Involvement of GABAergic and Adrenergic Neurotransmissions on Paraventricular Nucleus of Hypothalamus in the Control of Cardiac Function

Michelle M Mendonça,Eugene Nalivaiko,Gustavo R Pedrino,Reginaldo N Ferreira,Danielle Ianzer,Diego B Colugnati,Carlos H Xavier,Kellen R Da Cruz,Marco A P Fontes,Joice S Santana,Paulo C Ghedini

doi:10.3389/fphys.2018.00670

Abstract

Sympathetic premotor neurons of the paraventricular hypothalamus (PVN) play a role in hemodynamics adjustments during changes in body fluid homeostasis. However, PVN contribution to the tonic control of cardiac function remains to be systematically studied. In this study, we assessed whether GABAergic and adrenergic synapses, known for being active in the PVN, are involved in the control of cardiac function. Adult male Wistar rats (250–350 g; n = 27) were anesthetized with urethane (1.2–1.4 g/kg i.p.) and underwent catheterization of femoral artery to record blood pressure and heart rate. The femoral vein was used to inject the vasoactive agents phenylephrine (10 μg/kg) and sodium nitroprusside (10 μg/kg) and to supplement anesthesia. The cardiac left ventricle was catheterized to record left ventricular pressure and its derivative. Craniotomy allowed for injections (100 nL) into the PVN of: muscimol (20 mM), bicuculline methiodide (0.4 mM), propranolol (10 mM), isoproterenol (100 μM), phentolamine (13 mM), phenylephrine (30 nM). We found that: (i) inhibition of PVN by muscimol, reduced arterial pressure, cardiac chronotropy and inotropy; (ii) disinhibition of PVN neurons by bicuculline evoked positive chronotropy and inotropy, and increase blood pressure; (iii) PVN alpha adrenergic receptors control cardiac chronotropy and inotropy; (iv) beta adrenergic receptors of the PVN do not influence cardiac function; (v) afterload does not contribute to the PVN-evoked inotropy. Our results indicate that the modulation of the activity of PVN neurons exerted by GABAergic and adrenergic mechanisms contribute to the control of cardiac function.

Highlights

Sympathetic neural outflow to blood vessels and to the heart is prominently determined by activity of sympathetic premotor neurons located in the rostral ventrolateral medulla (RVLM) and in the paraventricular hypothalamus (PVN) (Dampney et al, 2005; Guyenet, 2006)
Through direct projections that connect to several topographic levels of intermediolateral column (IML) or by reaching sympathetic premotor neurons of the RVLM, the PVN controls the sympathetic outflow with pivotal influence on cardiovascular regulation (Sawchenko and Swanson, 1982a; Martin et al, 1991; Shafton et al, 1998; Daftary et al, 2000; Haywood et al, 2001)
The main findings of this study are: (i) inhibition of PVN neurons by the GABAA receptor agonist reduced blood pressure and cardiac inotropism; (ii) disinhibition of PVN neurons by the antagonist of GABAA receptors provoked pressor, positive chronotropic and inotropic responses; (iii) α-adrenergic receptors in the PVN control cardiac chronotropism and inotropism; (iv) β-adrenergic receptors of the PVN do not influence the control of cardiac function; (v) afterload seems to exert little influence on PVN-induced inotropic responses

Summary

Introduction

Sympathetic neural outflow to blood vessels and to the heart is prominently determined by activity of sympathetic premotor neurons located in the rostral ventrolateral medulla (RVLM) and in the paraventricular hypothalamus (PVN) (Dampney et al, 2005; Guyenet, 2006). Through direct projections that connect to several topographic levels of IML or by reaching sympathetic premotor neurons of the RVLM, the PVN controls the sympathetic outflow with pivotal influence on cardiovascular regulation (Sawchenko and Swanson, 1982a; Martin et al, 1991; Shafton et al, 1998; Daftary et al, 2000; Haywood et al, 2001). Increases in sympathetic outflow to the heart (Li et al, 2006), renal and splanchnic beds, are consequence of changes in PVN activity (Carillo et al, 2012) that is found in hypertensive models (Haywood et al, 2001; Allen, 2002; Akine et al, 2003). Patel and Schmid (1988) detected increases in the activity of lumbar sympathetic nerves after changes in the activity of PVN neurons. It was observed that alterations in the inhibitory activity upon PVN results in increased sympathetic efferent activity to the heart, likely contributing to the physiopathology of heart failure (Li and Patel, 2003)

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