Angiotensin-(1–7) in the Rostral Ventrolateral Medulla Modulates Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activation in Renovascular Hypertensive Rats

Abstract

Abstract-Enhancement of the cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic excitation in hypertension. The aim of the present study was to determine whether angiotensin (Ang)-(1-7) in the rostral ventrolateral medulla (RVLM) modulated the enhanced CSAR and sympathetic activation, and the signaling pathways that mediated these effects in the 2-kidney, 1-clip renovascular hypertension model. Cardiac sympathetic afferent reflex was evaluated using renal sympathetic nerve activity and mean arterial pressure responses to epicardial capsaicin application in anesthetized sinoaortic-denervated and cervical-vagotomized rats. RVLM microinjection of Ang-(1-7) induced greater increases in renal sympathetic nerve activity and mean arterial pressure, and greater enhancement in CSAR in 2-kidney, 1-clip rats than in sham-operated rats, which was blocked by Mas receptor antagonist A-779, adenylyl cyclase inhibitors SQ22536 and MDL-12,330A, and protein kinase A inhibitors rp-adenosine-3′,5′-cyclic monophosphorothionate and H-89. Mas receptor expression in RVLM was increased in 2-kidney, 1-clip rats. Treatment with A-779, SQ22536, MDL-12,330A, rp-adenosine-3′,5′-cyclic monophosphorothionate, or H-89 in RVLM inhibited CSAR and decreased renal sympathetic nerve activity and mean arterial pressure in 2-kidney, 1-clip rats, whereas cAMP analogue dibutyryl-cAMP had the opposite effects. Ang-(1-7) in RVLM increased, whereas A-779 decreased the cAMP level and the epicardial capsaicin application-induced increases in the cAMP level in RVLM. These results indicate that Ang-(1-7) in the RVLM enhances the CSAR and increases the sympathetic outflow and blood pressure via Mas receptor activation. The increased endogenous Ang-(1-7) and Mas receptor activity in RVLM contributes to the enhanced CSAR and sympathetic activation in renovascular hypertension, and the cAMP-protein kinase A pathway is involved in these Ang-(1-7)-mediated effects 24,30,31 Our recent study has shown that Ang-(1-7) in the RVLM enhances the CSAR and increases renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP), whereas A-779 microinjection into the RVLM decreases the RSNA and MAP and inhibits the CSAR in normal rats.32 However, it is not known whether Ang-(1-7) in the RVLM is involved in the enhanced CSAR and excessive sympathetic activation in hypertension.A recent study demonstrates that Mas receptor activation by Ang-(1-7) increases the intracellular cAMP level and activates protein kinase A (PKA) and that inhibition of either adenylyl cyclase (AC) or PKA activity attenuates Ang-(1-7)-induced extracellular signal-regulated kinase 1/2 activation in glomerular mesangial cells.33 Ang-(1-7) inhibits vascular growth via prostacyclin-mediated cAMP production and PKA activation. 34 These results demonstrate that the cAMP-PKA signaling pathway regulates Ang-(1-7) function in some peripheral tissues. However, whether the cAMP-PKA pathway is involved in Ang-(1-7)-mediated effects in the RVLM in hypertension is not well understood. The...

Hexamethonium attenuates sympathetic activity and blood pressure in spontaneously hypertensive rats

“…It has been demonstrated that the sympathetic activity of obese rats (4,24), renovascular hypertensive rats (5,25,26) and SHRs (6,27,28) is enhanced compared with normotensive rats. Hexamethonium is a ganglionic blocker (10,11) and reduces blood pressure in SHR and Wistar rats (8).…”

Angiotensin-(1–7) and Kidney Disease: Friend or Foe

“…5 The potential mechanism of these effects remains unclear, but may be related to the increased levels of angiotensin-converting enzyme or Ang-(1-7) metabolites, which may also be biologically active. Given the observation by Li et al, 1 one can also speculate that peripheral Ang-(1-7) may enter the central nervous system via the circumventricular organs, just as Ang II has been shown to do. An interesting future study would be to examine the changes in the rostral ventrolateral medulla after peripheral injections of Ang-(1-7) and determine whether Ang-(1-7) does cross the blood-brain barrier via the circumventricular organs.…”

Response to Angiotensin-(1–7) and Kidney Disease: Friend or Foe

“…3 The increased Ang-(1-7) and Mas receptor activity in RVLM contributes to the enhanced CSAR and excessive sympathetic activation, which could propel the pathogenesis of hypertension and progression of organ damage in renovascular hypertension. 1 Velkoska et al also have shown that Ang-(1-7) infusion has major adverse effects of increasing blood pressure and accelerating cardiac hypertrophy and fibrosis in rats with subtotal nephrectomy. 4 In addition, Ang-(1-7) causes transition of tubuloepithelial cells into myofibroblasts, which contributes to renal fibrosis.…”

“…1 It should be noted that we did not investigate the effects of Ang-(1-7) in periphery. The examination of the changes of Ang-(1-7) level in the RVLM after peripheral injection of Ang-(1-7), which was suggested by Velkoska et al might be helpful in determining whether peripheral Ang-(1-7) could cross the blood-brain barrier via the circumventricular organs in the 2-kidney, 1-clip renovascular hypertension model, which requires further study.…”