 4 mm Hg, 16 ± 2 mm Hg and 11 ± 1 mm Hg, respectively, Fig. 2). The pressor effect was accompanied by increases in HR, significantly different from saline at the dose of 40 ng (21 ± 

Discussion

Ang-(3–7), a fragment of the RAS that can be formed from Ang II or Ang-(1–7), was identified in the rat brain [24] and some renal and cerebral actions of Ang-(1–7) were attributed to this fragment [21], [25]. However, the cardiovascular effects of Ang-(3–7) are not yet completely defined. In the present study we showed that microinjection of Ang-(3–7) into the RVLM produces increases in MAP and HR, of similar magnitude of that observed for Ang II or Ang-(1–7). Further, the lack of effect of

Acknowledgements

This study was supported by PRONEX (Programa de Núcleos de Excelência-CNPq), FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and CAPES (Coordenadoria de Apoio ao Pessoal de Nível Superior). PM Ferreira was a recipient of CAPES-PICDT fellowship from the Federal University of Goiás to obtain the Doctoral Degree at the Post-Graduation Program in Biological Sciences: Physiology and Pharmacology-ICB-UFMG. We are

References (41)

  • L.T. Krebs et al.

    Characterization of the binding properties and physiological action of divalinal–angiotensin IV, a putative AT4 receptors antagonist

    Regul Pept

    (1996)
  • J.J. Braszko et al.

    Angiotensin II(3–8) hexapeptide affects motor activity, performance of passive avoidance and a conditioned avoidance response in rats

    Neuroscience

    (1988)
  • A.L. Albiston et al.

    Attenuation of scopolamine-induced learning deficits by LVV-hemorphin-7 in rats in the passive avoidance and water maze paradigms

    Behav Brain Res

    (2004)
  • J.W. Wright et al.

    Regulatory role of brain angiotensins in the control of physiological and behavioral responses

    Brain Res Rev

    (1992)
  • D.B. Averill et al.

    Angiotensin peptides and the baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata

    Brain Res Bull

    (1999)
  • R.A.S. Santos et al.

    Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas

    Proc Natl Acad Sci

    (2003)
  • R.A.L. Dampney

    Functional organization of central pathways regulating the cardiovascular system

    Physiol Rev

    (1994)
  • A.M. Allen et al.

    Angiotensin receptor binding and pressor effects in cat subretrofacial nucleus

    Am J Physiol

    (1988)
  • S.H. Andreatta et al.

    The ventrolateral medulla: a new site of action of the renin–angiotensin system

    Hypertension

    (1988)
  • S. Sasaki et al.

    Tonic cardiovascular effects of angiotensin II in the ventrolateral medulla

    Hypertension

    (1990)
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    PM Ferreira is an Associate Professor at the Department of Physiological Sciences, of the Biological Sciences Institute of the Federal University of Goiás, Goiania, Brazil.

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