Control of Heart Rate by Nucleus Ambiguus Cardiovagal Neurons

Stimulation of cardiopulmonary receptors with phenylbiguanide (PBG) elicits depressor cardiovascular reflex responses, including decreases in blood pressure and heart rate mediated in part by the brain stem parasympathetic cardiac neurons in the nucleus ambiguus (NAmb). The present study examined NAmb neurotransmitter mechanisms underlying the influence of electroacupuncture (EA) on the PBG-induced hypotension and bradycardia. We hypothesized that somatic stimulation during EA modulates PBG responses through opioid and γ-aminobutyric acid (GABA) modulation in the NAmb. Anesthetized and ventilated cats were studied during repeated stimulation with PBG or cardiac vagal afferents while low-frequency EA (2 Hz) was applied at P5–6 acupoints overlying the median nerve for 30 min and NAmb neuronal activity, heart rate, and blood pressure were recorded. Microinjection of kainic acid into the NAmb attenuated the PBG-induced bradycardia from −60 ± 11 to −36 ± 11 beats/min. Likewise, EA reduced the PBG-induced depressor and bradycardia reflex by 52 and 61%, respectively. Cardiac vagal afferent evoked preganglionic cellular activity in the NAmb was reduced by EA for about 60 min. Blockade of opioid or GABAA receptors using naloxone and gabazine reversed the EA-related modulation of the evoked cardiac vagal activity by 73 and 53%, respectively. Similarly, naloxone and gabazine reversed EA modulation of the negative chronotropic responses from −11 ± 5 to −23 ± 6 and −13 ± 4 to −24 ± 3 beats/min, respectively. Thus EA at P5–6 decreases PBG evoked hypotension and bradycardia as well as the NAmb PBG-sensitive preganglionic cardiac vagal outflow through opioid and GABA neurotransmitter systems.

Download Full-text

Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00451.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. R321-R332 ◽

Cited By ~ 11

Author(s):

Stephanie C. Tjen-A-Looi ◽

Zhi-Ling Guo ◽

Min Li ◽

John C. Longhurst

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Kynurenic Acid ◽

Nucleus Ambiguus ◽

Ventrolateral Medulla ◽

Sympathetic Outflow ◽

Gastric Distention ◽

Fos Protein ◽

Hypotensive Response

Electroacupuncture (EA) at P5–P6 acupoints overlying the median nerves typically reduces sympathoexcitatory blood pressure (BP) reflex responses in eucapnic rats. Gastric distention in hypercapnic acidotic rats, by activating both vagal and sympathetic afferents, decreases heart rate (HR) and BP through actions in the rostral ventrolateral medulla (rVLM) and nucleus ambiguus (NAmb), leading to sympathetic withdrawal and parasympathetic activation, respectively. A GABAA mechanism in the rVLM mediates the decreased sympathetic outflow. The present study investigated the hypothesis that EA modulates gastric distention-induced hemodynamic depressor and bradycardia responses through nuclei that process parasympathetic and sympathetic outflow. Anesthetized hypercapnic acidotic rats manifested repeatable decreases in BP and HR with gastric distention every 10 min. Bilateral EA at P5–P6 for 30 min reversed the hypotensive response from −26 ± 3 to −6 ± 1 mmHg and the bradycardia from −35 ± 11 to −10 ± 3 beats/min for a period that lasted more than 70 min. Immunohistochemistry and in situ hybridization to detect c-Fos protein and GAD 67 mRNA expression showed that GABAergic caudal ventral lateral medulla (cVLM) neurons were activated by EA. Glutamatergic antagonism of cVLM neurons with kynurenic acid reversed the actions of EA. Gabazine used to block GABAA receptors microinjected into the rVLM or cVLM reversed EA's action on both the reflex depressor and bradycardia responses. EA modulation of the decreased HR was inhibited by microinjection of gabazine into the NAmb. Thus, EA through GABAA receptor mechanisms in the rVLM, cVLM, and NAmb modulates gastric distention-induced reflex sympathoinhibition and vagal excitation.

Download Full-text

Endogenous Inhibition of the Trigeminally Evoked Neurotransmission to Cardiac Vagal Neurons by Muscarinic Acetylcholine Receptors

Journal of Neurophysiology ◽

10.1152/jn.00442.2010 ◽

2010 ◽

Vol 104 (4) ◽

pp. 1841-1848 ◽

Cited By ~ 22

Author(s):

C. Gorini ◽

K. Philbin ◽

R. Bateman ◽

D. Mendelowitz

Keyword(s):

Heart Rate ◽

Acetylcholinesterase Inhibitor ◽

Muscarinic Acetylcholine Receptors ◽

Nucleus Ambiguus ◽

Sudden Infant ◽

Muscarinic Agonist ◽

Muscarinic Acetylcholine ◽

Trigeminocardiac Reflex ◽

Stimulation Of

Stimulation of the nasal mucosa by airborne irritants or water evokes a pronounced bradycardia accompanied by peripheral vasoconstriction and apnea. The dive response, which includes the trigeminocardiac reflex, is among the most powerful autonomic responses. These responses slow the heart rate and reduce myocardial oxygen consumption. Although normally cardioprotective, exaggeration of this reflex can be detrimental and has been implicated in cardiorespiratory diseases, including sudden infant death syndrome (SIDS). An essential component of the diving response and trigeminocardiac reflex is activation of the parasympathetic cardiac vagal neurons (CVNs) in the nucleus ambiguus that control heart rate. This study examined the involvement of cholinergic receptors in trigeminally evoked excitatory postsynaptic currents in CVNs in an in vitro preparation from rats. CVNs were identified using a retrograde tracer injected into the fat pads at the base of the heart. Application of the acetylcholinesterase inhibitor neostigmine significantly decreased the amplitude of glutamatergic neurotransmission to CVNs on stimulation of trigeminal fibers. Whereas nicotine did not have any effect on the glutamatergic responses, the muscarinic acetylcholine receptor (mAChR) agonist bethanechol significantly decreased the excitatory neurotransmission. Atropine, an mAChR antagonist, facilitated these responses indicating this trigeminally evoked brain stem pathway in vitro is endogenously inhibited by mAChRs. Tropicamide, an m4 mAChR antagonist, prevented the inhibitory action of the muscarinic agonist bethanechol. These results indicate that the glutamatergic synaptic neurotransmission in the trigeminally evoked pathway to CVNs is endogenously inhibited in vitro by m4 mAChRs.

Download Full-text

Vagal bradycardia elicited by stimulation of the external cuneate nucleus in the cat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1978.235.5.r286 ◽

1978 ◽

Vol 235 (5) ◽

pp. R286-R293

Author(s):

J. Ciriello ◽

F. R. Calaresu

Keyword(s):

Heart Rate ◽

Marked Decrease ◽

Nucleus Ambiguus ◽

Cuneate Nucleus ◽

External Cuneate Nucleus ◽

Vagal Bradycardia ◽

A Site ◽

Dorsal Spinal ◽

Stimulation Of

The role of the external cuneate nucleus (ECN) in the control of heart rate was systematically investigated in 26 chloralosed and 2 decerebrated, paralyzed, and artifically ventilated cats. Electrical stimulation of histologically verified sites in the ventral ECN and dorsal spinal trigeminal tract elicited a marked decrease in heart rate, with threshold currents of 5-25 muA and an optimal frequency of 20 Hz when using a 0.2 ms pulse; this response was shown to be due to vagal excitation. In seven experiments intravenous pentobarbital sodium decreased the magnitude of the bradycardia elicited by stimulation of the ECN, of the nucleus ambiguus (AMB), and of the cervical vagus significantly less than the response from the nucleus of the tractus solitarius. In eight additional experiments in cats with lesions of the AMB made 11-27 days earlier stimulation of the ECN elicited a bradycardia of the same magnitude as that observed in intact animals, although the bradycardia elicited by stimulation of the ipsilateral cervical vagus was significantly reduced by the lesion. Similarly, lesions of the ECN in four cats significantly attenuated the bradycardia elicited by stimulation of the ipsilateral cervical vagus. These results suggest that the ECN is a site of origin of cardioinhibitory axons in the cat.

Download Full-text

Microinjections of α-melanocyte stimulating hormone into the nucleus ambiguus of the rat elicit vagally mediated bradycardia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90978.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. R1402-R1411 ◽

Cited By ~ 13

Author(s):

Vineet C. Chitravanshi ◽

Suresh Bhatt ◽

Hreday N. Sapru

Keyword(s):

Heart Rate ◽

Cerebrospinal Fluid ◽

Wistar Rats ◽

Direct Application ◽

Nucleus Ambiguus ◽

Melanocyte Stimulating Hormone ◽

Artificial Cerebrospinal Fluid ◽

Male Wistar Rats ◽

Bilateral Vagotomy ◽

Stimulating Hormone

Neurons that immunostain for alpha-melanocyte stimulating hormone (α-MSH) have been identified in the nucleus ambiguus (nAmb). The presence of mRNA for melanocortin type 4 receptors (MC4Rs) has also been reported in this nucleus. On the basis of this information, it was hypothesized that activation of MC4Rs in the nAmb may play a role in the regulation of cardiac function. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (30 nl) of α-MSH (0.1, 0.2, 0.4, 0.8, and 1.2 mM) into the nAmb of anesthetized rats elicited decreases in heart rate (HR; 1.3 ± 0.6, 3 ± 1, 11 ± 2, 46.3 ± 3, and 43.3 ± 7 bpm, respectively) and no changes in mean arterial pressure (MAP). Maximum decreases in HR were elicited by 0.8 mM concentration of α-MSH. Bradycardic responses to α-MSH were similar in unanesthetized midcollicular decerebrate rats. Microinjections of artificial cerebrospinal fluid (30 nl) into the nAmb did not elicit a HR response. Bilateral vagotomy completely abolished α-MSH-induced bradycardia. The decreases in HR elicited by α-MSH (0.8 mM) were completely blocked by a selective MC4R antagonist. Direct application of α-MSH on the nAmb neurons increased their firing, which was blocked by prior applications of the MC4R antagonist. Microinjections of the MC4R antagonist into the nAmb did not alter reflex bradycardic responses elicited by intravenous infusions of phenylephrine, suggesting that MC4Rs did not play a role in mediating the parasympathetic component of baroreflex-induced bradycardia. These results indicated that α-MSH microinjections into the nAmb exert excitatory effects on parasympathetic preganglionic nAmb neurons via MC4Rs, leading to bradycardic responses.

Download Full-text

Glycinergic Inputs to Cardiac Vagal Neurons in the Nucleus Ambiguus Are Inhibited by Nociceptin and μ-Selective Opioids

Journal of Neurophysiology ◽

10.1152/jn.01117.2002 ◽

2003 ◽

Vol 90 (3) ◽

pp. 1581-1588 ◽

Cited By ~ 16

Author(s):

Priya Venkatesan ◽

Sunit Baxi ◽

Cory Evans ◽

Robert Neff ◽

Xin Wang ◽

...

Keyword(s):

Heart Rate ◽

Nucleus Ambiguus ◽

Inhibitory Effects ◽

Endogenous Peptides ◽

Postsynaptic Currents ◽

Selective Agonist ◽

Parasympathetic Neurons ◽

Parasympathetic Regulation ◽

Μ Opioid Receptors ◽

Μ Receptor

Most parasympathetic regulation of heart rate originates from preganglionic cardiac vagal neurons within the nucleus ambiguus. Little is known regarding the modulation of glycinergic transmission to these neurons. However, the presence of μ-opioid receptors and opioid-receptor-like (ORL1) receptors within the ambiguus, together with the presence of endogenous ligands for both receptor types in the same area, suggests opioids may modulate synaptic transmission to cardiac vagal neurons. This study therefore examined the effects of endomorphin-1 and endomorphin-2 (the μ-selective endogenous peptides), DAMGO (a synthetic, μ-selective agonist), and nociceptin (the ORL1-selective endogenous peptide) on spontaneous glycinergic inhibitory postsynaptic currents (IPSCs) in rat cardiac parasympathetic neurons. All four of the opioids used in this study decreased spontaneous IPSCs. At concentrations of 100 μM, the amplitude of the IPSCs was reduced significantly by nociceptin (–56.6%), DAMGO (–46.5%), endomorphin-1 (–45.1%), and endomorphin-2 (–26%). IPSC frequency was also significantly reduced by nociceptin (–61.1%), DAMGO (–69.9%), and endomorphin-1 (–40.8%) but not endomorphin-2. Lower concentrations of nociceptin and DAMGO (10–30 μM) also effectively decreased IPSC amplitude and frequency. The inhibitory effects of DAMGO were blocked by d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (C-TOP; 10 μM), a selective μ-receptor antagonist. Neither nociceptin nor DAMGO inhibited the postsynaptic responses evoked by exogenous application of glycine or affected TTX-insensitive glycinergic mini-IPSCs. These results indicate that μ-selective opioids and nociceptin act on preceding neurons to decrease glycinergic inputs to cardiac vagal neurons in the nucleus ambiguus. The resulting decrease in glycinergic transmission would increase parasympathetic activity to the heart and may be a mechanism by which opioids induce bradycardia.

Download Full-text