Carotid Body Denervation Research Articles

Carotid Body Denervation Prevents the Development of Insulin Resistance and Hypertension Induced by Hypercaloric Diets

Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein, we propose that CB overstimulation is involved in the etiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes, and obstructive sleep apnoea. We demonstrate that CB activity is increased in IR animal models and that CSN resection prevents CB overactivation and diet-induced IR and HT. Moreover, we show that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.

Interactions between carotid body denervation and renal nerve denervation in lowering arterial blood pressure in the adult spontaneously hypertensive rat (SHR)

We have previously shown that bilateral carotid body denervation (CBD) in SHR reduces arterial pressure (AP). How CBD interacts with the more established technique of renal denervation (RDNX) is unknown. Here we test the hypothesis that CBD will lower AP over and above the fall in pressure achieved with RDNX. In 12 week‐old SHR previously instrumented to record AP telemetrically, denervation surgery (unilateral CBD n=6; bilateral CBD n=7; Sham CBD n=6; RDNX n=5; Sham RDNX n=5) was performed on Day 0. On Day 21 after CBD or Day 14 after RDNX, the renal nerves or carotid bodies were denervated respectively. Chemoreflex elimination was confirmed by i.v. sodium cyanide (120ìg.kg‐1; Sham 15±3mmHg, CBD 1±2mmHg). By Day 21 after bilateral CBD, AP was reduced by −17±2 mmHg from a baseline of 160±5 mmHg (p<0.05); unilateral CBD/Sham rats showed the expected developmental increase in AP of 7±2mmHg/9±3mmHg. Subsequent RDNX reduced AP by a further −8±2mmHg in bilateral CBD rats and by −8±3mmHg in Sham rats (p<0.05). Conversely, in RDNX rats (−7±2mmHg), bilateral CBD produced a further fall in AP of −12±3 mmHg(p<0.05). In summary, unilateral CBD alone seems insufficient to reduce AP in SHR. Bilateral CBD and RDNX appear to have an occlusive interaction. This is important clinically as it suggests further reductions in AP may be obtained in hypertensive patients post renal denervation. Supported by the British Heart Foundation and Cibiem.

Altered Glutamate Receptor Expression Following Carotid Body Denervation (CBD) in Goats

After CBD, goats hypoventilate and their CO2 sensitivity is reduced for several days followed by a partial recovery (Pan et al, 1998). Even after partial recovery 30 days post‐CBD, histochemical markers demonstrate a down regulation of the serotonergic system (Miller et al, EB 2012); thus, the mechanisms which contribute to the recovery of ventilation following CBD remain unclear. Recently, AMPA‐type glutamate receptors have been implicated with a form of activity‐dependent plasticity suggested to stabilize the output of neuronal networks (homeostatic plasticity) (Turrigiano and Nelson, 2004). Accordingly, to test the hypothesis that goats sacrificed 30 days post‐CBD exhibit altered AMPA receptor expression, we quantified immunolabeled neuronal GluR2 optical density (OD) at sites that contribute to ventilatory control. Relative to a control goat (n=1), in CBD goats (n=3) we observed increased GluR2 OD within the nucleus tractis solitarii (NTS), decreased GluR2 OD within the midline raphé (MR), and no change in the dorsal motor nucleus of the vagus or the hypoglossal motor nucleus. These preliminary findings suggest that increased glutamatergic drive within the NTS is associated with the partial recovery of ventilation post‐CBD and decreased glutamatergic drive within the MR may contribute to the down regulation of the serotonergic system. Supported by NIH 25739 and VA

Central modulation of arterial chemo‐baroreflex control by propofol during severe arterial hypoxia in the rabbit

During hypoxia specific deficits in neural control caused by propofol (2,6‐diisopropylphenol) anesthesia (Prop) are unknown. Dose‐related effects were analysed in rabbits with and without carotid body denervation (CBD) to partition arterial chemo‐baroreflex control. Minute ventilation (VE), tidal volume (VT), respiratory frequency (f), heart rate (HR), mean arterial pressure (MAP) were measured in 12 awake rabbits mask‐breathing room air, then 15 minutes of low oxygen air (PaO2 < 35 mm Hg), during Prop alone (0.2 and 0.5 mg kg−1min−1i.v.), and during matched Prop plus hypoxia. Prop alone caused dose‐related depression in f and rise in HR. Prop plus hypoxia abolished bradycardia, while MAP, VE and VT effects remained intact. CBD eliminated all chemoreflex responses to hypoxia and MAP fell while HR rose, effects enhanced by Prop in a dose‐related way. It is concluded that during Prop, carotid body function for respiratory and MAP defense is functionally intact. Central activation of the vagus is inhibited selectively, because electrical stimulation of peripheral vagus during Prop evokes normal bradycardia blocked by atropine. By contrast, Prop inhibits arterial baroreflex‐vagosympathetic defense against widespread hypoxic vasodilatation. We speculate that the data reflect dominant central GABAA receptor agonist effects on the arterial chemo‐baroreflex arc. Funding: ANZCA and HMRI.

Carotid Body Denervation Attenuates Oscillations in Respiratory Rate and Sympathetic Nerve Activity, and Decreases Apnea/Hypopnea Index in Congestive Heart Failure

Cheyne‐Stokes respiration is associated with increased morbidity and mortality in patients with congestive heart failure(CHF) and commonly coincides with high chemosensitivity. We hypothesized that incidence of disordered breathing patterns would be increased in a rabbit model of pacing‐induced CHF, and that denervation of the carotid body chemoreceptors (CBD) would attenuate these changes. Plethysmography was used to measure resting breathing pattern and the ventilatory responses to hypoxia (Hx) and hypercapnia (Hc). Sympathetic nerve activity was measured directly from the renal nerves (RSNA) of conscious animals. Resting respiratory pattern was quantified by an apnea‐hypopnea index (AHI) and a respiratory oscillation index. RSNA and ventilatory responses to Hx were augmented in CHF, and nearly abolished by CBD. CBD also resulted in a 40% reduction in Hc response. CHF resulted in increased incidence of oscillations in respiratory rate that were accompanied by surges in blood pressure, heart rate, and RSNA. The incidence of these oscillations was reduced after CBD (pre‐pace 26±3/h, CHF 48±5/h, CHF‐CBD 13±7/h). The AHI was increased with CHF and this increase was attenuated after CBD (pre‐pace 9±2, CHF 17±3, CHF‐CBD 5±1). Our findings suggest that CB denervation may be an effective treatment to reduce respiratory instability in CHF patients.Funding: NIH 1F32HL108592–01A1 & Coridea NC1.

Nucleus tractus solitarii (nTS) is required for phrenic long term facilitation (pLTF) after acute intermittent hypoxia (AIH)

Repeated episodes of acute hypoxia lead to pLTF which is thought to involve local mechanisms in the spinal cord. However, carotid body denervation decreases pLTF indicating chemoreceptor afferent input also contributes to pLTF. We hypothesized that the nTS, the first integration site of chemoreceptor afferents, is critical to the generation and maintenance of pLTF. Anesthetized, vagotomized, paralyzed and ventilated male rats were exposed to 10 hypoxic episodes (10% O2, 45sec, 5 min intervals) following bilateral nTS microinjection of aCSF or the GABA receptor agonist muscimol to inhibit nTS activity. After aCSF injection (n=4) integrated phrenic nerve activity increased during hypoxia (567±222% baseline) and amplitude remained elevated ≥1hr after AIH (131±28% baseline). Muscimol injection (2mM; 60nL) prior to AIH blocked increases in phrenic activity during hypoxia (7±14% baseline; n=3) and no LTF occurred (−3±8% baseline). Furthermore, muscimol injections after pLTF induction (130±33% baseline; n=3) decreased phrenic nerve amplitude toward pre‐AIH levels (6±10% baseline; n=3). Results indicate that nTS neuronal activity is required for the development and maintenance of pLTF. HL98602, AvH 1135664

Peripheral chemoreceptors mediate training‐induced plasticity in paraventricular nucleus pre‐autonomic oxytocinergic neurons

We showed previously that sino-aortic denervation prevented training-induced plasticity in pre-autonomic oxytocinergic neurons and blocked the beneficial effects of training. In this study, we investigate the combined effect of training and removal of specific chemoreceptor afferents on both cardiovascular parameters and oxytocin (OT) gene and protein expression within the hypothalamic paraventricular nucleus (PVN). Wistar rats and spontaneously hypertensive rats (SHRs) underwent carotid body denervation or sham surgery and were trained or kept sedentary for 3 months. After haemodynamic measurements at rest, rats were anaesthetized for brain perfusion. Fresh (perfused with PBS) and fixed brains (perfused with 4% paraformaldehyde) were processed for PVN OT mRNA (real-time PCR) and OT immunoreactivity within PVN subnuclei. In sham-operated rats, training improved treadmill performance and reduced resting heart rate (Wistar, -8%; SHRs, -10%), with a reduction in blood pressure only in SHRs (-8%). Training was accompanied by increased PVN OT mRNA expression (twofold increase in sham-operated SHRs) and peptide density in the posterior, ventromedial and dorsal cap PVN subnuclei (on average 70% increase in both strains), with significant correlations between OT content and training-induced resting bradycardia in sham-operated groups. Carotid body denervation did not interfere with the performance gain, abolished chemoreflex activation (without changing baroreflex control) and blocked training-induced cardiovascular adaptations and training-induced changes in PVN OT content in both strains. After carotid body denervation, there was no correlation between OT mRNA or OT immunoractivity and resting heart rate. The chronic absence of chemoreceptor inputs uncovers an unknown role of chemoreceptor signalling in driving the plasticity/activity of PVN oxytocinergic pre-autonomic neurons, thus mediating training-induced cardiovascular adaptive responses.

Acute and chronic effects of carotid body denervation on ventilation and chemoreflexes in three rat strains

Brown Norway (BN) rats have a relatively specific deficit in CO2 sensitivity. This deficit could be due to an abnormally weak carotid body contribution to CO2 sensitivity. Accordingly, we tested the hypothesis that CBD would have less of an effect on eupnoeic breathing and CO2 sensitivity in the BN rats compared to other rat strains.We measured ventilation and blood gases at rest (eupnoea) and during hypoxia (FIO2 =0.12) or hypercapnia (FICO2 =0.07) before and up to 23 days after bilateral or Sham CBD in BN, Sprague–Dawley (SD) and Dahl Salt-Sensitive (SS) rats. In all three rat strains, CBD elicited eupnoeic hypoventilation (PaCO2 +8.7–11.0 mmHg) 1–2 days post-CBD (P <0.05), and attenuated ventilatory responses to hypoxia (P <0.05) and venous sodium cyanide (NaCN; P<0.05), while sham CBD had no effect on resting breathing, blood gases or chemoreflexes (P >0.05). In contrast, CBD had no effect on CO2 sensitivity (˙VE/PaCO2) in all strains (P>0.05). Eupnoeic PaCO2 returned to pre-CBD values within 15–23 days post-CBD. Thus, the effects of CBD in rats (1) further support an important role for the carotid bodies in eupnoeic blood gas regulation, (2) suggest that the carotid bodies are not a major determinant of CO2 sensitivity in rats, and (3) may not support the concept of an interaction among the peripheral and central chemoreceptors in rats.

Respiratory neuroplasticity following carotid body denervation: Central and peripheral adaptations.

Historically, the role of the carotid bodies in ventilatory control has been understated, but the current view suggests that the carotid bodies (1) provide a tonic, facilitory input to the respiratory network, (2) serve as the major site of peripheral O2 chemoreception and minor contributor to CO2/H+ chemoreception, and (3) are required for ventilatory adaptation to high altitude. Each of these roles has been demonstrated in studies of ventilation in mammals after carotid body denervation. Following carotid body denervation, many of the compromised ventilatory “functions” show a time-dependent recovery plasticity that varies in the degree of recovery and time required for recovery. Respiratory plasticity following carotid body denervation is also dependent on species, with contributions from peripheral and central sites/mechanisms driving the respiratory plasticity. The purpose of this review is to provide a summary of the data pointing to peripheral and central mechanisms of plasticity following carotid body denervation. We speculate that after carotid body denervation there are altered excitatory and/or inhibitory neuromodulator mechanisms that contribute to the initial respiratory depression and the subsequent respiratory plasticity, and further suggest that the continued exploration of central effects of carotid body denervation might provide useful information regarding the capacity of the respiratory network for plasticity following neurologic injury in humans.

Effect of Carotid Body Denervation (CBD) on Breathing and Central Neuromodulation

After CBD, goats hypoventilate and exhibit reduced CO2 sensitivity followed by a partial recovery in the weeks following (Pan et al, 1998). Currently, the contribution of central mechanisms in these changes is unknown; however, perturbations involving the carotid bodies have been show to affect central neuromodulator/neurotransmitter (NM/NT) levels within the respiratory network (Goiny et al, 1991; Hoop at al, 1999). Here, we tested the hypothesis that the time‐dependent changes in breathing following CBD are associated with altered central NM/NT levels within the pre‐Bötzinger Complex (pre‐BötC). In 6 awake adult goats, on several days pre‐ and post‐CBD we assessed resting PaCO2, CO2 sensitivity, and the NM/NT content of mock cerebrospinal fluid (mCSF) dialyzed into the pre‐BötC. From days 0–15 post‐CBD, we observed hypoventilation and reduced CO2 sensitivity, with a concomitant increase in GABA and Glycine and a decrease in serotonin and Substance‐P in the dialyzed mCSF. From days 16–30 post‐CBD, we observed a partial recovery of resting PaCO2, but little recovery of CO2 sensitivity or NMs/NTs. In conclusion, a shift in the balance of NMs/NTs toward net inhibition at the pre‐BötC may contribute to the hypoventilation and reduced CO2 sensitivity following CBD. Supported by NIH 25739 and Veterans Association

Carotid body denervation does not affect CO2 sensitivity in multiple rat strains

O2 and CO2/pH are detected by the carotid bodies (CBs) and central respiratory chemoreceptors, respectively. CB activity appears to modulate central chemoreceptor activity, suggesting chemoreceptor interdependence. Here, we studied the effects of CB denervation in CO2‐insensitive Brown Norway (BN) and CO2‐sensitive Dahl Salt‐sensitive (SS) and Sprague Dawley (SD) rats by chronic measurements of ventilation (VE) and blood gases at rest, and during hypercapnia (7% CO2) or hypoxia (12% O2) before and for 21 days (d) after CBD. Peak eupneic hypoventilation (Δ PaCO2) occurred 1–2 d post‐CBD in all strains, increasing 11.0 (SS), 9.4 (BN) and 7.0 (SD) mmHg. Resting PaCO2 returned to control by 12 d post‐CBD (BN and SD), but remained elevated (+3.9 mmHg) in SS rats. SS and SD rats showed high sensitivity (VE ~300% of control) and BN rats a low sensitivity (VE ~150% of control) to hypercapnia pre‐CBD, which was unaffected by CBD. In addition, CO2 sensitivity (measured as ΔVE/ΔPaCO2) was also unaffected by CBD in all strains, despite a near‐complete loss of the hypoxic ventilatory response and attenuation of the ventilatory response to i.v. NaCN. As seen in other species, these data suggest that CBD in rats leads to eupneic hypoventilation and elimination of the hypoxic ventilatory response, but the lack of effect on CO2 sensitivity does not support the concept of chemoreceptor interdependence. Supported by NIH HL097033.

Activation of Opioid μ-Receptors in the Commissural Subdivision of the Nucleus Tractus Solitarius Abolishes the Ventilatory Response to Hypoxia in Anesthetized Rats

: The commissural subnucleus of the nucleus tractus solitarius (comNTS) is a key region in the brainstem responsible for the hypoxic ventilatory response (HVR) because it contains the input terminals of the carotid chemoreceptor. Because opioids inhibit the HVR via activating central μ-receptors that are expressed abundantly in the comNTS, the authors of the current study asked whether activating local μ-receptors attenuated the carotid body-mediated HVR. : To primarily stimulate the carotid body, brief hypoxia (100% N2) and hypercapnia (15% CO2) for 10 s and/or intracarotid injection of NaCN (10 μg/100 μl) were performed in anesthetized and spontaneously breathing rats. These stimulations were repeated after: (1) microinjecting three doses of μ-receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) (approximately 3.5 nl) into the comNTS; (2) carotid body denervation; and (3) systemic administration of DAMGO (300 μg/kg) without and with previous intracomNTS injection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a μ-receptor antagonist. : Study results showed that DAMGO at 0.25 and 2.5, but not 0.025 mM, caused a similar decrease in baseline ventilation (approximately 12%). DAMGO at 0.25 mM largely reduced (64%) the HVR, whereas DAMGO at 2.5 mM abolished the HVR (and the VE response to NaCN) and moderately attenuated (31%) the hypercapnic ventilatory response. Interestingly, similar HVR abolition and depression of the hypercapnic ventilatory response were observed after carotid body denervation. Blocking comNTS μ-receptors by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 significantly attenuated the HVR depression by systemic DAMGO with little change in the DAMGO modulatory effects on baseline ventilation and the hypercapnic ventilatory response. : The data suggest that opioids within the comNTS, via acting on μ-receptors, are able to abolish the HVR by affecting the afferent pathway of the carotid chemoreceptor.

Carotid body denervation blocks training induces resting bradycardia and reduces oxytocin immunoreactivity in preautonomic PVN subnuclei of rats

Carotid body denervation blocks training induces resting bradycardia and reduces oxytocin immunoreactivity in preautonomic PVN subnuclei of rats

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

Carotid Chemoreceptor Modulation of Regional Blood Flow Distribution During Exercise in Health and Chronic Heart Failure

Previous work has shown sensitization of carotid chemoreceptor (CC) responsiveness during exercise as well as in chronic heart failure (CHF). Accordingly, we hypothesized that the CCs contribute to the sympathetic restraint of skeletal muscle blood flow during exercise and CHF. We examined the effect of transient CC inhibition on total (Con(T)) and hindlimb (Con(L)) conductance, and blood pressure at rest and during exercise (2.5 miles per hour, 5% grade) in chronically instrumented dogs. Via a carotid arterial catheter, CCs were inhibited using dopamine (5 to 10 microg/kg) or hyperoxic lactated Ringer's solution. Although vasodilation did not occur with CC inhibition in resting healthy dogs, CC inhibition during exercise caused an immediate vasodilatory response (increase in Con(T) and Con(L) and decrease in blood pressure). When comparing the peak Con(L) response from CC inhibition versus alpha-adrenergic blockade (phentolamine), we found that the CCs accounted for approximately one-third of the total sympathetic restraint during exercise. CHF was then induced by chronic rapid cardiac pacing and characterized by impaired cardiac function, enhanced chemosensitivity, and greater sympathetic restraint at rest and during exercise. In contrast to healthy dogs, CC inhibition in resting CHF dogs produced vasodilation, whereas a similar vasodilatory response was observed during exercise in CHF as compared with healthy dogs. The vasodilation following CC inhibition during exercise and in CHF was abolished with alpha-adrenergic blockade and was absent in healthy exercising animals after carotid body denervation. These results establish an important role for the CCs in cardiovascular control in the healthy animal during exercise and in the CHF animal both at rest and during exercise.

Are the carotid bodies of the guinea-pig functional?

We have previously observed that the guinea-pig appears to have a relatively poor ventilatory (V (E)) response to hypoxia, compared to other mammals. Therefore, in this study, we questioned the ability of the carotid bodies (primary peripheral chemoreceptors) in the guinea-pig to detect hypoxia. The ventilatory responses to poikilocapnic hypoxia (8% O(2)), poikilooxic hypercapnia (8% CO(2)), hyperoxia (100% O(2)) and cyanide (NaCN - 200 mug/kg, i.v.) were assessed before and after carotid body denervation (CBD) in anaesthetized guinea-pigs. Although CBD attenuated the V (E) responses to hypercapnia and cyanide, it had no effect on normoxic breathing or the V (E) responses to hypoxia or hyperoxia. In a separate group of guinea-pigs, nerve activity was recorded from single or few-fibre preparations of the carotid sinus nerve (CSN). Basal chemoreceptor activity could not be detected from any of the nerve preparations. NaCN and hypercapnia consistently provoked an increase in neural activity. In contrast, hypoxia never clearly increased activity in any of the single or few-fibre preparations isolated from the CSN. In conclusion, although the carotid bodies of the guinea-pig, like those of other mammals, are able to detect hypercapnia and histotoxic hypoxia and elicit a reflex increase in V (E), they are essentially hypoxia-insensitive. The latter may explain, at least in part, the relatively poor V (E) response to hypoxia shown by the guinea-pig.

Carotid chemoreceptor modulation of regional blood flow distribution and vascular conductance during exercise

Stimulation of the carotid chemoreceptors (CC) causes increased sympathetic nervous activity. The CC is sensitive to [H+] and norepinephrine, and therefore we hypothesized that the CC may be active during exercise, contributing to the sympathetic restraint of blood flow to working muscle. We examined the effect of transiently inhibiting CC on cardiac output (QT), hind-limb flow (QL), total (ConT) and hindlimb (ConL) conductance and blood pressure (BP) during exercise (2.5 mph, 5% grade) in chronically instrumented dogs. Bolus injections of Dopamine (5–10 μg/kg) or 30 second infusions of hyperoxic lactated Ringers solution (PO2~700mmHg) were administered via a chronically implanted carotid arterial catheter. Within 10 seconds of injection, Dopamine produced a transient (<15 sec) increase in ConT (32%), ConL (49%), QT(11%) and QL(26%), while BP(−16%) was reduced (all data 5 heart-beat change from baseline). Similarly, hyperoxic Ringers resulted in a rapid, transient increase in ConT (13%), ConL (24%), QT(9%) and QL(19%), and reduction in BP(−4%). In constrast, isovolemic control injections of normoxic lactated Ringers elicited no cardiovascular response. Neither Dopamine nor hyperoxic Ringers caused vasodilation at rest. The vasodilatory response to dopamine and hyperoxic Ringers during exercise was virtually abolished with alpha adrenergic blockade, and was absent in animals following carotid body denervation. Our results indicate that the CC are tonically active during exercise, contributing to the sympathetic restraint of exercising muscle blood flow. (Funded by: NHLBI)

Modulation of emetic response by carotid baro- and chemoreceptor activations

We hypothesized that baroreceptor or chemoreceptor activation might be involved in the emetic, and prodromal cardiovascular and respiratory responses. To test this hypothesis, we induced the emetic responses by gastric distension in anesthetized Suncus murinus (house musk shrew), that had intact and absent baroreceptor and chemoreceptor afferents. Secondly, we stimulated the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Internal carotid artery ligation in the bifurcation area, which abolished reflex bradycardia by baroreceptor activation, and abolition of chemoreceptor reflex bradycardia and hyperventilation, by carotid body denervation, suppressed the emetic response but did not abolish it. ADN denervation, which produced no significant effects on the baroreceptor or chemoreceptor reflex bradycardia, had no effect on the emetic response, including the prodromal phase. CSN stimulation with gastric distension elicited retching accompanied by reflex bradycardia and hypotension during or just after stimulation, whereas ADN stimulation with gastric distension did not induce the cardiovascular reflex, and had no effects on the emetic response. These results indicate that carotid, rather than aortic, baroreceptor or chemoreceptor activation plays an important role in the augmentation of cardiac parasympathetic activity and the development of emetic response. In conclusion, carotid baroreceptor or chemoreceptor activation, which is non-emetic stimulation, acts as a modulator in the central mechanisms of emesis.

Carotid body denervation alters ventilatory responses to ibotenic acid injections or focal acidosis in the medullary raphe

Our aim was to determine the effects of carotid body denervation (CBD) on the ventilatory responses to focal acidosis and ibotenic acid (IA) injections into the medullary raphe area of awake, adult goats. Multiple microtubules were chronically implanted into the midline raphe area nuclei either before or after CBD. For up to 15 days after bilateral CBD, arterial PCO2 (PaCO2) (13.3 +/- 1.9 Torr) was increased (P < 0.001), and CO2 sensitivity (-53.0 +/- 6.4%) was decreased (P <0.001). Thereafter, resting PaCO2 and CO2 sensitivity returned (P <0.01) toward control, but PaCO2 remained elevated (4.8 +/- 1.9 Torr) and CO2 sensitivity reduced (-24.7 +/- 6.0%) > or =40 days after CBD. Focal acidosis (FA) at multiple medullary raphe area sites 23-44 days post-CBD with 50 or 80% CO(2) increased inspiratory flow (Vi), tidal volume (Vt), metabolic rate (VO2), and heart rate (HR) (P <0.05). The effects of FA with 50% CO2 after CBD did not differ from intact goats. However, CBD attenuated (P <0.05) the increase in Vi, Vt, and HR with 80% CO2, but it had no effect on the increase in VO2. Rostral but not caudal raphe area IA injections increased Vi, BP, and HR (P < 0.05), and these responses were accentuated (P <0.001) after CBD. CO2 sensitivity was attenuated (-20%; P <0.05) <7 days after IA injection, but thereafter it returned to prelesion values in CBD goats. We conclude the following: 1) the attenuated response to FA after CBD provides further evidence that the carotid bodies provide a tonic facilitory input into respiratory control centers, 2) the plasticity after CBD is not due to increased raphe chemoreceptor sensitivity, and 3) the "error-sensing" function of the carotid body blunts the effect of strong stimulation of the raphe.

Recovery of respiratory function following C2 hemi and carotid body denervation in adult rats: influence of peripheral adenosine receptors

The efficacy of the methylxanthine, theophylline, as a respiratory stimulant has been demonstrated previously in an animal model of spinal cord injury. In this model, an upper cervical (C2) spinal cord hemi paralyzes the ipsilateral hemidiaphragm. Theophylline restores respiratory-related activity in the paralyzed hemidiaphragm via activation of a latent respiratory motor pathway. Antagonism of central adenosine A 1 receptors mediates this action. Theophylline also enhances respiratory frequency, f, defined as breaths per minute . Thus, long-term use may result in respiratory muscle or motoneuron fatigue particularly after spinal cord injury. We assessed the effects of an adenosine A 1 receptor agonist, N 6- p-sulfophenyladenosine ( p-SPA) on theophylline's action in our model under standardized recording conditions. Four groups of rats, classified as hemisected/nonhemisected with the carotid bodies denervated (H-CBD or NH-CBD), and hemisected/nonhemisected with the carotid bodies intact (H-CBI or NH-CBI ) were used in the study. Eight days after recovery from carotid denervation, a left C2 hemi was performed in H-CBD rats. C2 hemi was also performed in H-CBI animals, and 24 h later, electrophysiologic experiments on respiratory activity were conducted in both groups of animals. Two groups using nonhemisected controls were also employed as described above. In H-CBD rats, theophylline significantly ( P < 0.05) enhanced f and induced respiratory-related activity in the previously quiescent left phrenic nerve. In NH-CBD rats, theophylline significantly enhanced f. In both H-CBD and NH-CBD rats, p-SPA (0.25 mg/kg) did not significantly change theophylline-induced effects. In H-CBI rats, theophylline significantly ( P < 0.05) enhanced f and induced activity in the previously quiescent left phrenic nerve. In H-CBI rats, p-SPA reduced the values to pre-theophylline discharge levels. Recovered activity was not obliterated with the agonist. In NH-CBI rats, p-SPA reduced theophylline-induced effects to pre-drug discharge levels. Adenosine A 1 and A 2A receptor immunoreactivity was detected in the carotid bodies. The significance of our findings is that theophylline-induced effects can be normalized to pre-drug levels by the selective activation of peripheral adenosine A 1 receptors. The therapeutic benefits of theophylline, i.e., recovered respiratory function after paralysis, however, persists. The potential therapeutic impact is that respiratory muscle fatigue associated with long-term theophylline use may be minimized by a novel therapeutic approach.