Bilateral Carotid Body Denervation Research Articles

Epigenetic changes to the carotid body drive hypertension in perinatal nicotine exposed rats

Background: Epigenetic changes can be shaped by a wide array of environmental cues as well as maternal health and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains as a significant risk factor for cardiovascular health and in particular, hypertension, as it has been shown to alter angiotensin signaling. Hypothesis: We hypothesized that perinatal nicotine exposure alters carotid body angiotensin signaling to induce hypertension in adult life. Methods: Pregnant Sprague-Dawley rats were exposed to nicotine (2mg/kg SQ, or PBS- control) from estrous day 6 to post-natal day (PND) 21. Experiments on pups took place from PND 56-90. Carotid bodies were harvested pooled together for RNAseq and confirmation of unbiased transcriptomics was conducted with qPCR. Blood pressure was measured with indwelling telemetry. ELISA assessed serum angiotensin. PC12 cells were used a surrogate for carotid body glomus cells and were used for calcium imaging. Results: Unbiased RNAseq of carotid bodies from nicotine exposed pups compared to saline control pups showed that KEGG pathways with significant angiotensin signaling components including Neuroactive ligand-receptor interaction (Log2FC=2.4, p=7.5x10−8) and Dopaminergic synapse (Log2FC=2.3, p=0.0007) were significantly upregulated. qPCR of carotid bodies demonstrated that Angiotensin II type 1 receptor (56%↑), Angiotensin II type 2 receptor (15%↑) and TRPV1 channels (63%↑) were upregulated in nicotine exposed pups compared to controls. Blood pressure measured in nicotine exposed pups was suppressed 1 day after bilateral carotid body denervation. Circulating angiotensin assessed from serum was similar between nicotine exposed and control pups. Calcium imaging of PC12 cells showed that nicotine significantly increased spike frequency in response to nicotine (0.2mg/ml). Incubation with nicotine + Angiotensin (50ng/ml) did not further increase spike frequency. This increased excitation was suppressed with losartan (3μM), AMG9810 (TRPV1 antagonist, 10μM) and combined blockade (p<0.05). Conclusion: Our data demonstrate that adverse maternal behaviors produce epigenetic changes to carotid bodies of offspring resulting in neurogenic hypertension. The epigenetic changes involve an Angiotensin-Angiotensin II type 1 receptor-TRPV1 channel axis in the carotid body without any significant systemic changes. We suggest carotid body modulation may have a significant health impact on offspring with adverse perinatal environmental exposures. UCOP TRDRP T32IP4707, T32KT4708. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

In anaesthetized rats, acute intermittent hypoxia increases sympathetic nerve activity, sympathetic peripheral chemoreflex sensitivity and central sympathetic-respiratory coupling. Renin-angiotensin system inhibition prevents the sympathetic effects of intermittent hypoxia, with intermittent injections of angiotensin II into the systemic circulation replicating these effects. Bilateral carotid body denervation reduces the sympathetic effects of acute intermittent hypoxia and eliminates the increases in chemoreflex sensitivity and sympathetic-respiratory coupling. Pharmacological inhibition of the subfornical organ also reduces the sympathetic effects of acute intermittent hypoxia, although it has no effect on the increases in chemoreflex sensitivity and central sympathetic-respiratory coupling. Combining both interventions eliminates the sympathetic effects of both intermittent hypoxia and angiotensin II. Circulating angiotensin II (AngII) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7±2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of AngII (Int.AngII) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.AngII, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating AngII, reduced the increase in SNA following AIH and Int.AngII by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.AngII. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

Respiratory rhythm irregularity after carotid body denervation in rats

Respiratory activity is controlled by inputs from the peripheral and central chemoreceptors. Since overactivity of the carotid bodies, the main peripheral chemoreceptors, is linked to the pathophysiology of disparate metabolic and cardiovascular diseases, carotid body denervation (CBD) has been proposed as a potential treatment. However, long-term effects of CBD on the respiratory rhythm and regularity of breathing remain unknown. Here, we show that five weeks after bilateral CBD in rats, the respiratory rhythm was slower and less regular. Ten weeks after bilateral CBD, the respiratory frequency was not different from the sham-operated group, but the regularity of the respiratory rhythm was still reduced. Increased frequency of randomly occurring apneas is likely to be responsible for the irregular breathing pattern after CBD. These results should be taken into consideration since any treatment that reduces the stability of the respiratory rhythm might exacerbate the cardio-respiratory instability and worsen the cardiovascular outcomes.

Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure.

Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure.

Changes in glutamate receptor subunits within the medulla in goats after section of the carotid sinus nerves.

The mechanisms which contribute to the time-dependent recovery of resting ventilation and the ventilatory CO2 chemoreflex after carotid body denervation (CBD) are poorly understood. Herein we tested the hypothesis that there are time-dependent changes in the expression of specific AMPA, NMDA, and/or neurokinin-1 (NK1R) receptors within respiratory-related brain stem nuclei acutely or chronically after CBD in adult goats. Brain stem tissues were collected acutely (5 days) or chronically (30 days) after sham or bilateral CBD, immunostained with antibodies targeting AMPA (GluA1 or GluA2), NMDA (GluN1), or NK-1 receptors, and optical density (OD) compared. Physiological measurement confirmed categorization of each group and showed ventilatory effects consistent with bilateral CBD (Miller et al. J Appl Physiol 115: 1088-1098, 2013). Acutely after CBD, GluA1 OD was unchanged or slightly increased, but GluA2 and GluN1 OD were reduced 15-30% within the nucleus tractus solitarius (NTS) and in other medullary respiratory nuclei. Chronically after CBD, GluA1 was reduced (P < 0.05) within the caudal NTS and in other nuclei, but there was significant recovery of GluA2 and GluN1 OD. NK1 OD was not significantly different from control after CBD. We conclude that the initial decrease in GluA2 and GluN1 after CBD likely contributes to hypoventilation and the reduced CO2 chemoreflex. The partial recovery of ventilation and the CO2 chemoreflex after CBD parallel a time-dependent return of these receptors to near control levels but likely depend upon additional initiating and maintenance factors for neuroplasticity.

RNA sequencing to profile transcriptional changes within the medullary raphe: potential mechanisms of central neuroplasticity driving the recovery of eupneic ventilation after bilateral carotid body denervation (713.7)

Bilateral carotid body denervation (CBD) in rats elicits eupneic (resting) hypoventilation 1‐2 d post‐CBD, which relatively rapidly returns to baseline values (14‐15 d). We have previously shown increases in brainstem serotonin (5‐HT) turnover and the 5‐HT transporter (SERT) acutely after CBD, leading to the hypothesis that the recovery of eupneic ventilation following CBD may be associated and/or initiated by activation of the medullary raphe nuclei (MRN). To test this hypothesis, we collected medullary raphe tissue punches (~1mm3) from rats euthanized acutely (1‐2 days) after sham (n=11) or CBD (n=10), or 15 days after sham (n=10) or CBD (n=10) surgery. Eupneic PaCO2 was increased acutely (p&lt;0.001) and chronically (p&lt;0.001) after CBD compared to pre‐CBD control, but PaCO2 15 days post‐CBD was not different than time‐control sham rats demonstrating recovery following CBD. Total RNA was collected using a phenol‐chloroform extraction protocol and quantified/qualified using an Agilent Bioanalyzer. 100 – 600 ng of total RNA was collected with an integrity number of 7 or greater for all samples, indicating high RNA quality. 12 cDNA libraries were created (3 or 4 per group x 4 groups) using the Illumina TruSeq RNA Sample Prep LS protocol for mRNA sequencing, from which all 12 libraries yielded pure cDNA. Ongoing mRNA sequencing will allow for the eventual coupling of our comprehensive physiologic measurements with raphe gene expression to provide unique insights into potential mechanisms of recovery or plasticity ventilatory control after CBD.Grant Funding Source: Supported by NIHHL097033, T32HL007852.

Increased Ca2+ permeable ampa receptor expression following carotid body denervation in goats (713.2)

The mechanisms which contribute to the time‐dependent recovery of resting ventilation and the ventilatory CO2 chemoreflex after carotid body denervation (CBD) are poorly understood. The initiation of neuronal plasticity often involves changes in Ca2+ permeability. Therefore, we tested the hypothesis that during recovery from the acute effects of CBD in goats, there is an increase in Ca2+ permeable GluA1R and GluN1R and/or a decrease in Ca2+ impermeable GluA2R expression at brainstem sites that contribute to respiratory control. We tested this hypothesis via optical densitometric (OD) quantification of medullary neurons immunostained with antibodies targeting GluA1R, GluA2R, and GluN1R at 5‐13 days or 30 days after bilateral CBD. CBD resulted in hypoventilation and a reduced CO2 chemoreflex, which both recovered significantly over 30 days post‐CBD. At 5‐13 days post‐CBD, GluA1 OD was unchanged from control goats, but GluA2 and GluN1 OD were reduced 15‐30% within 6 of medullary respiratory nuclei measured. However, at 30 days post‐CBD GluA1 OD remained unchanged, but GluA2 and GluN1 OD returned to control levels. We conclude that a shift toward Ca2+ permeable glutamate receptors 5‐13 days post‐CBD may initiate the recovery of ventilation after CBD. Furthermore, at 30 days post‐CBD the partial recovery of ventilation is maintained by relatively normal glutamate receptor expression.Grant Funding Source: Supported by National Heart, Lung, and Blood Institute Grants HL25739 and HL007852 and by VA

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&lt;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&lt;0.05). Conversely, in RDNX rats (−7±2mmHg), bilateral CBD produced a further fall in AP of −12±3 mmHg(p&lt;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.

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.

Chronic hypoxia abolishes posthypoxia frequency decline in the anesthetized rat.

In anesthetized rats, increases in phrenic nerve amplitude and frequency during brief periods of hypoxia are followed by a reduction in phrenic nerve burst frequency [posthypoxia frequency decline (PHFD)]. We investigated the effects of chronic exposure to hypoxia on PHFD and on peripheral and central O2-sensing mechanisms. In Inactin-anesthetized (100 mg/kg) Sprague-Dawley rats, phrenic nerve discharge and arterial pressure responses to 10 s N2 inhalation were recorded after exposure to hypoxia (10 +/- 0.5% O2) for 6-14 days. Compared with rats maintained at normoxia, PHFD was abolished in chronic hypoxic rats. Because of inhibition of PHFD, the increased phrenic burst frequency and amplitude after N2 inhalation persisted for 1.8-2.8 times longer in chronic hypoxic (70 s) compared with normoxic (25-40 s) rats (P < 0.05). After acute bilateral carotid body denervation, N2 inhalation produced a short depression of phrenic nerve discharge in both chronic hypoxic and normoxic rats. However, the degree and duration of depression of phrenic nerve discharge was smaller in chronic hypoxic compared with normoxic rats (P < 0.05). We conclude that after exposure to chronic hypoxia, a reduction in PHFD contributes to an increased duration of the acute hypoxic ventilatory response in anesthetized rats. Furthermore, after exposure to chronic hypoxia, the central network responsible for respiration is more resistant to the depressant effects of acute hypoxia in anesthetized rats.

Important role of carotid afferents in control of breathing.

The purpose of the present study was to determine the effect on breathing in the awake state of carotid body denervation (CBD) over 1-2 wk after denervation. Studies were completed on adult goats repeatedly before and 1) for 15 days after bilateral CBD (n = 8), 2) for 7 days after unilateral CBD (n = 5), and 3) for 15 days after sham CBD (n = 3). Absence of ventilatory stimulation when NaCN was injected directly into a common carotid artery confirmed CBD. There was a significant (P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. The maximum PaCO2 increase (8 Torr for unilateral and 11 Torr for bilateral) occurred approximately 4 days after CBD. This maximum was transient because by 7 (unilateral) to 15 (bilateral) days after CBD, PaCO2 was only 3-4 Torr above control. CO2 sensitivity was attenuated from control by 60% on day 4 after bilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO2 sensitivity returned to control temporally similar to the return of PaCO2 during the breathing of room air. During mild and moderate treadmill exercise 1-8 days after bilateral CBD, PaCO2 was unchanged from its elevated level at rest, but, 10-15 days after CBD, PaCO2 decreased slightly from rest during exercise. These data indicate that 1) carotid afferents are an important determinant of rest and exercise breathing and ventilatory CO2 sensitivity, and 2) apparent plasticity within the ventilatory control system eventually provides compensation for chronic loss of these afferents.

This Month in the Journal

This Month in the Journal

Modulation of respiratory rhythm by alpha 2-adrenoceptors in awake and anesthetized goats

The purpose of this study was to examine the effects of alpha 2-adrenoceptor agonists in the control of breathing with goats that were either awake (n = 7) or anesthetized and artificially ventilated (n = 11). Awake goats infused intravenously with either of the alpha 2-agonists clonidine (1.0-6.0 micrograms/kg) or guanabenz (15.0-63.0 micrograms/kg) exhibited two distinct ventilatory patterns. One pattern was characterized by tachypnea in which respiratory frequency and minute ventilation increased to approximately 50% above control values. A second ventilatory pattern consisted of slow breathing with reductions of respiratory frequency and minute ventilation and highly variable expiratory duration intervals. These two patterns were unaffected by bilateral carotid body denervation. In anesthetized goats, alpha 2-agonists also caused an arrhythmia in phrenic nerve activity that was similar to the slow breathing pattern seen in awake goats. Respiratory disturbances were abolished by the selective alpha 2-receptor antagonist SKF-86466 (100-500 micrograms/kg), indicating that the effects are mediated by alpha 2-receptors. The results suggest that stimulation of alpha 2-adrenoceptors generally has an inhibitory effect on breathing in goats. The disruption of ventilation with clonidine or guanabenz suggests that alpha 2-adrenoceptors may play an important role in the control of central respiratory rhythm.

Carotid Body Resection for COPD?

Bilateral carotid body denervation or resection (glomectomy) has been performed in three contexts over the past 35 years: 1) in the 1950s, Nakayama in Tokyo used glomectomy to treat childhood asthma.1 While many subjects were apparently relieved, the procedure was terminated after two of the youngsters died while attempting long underwater swims. Some of these patients were studied 30 years later and found still to be unresponsive to hypoxia.2 2) Bilateral carotid endarterectomy for arteriosclerotic occlusive disease was shown by Wade et al3 to result in carotid body denervation in most patients, with a resulting permanent 6 mm Hg rise of PCO2.

Brain transections demonstrate the central origin of hypoxic ventilatory depression in carotid body-denervated rats.

1. The characteristics of hypoxic ventilation were studied in awake adult rats after brain transections about the intercollicular level. The results were compared with studies made before transection, 17-24 h after bilateral carotid body denervation effected by carotid sinus nerve section. 2. Transection at or below the intercollicular level converted the depressive hypoxic frequency response of control studies to a stimulatory response, increased the stimulation of tidal volume by hypoxia, and so converted the dominant pattern of ventilation in hypoxia from a depression to a progressive stimulation. 3. Transection above the intercollicular level failed to reverse the hypoxic frequency response but increased the stimulation of tidal volume by hypoxia. Consequently minute ventilation progressively increased as the severity of hypoxia increased. 4. The experiments demonstrate that in the adult rat depression of respiratory frequency by hypoxia after carotid body denervation requires the integrity of a region at or immediately above the intercollicular level. In contrast, the stimulation of tidal volume by hypoxia is markedly dependent upon precollicular structures. 5. The results are discussed in relation to the hypoxic depression of fetal breathing and the biphasic hypoxic ventilatory response of the newborn.

Hypoxia potentiates, oxygen attenuates deflation-induced reflex tracheal constriction

The reflex tracheomotor responses of in situ isolated segments of the extrathoracic trachea of anesthetized, paralyzed, and ventilated dogs were monitored. Reflex tracheal constriction was evoked by passive lung deflation. The purpose of this study was to determine whether the prevailing state of oxygenation altered the magnitude of this reflex. Compared with the magnitude of the response during normoxia [arterial O2 tension (PaO2) = 78 Torr], that during hypoxia (PaO2 = 44 Torr) was nearly threefold larger while that during hyperoxia (PaO2 greater than 250 Torr) was about 50% smaller. The isocapnic changes in oxygenation by themselves usually had no effect on tracheomotor tone. The deflation-induced reflex tracheal constriction was eliminated by complete denervation of the tracheal segment but usually only diminished by partial denervation. Bilateral vagotomies or bilateral carotid body denervation also usually decreased the magnitude of the reflex. It appears that the magnitude of this reflex is dependent on the prevailing state of oxygenation and that a pulmonary stretch receptor-carotid body chemoreceptor interaction accounts for the exaggerated reflex tracheal constriction during hypoxia and the attenuated response during hyperoxia.

1829 VENTILATORY EFFECTS OF PERIPHERAL CHEMO-RECEPTOR STIMULATION IN MATURING RABBITS

While it is well known that significant changes in ventilatory control occur during postnatal development, the maturational influence of peripheral chemoreceptor stimulation (PCS) during normoxia (N) and hypoxia (H) have not been systematically evaluated. Accordingly, in the present study, we separately assessed the ventilatory responses to PCS with sodium cyanide (NaCN), both during steady-state inhalation of 21% (N) and 10% (H) O2. Following tracheostomy and carotid artery catheterization under light ether anesthesia, pulmonary ventilation (VE) was continually monitored in newborn rabbits (age range: 1-30 days) placed in a body plethysmograph. During N, while saline had no effect, infusions of NaCN (dose range: 0.01 to 0.4 mg/kg) established reproducible dose-dependent increases in VE. The maximal percent increases in VE (VEmax) with NaCN systematically increased with age; however, “sensitivity” to NaCN, represented by the dose of NaCN producing 50% of VEmax, was not age related. In marked contrast to N, during steady-state H, lower doses of NaCN (i.e., less than 0.1 mg/kg) produced less VE stimulation, while higher doses produced VE depression resulting in some cases in acute apnea. Bilateral carotid body denervation abolished the VE responses to NaCN. These findings in maturing rabbits indicate that: (1) during normoxia, PCS with NaCN produces ventilatory stimulation; however, (2) during steady-state hypoxia PCS produces ventilatory depression which may lead to apnea.

CAROTID BODIES MEDIATE THE ATTENUATING EFFECT OF BETA-ADRENERGIC AGONISTS ON APNEA REFLEX RESPONSE TO LARYNGEAL WATER ADMINISTRATION IN NEWBORN LAMBS

Terbutaline (T), a beta-adrenergic agonist, was reported to attenuate the apnea reflex response to laryngeal water stimulation in newborn lambs (Pediatr. Res. 17:213, 1983). In order to delineate the mechanism of this drug action--central or via arterial chemoreceptors--laryngeal water administration was performed before and after bilateral carotid body denervation (CBD) in 4 term lambs, 2-4 weeks old. The apnea reflex response was expressed as % decrease in ventilation (Δ V) during water administration. Before CBD, T reduced Δ V significantly* (60 ± 11 to 23 ± 12%)+. This drug effect on Δ V was abolished by CBD (97 ± 4 vs 97 ± 3%). The effect of T on an index of "central respiratory drive" was studied by airway occlusion technique (P0.1) before and after CBD. T given before CBD increased P0.1 (4.5 ± 1.0 to 9.1 ± 1.5 cm H20)*. No change in P0.1 was seen when T was given after CBD (2.0 ± 0.4 vs 2.0 ± 0.2 cm H2O). Two sham operated lambs did not show the above described changes related to CBD. It is concluded that the attenuating effect of T on the apnea response to laryngeal water administration is mediated by the carotid bodies. An increase in "central respiratory drive" as determined by P0.1 was seen after T. This effect, however, also appears to be mediated by the carotid bodies. *p < 0.05, and +values are Mean ± SEM (Supported by MOD 1-739 and BRSG 21-25).

Dopaminergic modulation of respiratory timing mechanisms in carotid body-denervated dogs

The role of central dopaminergic mechanisms in ventilatory control was investigated by monitoring phrenic motorneuronal output of anesthetized dogs which were vagotomized, paralyzed and artificially ventilated and in which bilateral carotid body denervation had been performed. Intravenous administration of dopamine (DA) had no effect on phrenic output in these dogs. In contrast, apomorphine (APO), a potent dopaminergic agonist, which unlike dopamine, crosses the blood-brain barrier consistently and significantly prolonged inspiratory duration and shortened expiratory duration without altering phrenic amplitude. The dopaminergic antagonist haloperidol produced a frequency-dependent decrease in basal phrenic minute activity and reversed or abolished APO-induced changes in the phrenic profile. These data verify the specificity of APO for dopamine receptors and further suggest that DA receptors in the central nervous system exert a tonic effect on central respiratory control mechanisms. In contrast, domperidone, a dopaminergic antagonist which poorly penetrates the blood-brain barrier did not alter basal phrenic characteristics. Moreover, with the exception of inspiratory duration, domperidone did not antagonize APO-induced alterations in the phrenic profile. We conclude that dopaminergic mechanisms within the brain or spinal cord modulate timing relationships of central respiratory output.

Effects of p-chlorophenylalanine on ventilatory control in goats.

The effects of tryptophan hydroxylase inhibition with p-chlorophenylalanine (PCPA; 100 mg/kg iv) on ventilatory control were studied in awake goats. Ventilation, CO2 production, and blood gases were measured 16-24 h after PCPA at rest and during mild exercise in normoxia and at rest in hypoxia and hypercapnia. PCPA increased ventilation 36% at rest, predominantly through an effect on respiratory frequency, and decreased arterial PCO2 (PaCO2) 6.5 Torr. Ventilatory gain in exercise (delta VI/deltaVCO2) was increased 20% by PCPA thereby maintaining PaCO2 at its new resting value. Hypoxia (fractional inspired O2 concentration = 0.12) had little effect on ventilation or PaCO2 at rest, either on control or on PCPA test days. Ventilatory sensitivity to CO2 at rest (delta VI/delta PaCO2) was unaffected by PCPA. Bilateral carotid body denervation (CBX) was performed in the animals, and experiments were repeated 3 mo after the first administration of PCPA. CBX alone decreased ventilation 29% and increased PaCO2 9.4 Torr. Administration of PCPA increased ventilation 35%, decreased PaCO2 by 10.2 Torr at rest, and increased ventilatory gain in exercise 26%. Thus carotid bodies are not necessary for the ventilatory response to PCPA. Furthermore, the primary neural pathways associated with exercise or hypercapnia are not specifically affected by inhibition of serotonin metabolism via PCPA.