The role of GαO-mediated signaling in the rostral ventrolateral medulla oblongata in cardiovascular reflexes and control of cardiac ventricular excitability.

Richard Ang,Andrew Tinker,Lutz Birnbaumer,Joel Abramowitz,Alexander V Gourine

doi:10.14814/phy2.12860

Abstract

The heart is controlled by the sympathetic and parasympathetic limbs of the autonomic nervous system with inhibitory signaling mechanisms recruited in both limbs. The aim of this study was to determine the role of inhibitory heterotrimeric G proteins in the central nervous mechanisms underlying autonomic control of the heart and its potential role in arrhythmogenesis. Mice with conditional deletion of the inhibitory heterotrimeric G protein Gα O in the presympathetic area of the rostral ventral lateral medulla (RVLM) were generated to determine the role of GαO‐mediated signalling in autonomic control and electrophysiological properties of the heart. Gα O deletion within the RVLM was not associated with changes in heart rate (HR) or the arterial blood pressure at rest (home cage, normal behavior). However, exposure to stressful conditions (novel environment, hypoxia, or hypercapnia) in these mice was associated with abnormal HR responses and an increased baroreflex gain when assessed under urethane anesthesia. This was associated with shortening of the ventricular effective refractory period. This phenotype was reversed by systemic beta‐adrenoceptor blockade, suggesting that Gα O depletion in the RVLM increases central sympathetic drive. The data obtained support the hypothesis that Gα O‐mediated signaling within the presympathetic circuits of the RVLM contributes to the autonomic control of the heart. Gα O deficiency in the RVLM has a significant impact on cardiovascular responses to stress, cardiovascular reflexes and electrical properties of the heart.

Highlights

The heart is controlled by the autonomic nervous system via its two functional limbs: the sympathetic and parasympathetic (Spyer 1994)
GaO flx/flx mice responded to hypoxia (10% O2) with an increase in heart rate (HR), respiratory rate, tidal volume, and minute ventilation, but there was no significant change in the systolic Blood pressure (BP)
In conditions of GaO deletion in the rostral ventral lateral medulla (RVLM), the animals were more tachycardic at baseline (579 Æ 10 vs. 504 Æ 26 bpm, P = 0.023, mixed-level modeling), during the hypoxic challenge (721 Æ 7 vs. 656 Æ 10 bpm, P < 0.001) and during reoxygenation (633 Æ 14 vs. 560 Æ 26 bpm, P = 0.049) compared to the preinjection state

Summary

Introduction

The heart is controlled by the autonomic nervous system via its two functional limbs: the sympathetic and parasympathetic (Spyer 1994). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. GaO-Mediated Signaling in the RVLM polymorphic ventricular tachycardia (Verrier and Antzelevitch 2004), and in patients with ischemic heart disease (Nolan et al 1998). Sympathetic denervation has been used as an adjunct to pharmacotherapy with beta-adrenoceptor antagonists in the management of patients with resistant ventricular arrhythmias (Vaseghi et al 2014). The efficacy of current therapeutic strategies remains limited, perhaps reflecting the fact that only the downstream peripheral mechanisms are targeted

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