Ang, R; (2015) The role of inhibitory G proteins in the central nervous mechanisms of autonomic control of the heart. Doctoral thesis , UCL (University College London).

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Abstract

The heart is controlled by the sympathetic and parasympathetic limbs of the autonomic nervous system with inhibitory signalling mechanisms recruited in both limbs. This study aimed to determine the role of inhibitory G proteins in the mechanisms underlying autonomic control of the heart. Mice with conditional deletion of G protein GαO in the cardiac conduction tissue and the central nervous system (CNS) were generated to determine the effect of specific GαO deletions on autonomic control and electrophysiological properties of the heart. Mice with conditional deletion of GαO in the cardiac conduction tissue demonstrated normal diurnal heart rate (HR) profile and heart rate variability (HRV). Mice with conditional deletion of Gαi2 displayed higher daytime HR and selective loss of the high frequency component of HRV, suggesting that signalling mediated by Gαi2 (but not by GαO) is important for the parasympathetic control of the sinoatrial node. GαO deletion in the presympathetic area of the rostral ventral lateral medulla (RVLM) was not associated with changes in HR or the arterial blood pressure (BP) at rest (home cage, normal behaviour). However, exposure to stressful conditions (novel environment, hypoxia or hypercapnia) in these mice was associated with profoundly exaggerated heart rate responses and an increased baroreflex gain when studied under urethane anaesthesia. This was associated with a reduced ventricular effective refractory period and lower ventricular tachycardia threshold. This phenotype was reversed by systemic administration of a beta-adrenoceptor blocker atenolol, suggesting that GαO loss in the RVLM increases central sympathetic drive. The data obtained suggest that GαO-mediated signalling within the presympathetic circuits of the RVLM but not at the level of the cardiac conduction system contributes to the autonomic control of the heart. GαO deficiency in the RVLM is associated with exaggerated cardiovascular responses to stress, altered cardiovascular reflexes and electrical properties of the heart.

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