Carotid Chemoreceptor Stimulation Research Articles

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure

BackgroundThe carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation, which carries out essential functions in cardiorespiratory control. In response to hypoxia, carotid chemosensory discharge produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. Previous studies have shown that chemoreflex sensitivity is augmented animal models of heart failure (HF). However, the role of the chemoreflex in modulating coronary blood flow during HF is not clear. We hypothesized that carotid chemoreceptor stimulation would increase coronary blood flow in both normal sheep and sheep with HF.MethodsHeart failure was induced by the microembolization technique and instrumentation was performed when ejection fraction was below 40%. Both groups of sheep were implanted with a coronary artery flow probe and an arterial pressure catheter. The responses of mean arterial pressure (MAP) and coronary blood flow (CoBF) were determined in conscious sheep following CB stimulation with intracarotid potassium cyanide (KCN; 30μg/kg). To determine the cardiac vagal contribution to the CoBF response, CB activation was repeated following atropine infusion (8 mg bolus followed by 24 mg/h infusion for 30 minutes).ResultsIn control animals, activation of the CB increased MAP (114±1%) and CoBF (116±4%) but coronary vascular conductance (CVC) was unaltered. In the HF group, CB stimulation increased MAP (108±1%), CoBF (126±3%), and CVC (114±2%). The MAP increase was significantly attenuated after atropine infusion in both animal groups, however, the CoBF and CVC responses to KCN were unchanged. These responses persisted when the heart was paced at a constant rate to eliminate the role of altered metabolic demand.DiscussionOur data indicate that in an ovine model of HF, carotid body mediated increases in MAP are attenuated compared to control animals. There was a significant increase in coronary vascular conductance in the HF animals following CB activation which was absent in the normal animals. Overall, our data suggest that the hyperactive carotid body chemoreflex may serve to increase coronary blood flow in the HF condition.Support or Funding InformationHealth Research Council of New Zealand, National Heart Foundation of New Zealand

Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations.

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius (p-NTS)-medial medulla, the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphe nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for postinspiratory neuron inhibition of rostral VRC I-Driver (pre-Bötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive pericolumnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL-pF neurons with functional links to widespread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns. NEW & NOTEWORTHY We tested the long-standing hypothesis that carotid chemoreceptors tune the frequency and depth of breathing through parallel circuit operations targeting the ventral respiratory column. Responses to stimulation of the chemoreceptors and identified functional connectivity support differential tuning of inspiratory neuron burst duration and firing rate and a model of brain stem network architecture incorporating tonic expiratory "hub" neurons regulated by convergent neuronal chains and loops through rostral lateral tegmental field neurons with quasi-periodic discharge patterns.

Effects of alprazolam and cannabinoid-related compounds in an animal model of panic attack

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80μg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder.

Glutamatergic Receptor Activation in the Commisural Nucleus Tractus Solitarii (cNTS) Mediates Brain Glucose Retention (BGR) Response to Anoxic Carotid Chemoreceptor (CChr) Stimulation in Rats.

Glutamate, released from central terminals of glossopharyngeal nerve, is a major excitatory neurotransmitter of commissural nucleus tractus solitarii (cNTS) afferent terminals, and brain derived neurotrophic factor (BDNF) has been shown to attenuate glutamatergic AMPA currents in NTS neurons. To test the hypothesis that AMPA contributes to glucose regulation in vivo modulating the hyperglycemic reflex with brain glucose retention (BGR), we microinjected AMPA and NBQX (AMPA antagonist) into the cNTS before carotid chemoreceptor stimulation in anesthetized normal Wistar rats, while hyperglycemic reflex an brain glucose retention (BGR) were analyzed. To investigate the underlying mechanisms, GluR2/3 receptor and c-Fos protein expressions in cNTS neurons were determined. We showed that AMPA in the cNTS before CChr stimulation inhibited BGR observed in aCSF group. In contrast, NBQX in similar conditions, did not modify the effects on glucose variables observed in aCSF control group. These experiments suggest that glutamatergic pathways, via AMPA receptors, in the cNTS may play a role in glucose homeostasis.

Peripheral chemoreceptors tune inspiratory drive via tonic expiratory neuron hubs in the medullary ventral respiratory column network.

Models of brain stem ventral respiratory column (VRC) circuits typically emphasize populations of neurons, each active during a particular phase of the respiratory cycle. We have proposed that "tonic" pericolumnar expiratory (t-E) neurons tune breathing during baroreceptor-evoked reductions and central chemoreceptor-evoked enhancements of inspiratory (I) drive. The aims of this study were to further characterize the coordinated activity of t-E neurons and test the hypothesis that peripheral chemoreceptors also modulate drive via inhibition of t-E neurons and disinhibition of their inspiratory neuron targets. Spike trains of 828 VRC neurons were acquired by multielectrode arrays along with phrenic nerve signals from 22 decerebrate, vagotomized, neuromuscularly blocked, artificially ventilated adult cats. Forty-eight of 191 t-E neurons fired synchronously with another t-E neuron as indicated by cross-correlogram central peaks; 32 of the 39 synchronous pairs were elements of groups with mutual pairwise correlations. Gravitational clustering identified fluctuations in t-E neuron synchrony. A network model supported the prediction that inhibitory populations with spike synchrony reduce target neuron firing probabilities, resulting in offset or central correlogram troughs. In five animals, stimulation of carotid chemoreceptors evoked changes in the firing rates of 179 of 240 neurons. Thirty-two neuron pairs had correlogram troughs consistent with convergent and divergent t-E inhibition of I cells and disinhibitory enhancement of drive. Four of 10 t-E neurons that responded to sequential stimulation of peripheral and central chemoreceptors triggered 25 cross-correlograms with offset features. The results support the hypothesis that multiple afferent systems dynamically tune inspiratory drive in part via coordinated t-E neurons.

P.1.h.008 A new model of depression-like behaviour in rodents for screening of prospective drugs with antidepressant action

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80 μg) in rats. Alprazolam (1, 2, 4 mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1 mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1 mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5 mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40 mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder.

Nitric oxide in the commissural nucleus tractus solitarii regulates carotid chemoreception hyperglycemic reflex and c-Fos expression

Carotid body chemoreceptors function as glucose sensors and contribute to glucose homeostasis. The nucleus tractus solitarii (NTS) is the first central nervous system (CNS) nuclei for processing of information arising in the carotid body. Here, we microinjected a nitric oxide (NO) donor sodium nitroprusside (SNP), an NO-independent activator of the soluble guanylyl cyclase (sGC) (YC1) or an NO-synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) into the commissural NTS (cNTS) before carotid chemoreceptor anoxic stimulation and measured arterial glucose and the expression of Fos-like immunoreactivity (Fos-ir). Male Wistar rats (250–300g) were anesthetized, and the carotid sinus was vascularly isolated. Either artificial cerebrospinal fluid (aCSF), SNP, YC1 or L-NAME were stereotaxically injected into the cNTS. The SNP and YC1 infused into the cNTS before carotid chemoreceptor stimulation (SNP-2 and YC1-2 groups) similarly increased arterial glucose compared to the aCSF-2 group. By contrast, infusion of L-NAME into the cNTS before carotid chemoreceptor stimulation (L-NAME-2 group) decreased arterial glucose concentration. The number of cNTS Fos-ir neurons, determined in all the groups studied except for YC1 groups, significantly increased in SNP-2 rat when compared to the aCSF-2 or SNP-2 groups. Our findings demonstrate that NO signaling, and the correlative activation of groups of cNTS neurons, plays key roles in the hyperglycemic reflex initiated by carotid chemoreceptor stimulation.

Role of Central and Peripheral Chemoreceptors in Vasopressin Secretion Control

In this review, we analyzed the role played by central and peripheral chemoreceptors (CHRs) in vasopressin (AVP) secretion control. Central neural pathways subserving osmotic and non-osmotic control of AVP secretion are strictly correlated to brain areas participating in chemoreception mechanisms. Among the different brain areas involved in central chemoreception, the most important site has been localized in the retrotrapezoid nucleus of the rostral ventrolateral medulla. These central CHRs are able to detect very small pH/CO2 fluctuations, participating in brain blood flow regulation, acid-base balance and blood pressure control. Decreases in arterial pH and increases in arterial pCO2 stimulate AVP release by the Supraoptic and Paraventricular Nuclei. Carotid CHRs transduce low arterial O2 tension into increased action potential activity, leading to bradycardia and coronary vasodilatation via vagal stimulation, and systemic vasoconstriction via catecholaminergic stimulation. Stimulation of carotid CHRs by hypoxia increases neurohypophyseal blood flow and AVP release, an effect inhibited by CHRs denervation. Two renal CHRs have been identified: Type R1 CHRs do not have a resting discharge but are activated by renal ischemia and hypotension; Type R2 CHRs have a resting discharge and respond to backflow of urine into the renal pelvis. Signals arising from renal CHRs modulate the activity of hypothalamic AVPergic neurons: activation of R1 and R2 CHRs, following increased intrapelvic pressure with solutions of mannitol, NaCl and KCl, produces a significant increase of AVP secretion and the same effect has been obtained by the intrarenal infusion of bradykinin, which excites afferent renal nerves, as well as by the electrical stimulation of these nerves.

Neurons of the A5 region are required for the tachycardia evoked by electrical stimulation of the hypothalamic defence area in anaesthetized rats

In order to assess the possible interactions between the pontine A5 region and the hypothalamic defence area (HDA), we have examined the pattern of double staining for c-Fos protein immunoreactivity (c-Fos-ir) and tyrosine hydroxylase, throughout the rostrocaudal extent of the A5 region in spontaneously breathing anaesthetized male Sprague-Dawley rats during electrical stimulation of the HDA. Activation of the HDA elicited a selective increase in c-Fos-ir with an ipsilateral predominance in catecholaminergic and non-catecholaminergic A5 somata (P < 0.001 in both cases). A second group of experiments was done to examine the importance of the A5 region in modulating the cardiorespiratory response evoked from the HDA. Cardiorespiratory changes were analysed in response to electrical stimulation of the HDA before and after ipsilateral microinjection of muscimol within the A5 region. Stimulation of the HDA evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (P < 0.001) due to a decrease in expiratory time (P < 0.01). The respiratory response was accompanied by a pressor response (P < 0.001) and tachycardia (P < 0.001). After muscimol microinjection within the A5 region, pressor and heart rate responses to HDA stimulation were reduced (P < 0.01 and P < 0.001, respectively). The respiratory response persisted unchanged. Finally, to confirm functional interactions between the HDA and the A5 region, extracellular recordings of putative A5 neurones were obtained during HDA stimulation. Seventy-five A5 cells were recorded, 35 of which were affected by the HDA (47%). These results indicate that neurones of the A5 region participate in the cardiovascular response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

Ventral respiratory column tonic expiratory neurons: Nodes for convergent afferent modulation of inspiratory drive

The medullary ventral respiratory column (VRC) has an essential role in generating the motor pattern for breathing and inspiratory (I) drive. Contemporary models include a rostral‐to‐caudal excitatory I neuron chain extending to premotor populations that also acts upon inhibitory I neurons with recurrent and feed‐forward connections upon other VRC excitatory and inhibitory I neurons and expiratory (E) neurons. Prior work suggests (i) baroreceptor stimulation inhibits inspiratory drive in part via evoked tonic E (t‐E) neuron activity and (ii) central chemoreceptor stimulation enhances I drive via disinhibition through reduced t‐E neuron activity. A recent computational neuromechanical model (O'Connor et al. 2012) predicted that inhibition of t‐E neurons amplifies I drive during coughing ‐ a result supported by in vivo data (Segers et al. 2012). We now report recording sites of pericolumnar t‐E neurons (n=140) and show that selective stimulation of carotid chemoreceptors via close injection of CO2‐saturated saline reduces the I‐phase activity of t‐E cells coincident with increased I drive in vagotomized decerebrate cats. Spike train cross correlation and gravity clustering methods revealed short‐time scale impulse synchrony in 24 t‐E neuron pairs. We conclude that multiple afferent systems tune inspiratory drive via actions of coordinated groups of VRC t‐E neurons. Support: NIH grant NS19814.

Persistent activity and interactions in the brainstem respiratory network during hyperventilatory apnea

Brainstem respiratory neuron interactions during hyperventilatory apnea (HA) and the dissolution and reemergence of the motor pattern for breathing remain poorly understood. We used multi‐array recording, cross‐correlation, and gravity clustering methods to evaluate spike train data from the ventral respiratory column (VRC), pontine respiratory group, and medullary raphé nuclei of decerebrate vagotomized neuromuscularly‐blocked cats. Phrenic activity, blood pressure, end‐tidal CO2, and arterial blood gas measures of O2, CO2 and pH were monitored. During HA: (i) tonic activities persisted in subsets of VRC inspiratory (I) and expiratory (E) neurons; (ii) short‐time scale correlations indicated interactions among neurons that expressed E and non‐respiratory modulated discharge patterns during control conditions, including neurons with functional inhibitory actions on I neurons; (iii) selective stimulation of carotid chemoreceptors by close injection of CO2‐saturated saline transiently evoked rhythmic respiratory network activity and suppressed tonic E neuron activity; (iv) respiratory and slower (0.04 – 0.1 Hz) network oscillations were disrupted. We conclude that VRC tonic E neurons contribute to I drive inhibition during HA (cf. Sears et al. 1982) and document the loss of multiple rhythms during HA. Support: NIH grant NS19814

Control of breathing and blood pressure by parafacial neurons in conscious rats

The retrotrapezoid nucleus (RTN), located in the parafacial region, contains glutamatergic neurons that express the transcriptor factor Phox2b and that are suggested to be central respiratory chemoreceptors. Studies in anaesthetized animals or in vitro have suggested that RTN neurons are important in the control of breathing by influencing respiratory rate, inspiratory amplitude and active expiration. However, the contribution of these neurons to cardiorespiratory control in conscious rats is not clear. Male Holtzman rats (280-300 g, n = 6-8) with bilateral stainless-steel cannulae implanted into the RTN were used. In conscious rats, the microinjection of the ionotropic glutamatergic agonist NMDA (5 pmol in 50 nl) into the RTN increased respiratory frequency (by 42%), tidal volume (by 21%), ventilation (by 68%), peak expiratory flow (by 24%) and mean arterial pressure (MAP, increased by 16 ± 4, versus saline, 3 ± 2 mmHg). Bilateral inhibition of the RTN neurons with the GABA(A) agonist muscimol (100 pmol in 50 nl) reduced resting ventilation (52 ± 34, versus saline, 250 ± 56 ml min(-1) kg(-1) with absolute values) and attenuated the respiratory response to hypercapnia and hypoxia. Muscimol injected into the RTN slightly reduced resting MAP (decreased by 13 ± 7, versus saline, increased by 3 ± 2 mmHg), without changing the effects of hypercapnia or hypoxia on MAP and heart rate. The results suggest that RTN neurons activate facilitatory mechanisms important to the control of ventilation in resting, hypoxic or hypercapnic conditions in conscious rats.

Nitric oxide infused in the solitary tract nucleus blocks brain glucose retention induced by carotid chemoreceptor stimulation

Previous work has shown that the carotid body glomus cells can function as glucose sensors. The activation of these chemoreceptors, and of its afferent nucleus in the brainstem (solitary tract nucleus – STn), induces rapid changes in blood glucose levels and brain glucose retention. Nitric oxide (NO) in STn has been suggested to play a key role in the processing of baroreceptor signaling initiated in the carotid sinus [1]. However, the relationship between changes in NO in STn and carotid body induced glycemic changes has not been studied. Here we investigated in anesthetized rats how changes in brain glucose retention, induced by the local stimulation of carotid body chemoreceptors with sodium cyanide (NaCN), were affected by modulation of NO levels in STn. We found that NO donor sodium nitroprusside (SNP) micro-injected into STn completely blocked the brain glucose retention reflex induced by NaCN chemoreceptor stimulation. In contrast, NOS inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) increased brain glucose retention reflex compared to controls or to SNP rats. Interestingly, carotid body stimulation doubled the expression of nNOS in STn, but had no effect in iNOS. NO in STn could function to terminate brain glucose retention induced by carotid body stimulation. The work indicates that NO and STn play key roles in the regulation of brain glucose retention.

Nitric oxide in the hypothalamus–pituitary axis mediates increases in brain glucose retention induced by carotid chemoreceptor stimulation with cyanide in rats

Neuronal nitric oxide synthase (nNOS), which catalyzes the generation of nitric oxide (NO), is expressed by neuron subpopulations in the CNS. Nitric oxide is involved in neurotransmission and central glucose homeostasis. Our prior studies have shown that carotid body receptors participate in brain glucose regulation in vivo, and suggest the presence of a NO tonic mechanism in the solitary tract nucleus (STn). However, the role of NO within STn in glucose control remains unknown. In this study, we explored the potential regulatory role of NO on brain glucose retention induced by carotid body chemoreceptor anoxic stimulation with sodium cyanide (NaCN) which inhibits oxidative metabolism. Intracisternal infusions of nitroxidergic drugs before carotid chemoreceptor stimulation in anesthetized rats, elicited changes in nitrite concentration in plasma and hypothalamus–pituitary (H–P) tissue, as well as in gene expression of neuronal and inducible isoforms (nNOS and iNOS) in H–P tissue. The changes observed in above variables modified brain glucose retention in an opposite direction. When the NO donor, sodium nitroprusside (SNP), was given before carotid stimulation, nitrite concentration in plasma and H–P tissue, and gene expression of nNOS and iNOS in H–P tissue increased, whereas brain glucose retention decreased. In contrast, when the NOS inhibitor, Nω-nitro- l-arginine methyl ester ( l-NAME) was infused immediately before carotid chemoreceptor stimulation, nitrite levels and nNOS expression decreased in plasma and H–P tissue, whereas brain glucose retention increased. Anoxic stimulation by itself induced an increase in the expression of both genes studied. All these results indicate that de novo expression of the nNOS gene in H–P tissue may be critically involved in central glucose changes observed after anoxic carotid chemoreceptor stimulation in conjunction with NO.

Contributions of central and peripheral chemoreceptors to the ventilatory response to CO2/H+

The major objective of this review is to evaluate existing information and reach conclusions regarding whether there is interaction between P(CO(2))/H(+) stimulation of carotid (peripheral) and intracranial (central) chemoreceptors. Interaction is defined as a ventilatory response to simultaneous changes in the degree of Pco2/H(+) stimulation of both chemoreceptors that is greater (hyperadditive) or less (hypoadditive) than the sum of the responses when stimulation of each set of chemoreceptors is individually altered. Simple summation of the simultaneous changes in stimuli results in no interaction (i.e., additive interaction). Knowledge of the nature of central/peripheral interaction is crucial for determining the physiological significance of newer models of ventilatory control based on recent neuroanatomic observations of the circuitry of key elements of the ventilatory control system. In this review, we will propose that these two sets of receptors are not functionally separate but rather that they are dependent on one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the peripheral chemoreceptors and possibly other breathing-related reflex afferents as well. The short format of this minireview demands that we be somewhat selective in developing our ideas. We will briefly discuss the limitations of experiments used to study CO(2)/H(+) sensitivity and interaction to date, traditional views of the relative contributions of peripheral and central chemoreceptors to CO(2)/H(+) sensitivity, the evidence for and against different types of interaction, and the effect of tonic carotid chemoreceptor afferent activity on central control mechanisms.

Carotid chemoreceptor modulation of sympathetic vasoconstrictor outflow during exercise in healthy humans

Recently, we have shown that specific, transient carotid chemoreceptor (CC) inhibition in exercising dogs causes vasodilatation in limb muscle. The purpose of the present investigation was to determine if CC suppression reduces muscle sympathetic nerve activity (MSNA) in exercising humans. Healthy subjects (N = 7) breathed hyperoxic gas (F(IO(2)) approximately 1.0) for 60 s at rest and during rhythmic handgrip exercise (50% maximal voluntary contraction, 20 r.p.m.). Microneurography was used to record MSNA in the peroneal nerve. End-tidal P(CO(2)) was maintained at resting eupnoeic levels throughout and breathing rate was voluntarily fixed. Exercise increased heart rate (67 versus 77 beats min(-1)), mean blood pressure (81 versus 97 mmHg), MSNA burst frequency (28 versus 37 bursts min(-1)) and MSNA total minute activity (5.7 versus 9.3 units), but did not change blood lactate (0.7 versus 0.7 mm). Transient hyperoxia had no significant effect on MSNA at rest. In contrast, during exercise both MSNA burst frequency and total minute activity were significantly reduced with hyperoxia. MSNA burst frequency was reduced within 9-23 s of end-tidal P(O(2)) exceeding 250 mmHg. The average nadir in MSNA burst frequency and total minute activity was -28 +/- 2% and -39 +/- 7%, respectively, below steady state normoxic values. Blood pressure was unchanged with hyperoxia at rest or during exercise. CC stimulation with transient hypoxia increased MSNA with a similar time delay to that obtained with CC inhibition via hyperoxia. Consistent with previous animal work, these data indicate that the CC contributes to exercise-induced increases in sympathetic vasoconstrictor outflow.

Transient carbon monoxide inhibits the ventilatory responses to hypoxia through peripheral mechanisms in the rat

Hypoxia inhibits K + channels of chemoreceptors of the carotid body (CB), which is reversed by transient carbon monoxide (CO), suggesting an inhibitory effect of CO on hypoxic stimulation of carotid chemoreceptors. Therefore, we hypothesized that the ventilatory responses to hypoxic stimulation of the CB might be depressed in intact rats by transient inhalation of CO. Anesthetized, spontaneously breathing rats were exposed to room air, and 1 min of 11% O 2 (HYP) and CO (0.25–2%) alone and in combination (HYP + CO). We found that transient CO did not affect baseline cardiorespiratory variables, but significantly attenuated hypoxic ventilatory augmentation, predominantly via reduction of tidal volume. To distinguish whether this CO modulation occurs at the CB or within the central nervous system, the cardiorespiratory responses to electrical stimulation of the fastigial nucleus (FN), a cerebellar nucleus known excitatory to respiration, were compared before and during transient CO. Our results showed that the FN-mediated cardiorespiratory responses were not significantly changed by transient CO exposure. To evaluate the effect of CO accumulation, we also compared baseline cardiorespiratory responses to 5 min of 1% and 2% CO, respectively. Interestingly, only the latter produced a biphasic ventilatory response (initial increase followed by decrease) associated with hypotension. We conclude that eupneic breathing in anesthetized rat was not affected by transient CO, but was altered by prolonged exposure to higher levels of CO. Moreover, transient CO depresses hypoxic ventilatory responses mainly through peripherally inhibiting hypoxic stimulation of carotid chemoreceptors.

The Interaction Between Carotid Baroreceptor and Chemoreceptor Relexes on Cardiopulmonary Responses in Anaesthetized Cats

Hypertension and hypoxia often occur together in the clinical setting implying that the carotid baroreceptor and carotid chemoreceptors are affected simultaneously. This work was designed to study the effects of increased reflex sympathetic activity following carotid baroreceptor and chemoreceptor stimulation on reflex cardiopulmonary responses. The effects of unilateral carotid occlusion and chemoreceptor stimulation by intracarotid injection of sodium dithionite were studied singly and combined in 15 anaesthetized cats. Combined activation of the receptors resulted in responses that were generally more than the individual responses to activation of the receptors. We conclude that there is an interaction between the carotid baroreflex and chemoreflex but this, though synergistic is not additive. Nig. Qt. J. Hosp. Med. Vol.12(1-4) 2002: 6-9

Benzodiazepine-sensitive GABA A receptors in the commissural subnucleus of the NTS are involved in the carotid chemoreceptor reflex in rats

We studied the role of benzodiazepine (BDZ) receptors in the commissural subnucleus of the nucleus tractus solitarius (commNTS) in chemoreceptor reflex in urethane-anesthetized, pancronium-immobilized, artificially ventilated and bilaterally vagotomized rats. A BDZ agonist, diazepam (1–4 μmol/kg), administered intravenously reduced resting phrenic nerve activity (PNA) and blood pressure (BP). Stimulation of carotid chemoreceptors induced an increase in PNA and an increase in BP. Diazepam inhibited this chemoreceptor reflex. The effects of intravenous injection of diazepam (4 μmol/kg) on the chemoreceptor reflex were antagonized by microinjection of the BDZ antagonist flumazenil (100 pmol) into the commNTS. Microinjection of flumazenil (100 pmol) alone had no effect on the basal PNA and BP, and the chemoreceptor reflex. These results suggest that BDZ receptors are present in the carotid chemoreceptor reflex pathway in the commNTS and potentiate GABA A transmission.