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

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.

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

“…Although both the loss of sinus rhythm during the clonic phase and the abrupt return of sinus rhythm during mechanical resuscitation closely coincide with respiratory changes, the pO2 and pCO2 are undoubtedly very different at these two points in time. Furthermore, several studies in mice have demonstrated that the initial response to hypoxia, ≤12% O 2 , is a reflex increase in heart rate followed by a decrease with no loss of P-wave over several minutes [16–19]. Hypercapnia (5%-6% CO 2 ) decreases heart rate, but does not eliminate SA nodal activity [19,20].…”

“…Furthermore, several studies in mice have demonstrated that the initial response to hypoxia, ≤12% O 2 , is a reflex increase in heart rate followed by a decrease with no loss of P-wave over several minutes [16–19]. Hypercapnia (5%-6% CO 2 ) decreases heart rate, but does not eliminate SA nodal activity [19,20]. Thus, it seems unlikely that alterations in blood gases per se contribute to the rapid changes in heart rhythm during C/T seizure.…”

GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells

“…C57BL/6J mice, bred on site or purchased from The Jackson Laboratory, were used as wild-type controls for these studies. Mice lacking either Gα o or Gα i2 selectively in atrial/SAN tissue were generated by crossing the SLNCre driver mouse line (34) with floxed versions of either Gα o (35) or Gα i2 (32), resulting in SLNCre:Gα o fl/fl and SLNCre:Gα i2 fl/fl mouse lines, respectively. Male and female mice were group-housed on a 12-h light/dark cycle, given free access to food and water, and used for experiments at ages 8 to 12 wk.…”

Inhibitory effects of sulfur dioxide within the nucleus tractus solitarii of rats

“…We have previously shown that aspartate aminotransferase (AAT), a key enzyme in endogenous SO 2 generation, is produced in the mammalian brain [5] and causes hypertension and tachycardia [6]. The central nervous system (CNS) is known to be involved in regulating arterial pressure [7–9]. The present study was designed to test the hypothesis that SO 2 regulates blood pressure (BP) by a central mechanism.…”