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...