Essential role of RVL medullary neuronal activity in the long term maintenance of hypertension in conscious SHR Vera Geraldes a , Nataniel Goncalves-Rosa a , Beihui Liu b , Julian F.R. Paton b , Isabel Rocha a, ⁎ a Faculty of Medicine & Centro de Cardiologia of University of Lisbon, Portugal b School of Physiology & Pharmacology, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK abstract article info Article history: Received 28 March 2014 Received in revised form 14 August 2014 Accepted 5 September 2014 Available online xxxx Keywords: Hypertension Sympathetic nervous system Potassium channels (Kir2.1) Lentiviral vector Rostroventrolateral medulla Spontaneously hypertensive rats (SHR) Blood pressure Background: It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. Objective: To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neu- ron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). Methods: In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. Results: LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Conclusion: Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Hyperactivity of the sympathetic nervous system has for a long time been hypothesized as a mechanism for the initiation, development and maintenance of elevated blood pressure (BP) in human hypertensive patients and animal models (Bourjeili et al., 1995; Carlson et al., 2000; Esler, 1995; Fisher and Paton, 2012; Grassi, 2004b; Johansson et al., 1999; Mancia et al., 1999). Recently, the development of non- pharmacological therapeutics through medical devices for the treatment of resistant hypertension has further emphasized the association between sympathetic hyperactivity and the generation of high blood pressure. The findings that baroreflex impairment has been associated with a higher risk of developing hypertension in normotensive children with a family history of hypertension (Yamada et al., 1988) suggest that a neurogenic component could be causal. This interpretation is consistent with increased levels of sympathetic activity and plasma noradrenaline in white coat and borderline hypertensive individuals (Grassi, 1998, 2004a, 2009; Smith et al., 2004). These studies imply that sympatho- excitation precedes hypertension and may be a cause for this condition (Guyenet, 2006; Lucini et al., 2002). The increase of sympathetic drive to the heart and peripheral circulation not only increases cardiac output and vascular resistance, causing elevated BP values (Schlaich et al., 2012), but also to end organ damage (Zubcevic et al., 2011), which worsens patient prognosis. Based mainly on anesthetized animals, the rostroventrolateral medulla (RVLM) has been shown to be a pivotal area regulating cardio- vascular sympathetic tone. The RVLM lies ventral to the rostral part of the nucleus ambiguus (NA), caudal to the facial nucleus and ventral to the Bötzinger complex (Dampney, 1994; Janig, 2006b). The RVLM neurons project to the sympathetic preganglionic neurons in the intermediolateral (IML) cell column of the spinal cord (Card et al., 2006; Dampney, 1994; Guertzenstein and Silver, 1974; Leman et al., 2000) and receive a direct glutamatergic projection from the NTS, believed to be part of the peripheral chemoreflex (Koshiya and Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx ⁎ Corresponding author at: Instituto de Fisiologia, Fac Medicina de Lisboa, Av Prof Egas Moniz, 1649-028 Lisbon, Portugal. E-mail address: Isabelrocha@fm.ul.pt (I. Rocha). AUTNEU-01688; No of Pages 10 http://dx.doi.org/10.1016/j.autneu.2014.09.002 1566-0702/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu Please cite this article as: Geraldes, V., et al., Essential role of RVL medullary neuronal activity in the long term maintenance of hypertension in conscious SHR, Auton. Neurosci. (2014), http://dx.doi.org/10.1016/j.autneu.2014.09.002