Thiago S Moreira1, Vagner R Antunes1, Barbara Falquetto2, Nephtali Marina3,4. 1. Department of Physiology and Biophysics. 2. Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil. 3. Division of Medicine. 4. Department of Clinical Pharmacology and Experimental Therapeutics, Division of Medicine, Centre for Cardiovascular and Metabolic Neuroscience, University College London, London, UK.
Abstract
BACKGROUND: Arterial hypertension is associated with autonomic nervous system dysfunction. Different interventional strategies have been implemented in recent years for the reduction of sympathetic activity in patients with hypertension. However, the therapeutic benefit of increasing vagal tone in hypertensive patients remains largely unexplored. OBJECTIVE: Here, we describe the effects of long-term activation of vagal neural pathways on arterial pressure, heart rate arterial pressure variability and spontaneous baroreflex sensitivity in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. METHODS: Brainstem vagal preganglionic neurons residing in the dorsal vagal motor nucleus (DVMN) were targeted with a lentiviral vector to induce the expression of an artificial G(s) protein-coupled receptor termed designer receptors exclusively activated by designer drugs (DREADD-Gs). The transduced neurons were activated daily by systemic administration of otherwise inert ligand clozapine-n-oxide. Arterial pressure measurements were recorded in conscious freely moving animals after 21 consecutive days of DVMN stimulation. RESULTS: Resting arterial pressure was significantly lower in SHRs expressing DREADD-Gs in the DVMN, compared with control SHRs expressing enhanced green fluorescent protein. No changes in arterial pressure were detected in Wistar rats expressing DREADD-Gs compared with rats expressing enhanced green fluorescent protein in the DVMN. Pharmacogenetic activation of DREADD-Gs-expressing DVMN neurons in SHRs was accompanied with increased baroreflex sensitivity and a paradoxical decrease in cardio-vagal components of heart rate and systolic arterial pressure variability in SHRs. CONCLUSION: These results suggest that long-term activation of vagal parasympathetic pathways is beneficial in restoring autonomic balance in an animal model of neurogenic hypertension and might be an effective therapeutic approach for the management of hypertension.
BACKGROUND: Arterial hypertension is associated with autonomic nervous system dysfunction. Different interventional strategies have been implemented in recent years for the reduction of sympathetic activity in patients with hypertension. However, the therapeutic benefit of increasing vagal tone in hypertensive patients remains largely unexplored. OBJECTIVE: Here, we describe the effects of long-term activation of vagal neural pathways on arterial pressure, heart rate arterial pressure variability and spontaneous baroreflex sensitivity in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. METHODS: Brainstem vagal preganglionic neurons residing in the dorsal vagal motor nucleus (DVMN) were targeted with a lentiviral vector to induce the expression of an artificial G(s) protein-coupled receptor termed designer receptors exclusively activated by designer drugs (DREADD-Gs). The transduced neurons were activated daily by systemic administration of otherwise inert ligand clozapine-n-oxide. Arterial pressure measurements were recorded in conscious freely moving animals after 21 consecutive days of DVMN stimulation. RESULTS: Resting arterial pressure was significantly lower in SHRs expressing DREADD-Gs in the DVMN, compared with control SHRs expressing enhanced green fluorescent protein. No changes in arterial pressure were detected in Wistar rats expressing DREADD-Gs compared with rats expressing enhanced green fluorescent protein in the DVMN. Pharmacogenetic activation of DREADD-Gs-expressing DVMN neurons in SHRs was accompanied with increased baroreflex sensitivity and a paradoxical decrease in cardio-vagal components of heart rate and systolic arterial pressure variability in SHRs. CONCLUSION: These results suggest that long-term activation of vagal parasympathetic pathways is beneficial in restoring autonomic balance in an animal model of neurogenic hypertension and might be an effective therapeutic approach for the management of hypertension.
Authors: Ellen Boswijk; Renee Franssen; Guy H E J Vijgen; Roel Wierts; Jochem A J van der Pol; Alma M A Mingels; Erwin M J Cornips; Marian H J M Majoie; Wouter D van Marken Lichtenbelt; Felix M Mottaghy; Joachim E Wildberger; Jan Bucerius Journal: EJNMMI Res Date: 2019-11-27 Impact factor: 3.138
Authors: Patrick S Hosford; Natalia Ninkina; Vladimir L Buchman; Jeffrey C Smith; Nephtali Marina; Shahriar SheikhBahaei Journal: Brain Sci Date: 2020-08-24
Authors: Nathalia Juocys Dias Moreira; Fernando Dos Santos; Edson Dias Moreira; Daniela Farah; Leandro Eziquiel de Souza; Maikon Barbosa da Silva; Ivana Cinthya Moraes-Silva; Gisele Silvério Lincevicius; Elia Garcia Caldini; Maria Cláudia Costa Irigoyen Journal: Sci Rep Date: 2020-12-11 Impact factor: 4.379
Authors: Svetlana Mastitskaya; Egor Turovsky; Nephtali Marina; Shefeeq M Theparambil; Anna Hadjihambi; Sergey Kasparov; Anja G Teschemacher; Andrew G Ramage; Alexander V Gourine; Patrick S Hosford Journal: J Neurosci Date: 2020-03-04 Impact factor: 6.167