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Link to original content: http://pubmed.ncbi.nlm.nih.gov/27528004/
The role of GαO-mediated signaling in the rostral ventrolateral medulla oblongata in cardiovascular reflexes and control of cardiac ventricular excitability - PubMed Skip to main page content
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. 2016 Aug;4(15):e12860.
doi: 10.14814/phy2.12860.

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

Richard Ang  1 , Joel Abramowitz  2 , Lutz Birnbaumer  2 , Alexander V Gourine  3 , Andrew Tinker  4
Affiliations

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

Richard Ang et al. Physiol Rep. 2016 Aug.

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 GαO 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. GαO 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 GαO depletion in the RVLM increases central sympathetic drive. The data obtained support the hypothesis that GαO-mediated signaling within the presympathetic circuits of the RVLM contributes to the autonomic control of the heart. GαO deficiency in the RVLM has a significant impact on cardiovascular responses to stress, cardiovascular reflexes and electrical properties of the heart.

Keywords: Autonomic nervous system; G proteins; blood pressure; cardiac excitability; rostral ventral lateral medulla.

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Figures

Figure 1
Figure 1
Experimental protocol for conscious experiments. Figure showing timeline of conscious experimental protocols. Adenoviral vectors (AVV) injection to the brainstem is performed at Day 0.
Figure 2
Figure 2
Green fluorescent protein (GFP) expression in TH‐positive neurons in the brainstem. (A), GFP expression in the C1 region of the rostral ventral lateral medulla (RVLM) (TH, tyrosine hydroxylase). Bottom image is a high magnification micrograph showing two TH‐positive neurons expressing GFP. (B), Schematic drawing of the mouse brainstem in a series of coronal projections illustrating the representative extent of GFP expression in relation to the anatomic location of the RVLM presympathetic circuits. Numbers indicate distance from Bregma. GFP expression was highest in the ventrolateral medullary regions located at −6.80 mm from Bregma.
Figure 3
Figure 3
A 24‐h hemodynamic profile in conscious freely moving mice under normal housing conditions. (A) Heart rate (HR) and systolic blood pressure (SBP) of Gα O flx/flx mice pre‐ and post‐GFP and Cre/GFP adenoviral vectors (AVV) injections into the brainstem measured using biotelemetry over a 24‐h period. (B) Summary data of mean systolic arterial BP recorded (top) and HR (bottom) in Gα O flx/flx mice pre‐ and post‐GFP AVV (GFP) and Cre/GFP AVV (Cre) injections into the brainstem. Data expressed as mean ± SEM, n = 6 in all groups.
Figure 4
Figure 4
Hemodynamic and respiratory responses to hypoxia. (A) Representative heart rate (HR), arterial blood pressure (BP), respiratory rate (RR), and respiratory pressure (RESP) tracings of a Gα O flx/flx mouse post‐GFP adenoviral vectors (AVV) (left panel) and Cre/GFP AVV (right panel) injections, respectively, subjected to normoxia, hypoxia (10% inspired O2), and a recovery period. (B) HR, SBP, RR, and minute volume ventilation (MV) pre and post control GFP AVV (n = 4, left panel) and Cre/GFP AVV (n = 6, right panel) injections. Individual data and mean ± SEM are shown. *P < 0.05, ***P < 0.001. a.u., arbitrary units.
Figure 5
Figure 5
Hemodynamic and respiratory responses to hypercapnia. (A) Representative heart rate (HR) and arterial blood pressure (BP), respiratory rate (RR) and respiratory pressure (RESP) tracings of a Gα O flx/flx mouse post‐GFP adenoviral vectors (AVV) (left panel) and Cre/GFP AVV (right panel) injections, respectively, subjected to normoxia, 3% inspired CO 2 and 6% inspired CO 2. (B) HR, SBP, RR, and minute volume ventilation (MV) pre and post control GFP AVV (n = 4, left panel) and Cre/GFP AVV (n = 6, right panel) injections. Individual data and mean ± SEM are shown. *P < 0.05, **P < 0.01. abu, arbitrary units.
Figure 6
Figure 6
Changes in heart rate (HR) and systolic blood pressure (BP) in response to hypoxia and hypercapnia. Plots of the mean difference and 95% CI of HR and systolic BP (SBP) in Gα O flx/flx mice in response to (A) hypoxia and (B) hypercapnia.
Figure 7
Figure 7
Baroreflex response under urethane anesthesia. (A) Representative tracings of arterial blood pressure (BP) and heart rate (HR) of a Gα O flx/flx mouse post‐Cre/GFP injection given alternating boluses of phenylephrine (PE) and sodium nitroprusside (SNP). (B) An example of a best‐fit HR and systolic BP baroreflex curve constructed from data points obtained. (C) Mean baroreflex curves (bold lines) for mice injected with Cre/GFP and GFP AVV (n = 5 in each group). Bold points represent mean HR 50 and SBP 50 for each group.
Figure 8
Figure 8
Effect of autonomic blockade on heart rate and ventricular excitability. (A) Representative in vivo cardiac electrophysiology data produced by programmed electrical stimulation showing an example of right ventricular effective refractory period (VERP) in Gα O flx/flx mouse injected with Cre/GFP adenoviral vectors (AVV) compared to control GFP AVV with lengthening of VERP on administration of atenolol. (B) Comparison of HR and (C) VERP 750 between Gα O flx/flx mice post‐GFP (GFP, n = 7) and Cre/GFP (Cre, n = 9) AVV injections at baseline and after administration of atenolol 1 mg kg−1 ip ± atropine 1 mg kg−1 ip. Data expressed as mean ± SEM. *P < 0.05, ***P < 0.001. ECG, surface ECG; Intracardiac, intracardiac electrograms; Stim, pacing stimulus.
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