Arterial Chemoreceptor Inputs Research Articles

Neurogenic mechanisms underlying the rapid onset of sympathetic responses to intermittent hypoxia.

Sleep apnea (SA) leads to metabolic abnormalities and cardiovascular dysfunction. Rodent models of nocturnal intermittent hypoxia (IH) are used to mimic arterial hypoxemias that occur during SA. This mini-review focuses on our work examining central nervous system (CNS) mechanisms whereby nocturnal IH results in increased sympathetic nerve discharge (SND) and hypertension (HTN) that persist throughout the 24-h diurnal period. Within the first 1-2 days of IH, arterial pressure (AP) increases even during non-IH periods of the day. Exposure to IH for 7 days biases nucleus tractus solitarius (NTS) neurons receiving arterial chemoreceptor inputs toward increased discharge, providing a substrate for persistent activation of sympathetic outflow. IH HTN is blunted by manipulations that reduce angiotensin II (ANG II) signaling within the forebrain lamina terminalis suggesting that central ANG II supports persistent IH HTN. Inhibition of the hypothalamic paraventricular nucleus (PVN) reduces ongoing SND and acutely lowers AP in IH-conditioned animals. These findings support a role for the PVN, which integrates information ascending from NTS and descending from the lamina terminalis, in sustaining IH HTN. In summary, our findings indicate that IH rapidly and persistently activates a central circuit that includes the NTS, forebrain lamina terminalis, and the PVN. Our working model holds that NTS neuromodulation increases transmission of arterial chemoreceptor inputs, increasing SND via connections with PVN and rostral ventrolateral medulla. Increased circulating ANG II sensed by the lamina terminalis generates yet another excitatory drive to PVN. Together with adaptations intrinsic to the PVN, these responses to IH support rapid onset neurogenic HTN.

Chemosensory pathways in the brainstem controlling cardiorespiratory activity.

Cardiorespiratory activity is controlled by a network of neurons located within the lower brainstem. The basic rhythm of breathing is generated by neuronal circuits within the medullary pre-Bötzinger complex, modulated by pontine and other inputs from cell groups within the medulla oblongata and then transmitted to bulbospinal pre-motor neurons that relay the respiratory pattern to cranial and spinal motor neurons controlling respiratory muscles. Cardiovascular sympathetic and vagal activities have characteristic discharges that are patterned by respiratory activity. This patterning ensures ventilation-perfusion matching for optimal respiratory gas exchange within the lungs. Peripheral arterial chemoreceptors and central respiratory chemoreceptors are crucial for the maintenance of cardiorespiratory homeostasis. Inputs from these receptors ensure adaptive changes in the respiratory and cardiovascular motor outputs in various environmental and physiological conditions. Many of the connections in the reflex pathway that mediates the peripheral arterial chemoreceptor input have been established. The nucleus tractus solitarii, the ventral respiratory network, pre-sympathetic circuitry and vagal pre-ganglionic neurons at the level of the medulla oblongata are integral components, although supramedullary structures also play a role in patterning autonomic outflows according to behavioural requirements. These medullary structures mediate cardiorespiratory reflexes that are initiated by the carotid and aortic bodies in response to acute changes in PO(2), PCO(2) and pH in the arterial blood. The level of arterial PCO(2) is the primary factor in determining respiratory drive and although there is a significant role of the arterial chemoreceptors, the principal sensor is located either at or in close proximity to the ventral surface of the medulla. The cellular and molecular mechanisms of central chemosensitivity as well as the neural basis for the integration of central and peripheral chemosensory inputs within the medulla remain challenging issues, but ones that have some emerging answers.

Afferent input modulates the chronic hypercapnia-induced increase in respiratory-related central pH/CO2 chemosensitivity in the cane toad (Bufo marinus)

The goal of this study was to examine the role of respiratory-related afferent input on the chronic hypercapnia (CHC)-induced increase in central respiratory-related pH/CO2 chemosensitivity in cane toads (Bufo marinus). Toads were exposed to CHC (3.5% CO2) for 10 days, following which in vitro brainstem-spinal cord preparations were used to assess central respiratory-related pH/CO2 chemosensitivity. Motor output from the vagus nerve root was used as an index of breathing (fictive breathing). Olfactory denervation (OD), prior to exposure to CHC, was used to remove the influence of CO2-sensitive olfactory chemoreceptors, which inhibit breathing. Exposure to chronic hyperoxic hypercapnia (CHH) was used to reduce the level of arterial chemoreceptor input compared with CHC alone. In vivo experiments examined the effects of CHC, CHH and OD on the acute hypercapnic ventilatory response of intact animals. In vitro, a reduction in artifical cerebral spinal fluid (aCSF) pH increased fictive breathing in preparations taken from control and CHC animals. CHC caused an increase in fictive breathing compared with controls. OD and CHH abolished the CHC-induced augmentation of fictive breathing. In vivo, CHC did not cause an augmentation of the acute hypercapnic ventilatory response. CHH reduced the in vivo acute hypercapnic ventilatory response compared with animals exposed to CHC. In vivo, OD reduced breathing frequency and increased breath amplitude in both control and CHC animals. The results suggest that afferent input from olfactory and arterial chemoreceptors, during CHC, is involved in triggering the CHC-induced increase in central respiratory-related pH/CO2 chemosensitivity.

Chronic intermittent hypoxia (IH) increases blood pressure in carotid denervated rats

To determine if denervation of the carotid sinus region to eliminate arterial chemoreceptor inputs alters the mean arterial pressure (MAP) response to exposures to IH, the carotid sinus nerves were sectioned bilaterally in rats and the carotid bifurcation region painted with phenol. After a one week recovery period, rats were instrumented with telemetry transmitters. After a one week recovery period, the denervation was considered adequate if a 10 min reduction in inspired O2 to 10% resulted in a fall in MAP instead of the increase in MAP observed in carotid sinus nerve intact rats. Carotid denervated rats (n=7) and carotid intact rats (13) were exposed to IH (7 days for 8 hr/day, 3 min room air alternating with 3 min 10% O2). During the period of the day when exposed to IH, there was a significant effect of IH on MAP (p=.003). In intact rats MAP on control days was significantly different from the IH exposure days (p=.001) but not in denervated rats (p=.067). During the dark period of the day there was a significant effect of IH on MAP (p=.001) but no difference between intact and denervated rats. The change in MAP during the control period (average of control days 3–7) compared to during IH exposure (average of days 3–7) was 6.1±0.5mmHg in intact rats and −2.29±0.7mmHg in denervated rats during the period of the day when exposed to IH (p ≤ .001) and 5.9±0.2mmHg in intact rats and 4.2±0.6mmHg in denervated rats during the dark period of the day (p=.028). In conclusion, the arterial chemoreceptors prevent falls in MAP during exposure to IH, and mechanisms independent of the arterial chemoreceptors are capable of increasing MAP following exposure to IH.

Chronic hypoxia abolishes expiratory prolongation following carotid sinus nerve stimulation in the anesthetized rat

In anesthetized rats, increases in phrenic nerve (PN) amplitude and frequency during brief periods of hypoxia or electrical stimulation of the carotid sinus nerve (CSN) are followed by an increase in expiratory duration. We investigated the effects of chronic exposure to hypoxia on PN responses to CSN stimulation. In Inactin anesthetized (100 mg/kg) Sprague-Dawley rats PN discharge and arterial pressure responses to 10-120 s of CSN stimulation (20 Hz, 0.2 ms duration pulses) were recorded after 7-10 days exposure to hypoxia (10 +/- .5% O2). In normoxic rats, the degree of CSN-evoked expiratory prolongation was dependent upon the duration of CSN stimulation. CSN-evoked increases in PN burst amplitude were not different comparing chronic hypoxic rats to rats maintained at normoxia while CSN-evoked increases in PN burst frequency were greater in chronic hypoxic rats (p<.05). CSN-evoked expiratory prolongation was abolished in chronic hypoxic rats. Following chronic hypoxia, changes occur within the central processing of arterial chemoreceptor inputs so that CSN stimulation evokes an enhanced PN frequency response and no expiratory prolongation.

Chronic hypoxia induces changes in the central nervous system processing of arterial chemoreceptor input.

Chronic hypoxia increases the hypoxic ventilatory response (HVR) in awake rats and the phrenic nerve response to carotid sinus nerve stimulation in anesthetized rats. An increased O2 sensitivity of the arterial chemoreceptors contributes to the increase in the HVR, but changes in the CNS processing of afferent information from arterial chemoreceptors are also involved. Adult male Sprague-Dawley rats were exposed to 0-7 days of hypobaric hypoxia (PIO2 = 80 Torr). Ventilation was measured in rats exposed to 0, 2 and 7 days of hypoxia using whole-body plethysmography. Ventilation increased after 2 days and remained elevated after 7 days of hypoxia. Following dopamine D2 receptor (D2-R) blockade in the CNS, frequency significantly decreased after 0 and 7 days of hypoxia, but did not change significantly after 2 days of hypoxia. In anesthetized rats, the phrenic nerve response to carotid sinus nerve stimulation was reduced following systemic D2-R blockade in control rats and those exposed to 7 days of hypoxia. After 2 days of hypoxia, there was no effect of blocking systemic D2-R. To determine whether changes in D2-R mRNA precede physiological changes, competitive RT-PCR was used to quantify D2-R mRNA in micropunches from the nucleus tractus solitarius (NTS) in normoxic and chronically hypoxic rats. In hypoxia, D2-R mRNA in the caudal NTS initially increased (6-12 hours) and then decreased below control levels (24 hours-7 days). These results show that chronic hypoxia causes time-dependent changes in D2-R that could result in changes in the ventilatory response to hypoxia.

Attenuation of the hypoxic ventilatory response in adult rats following one month of perinatal hyperoxia.

1. This study was designed to test the hypothesis that perinatal suppression of peripheral arterial chemoreceptor inputs attenuates the hypoxic ventilatory response in adult rats. Perinatal suppression of peripheral chemoreceptor activity was achieved by exposing rats to hyperoxia throughout the first month of life. 2. Late-gestation pregnant rats were housed in a 60% O2 environment, exposing the pups to hyperoxia from several days prior to birth until they were returned to normoxia on postnatal day 28. These perinatally treated rats were then reared to adulthood (3-5 months old) in normoxia. In addition to the mother rats, adult male rats were also exposed to hyperoxia, creating an adult-treated control group. Two to four months after the hyperoxic exposure, treated rats were compared with untreated male rats of similar age. 3. A whole-body, flow-through plethysmograph was used to measure hypoxic and hypercapnic ventilatory responses of the unanaesthetized adult rats. In moderate hypoxia (arterial oxygen partial pressure, Pa,O2 approximately 48 mmHg). VE (minute ventilation) and the ratio VE/VCO2 (ventilation relative to CO2 production) increased by 16.7 +/- 4.0 and 35.4 +/- 3.4%, respectively, in perinatal-treated rats (means +/- S.E.M.), but increased more in untreated control rats (51.4 +/- 2.8 and 83.1 +/- 4.3%; both P < 10(-6)). 4. In contrast to the impaired hypoxic ventilatory response, ventilatory responses to hypercapnia (5% CO2) were similar between untreated control and perinatal-treated rats. 5. Impaired hypoxic responsiveness was unique to the perinatal-treated rats since hypoxic ventilatory responses were not attenuated in adult-treated rats. 6. The results indicate that ventilatory responses to hypoxaemia are greatly attenuated in adult rats that had experienced hyperoxia during their first month of life, and suggest that normal hypoxic ventilatory control mechanisms are susceptible to developmental plasticity.

Inhibition of chemoreceptor inputs to nucleus of tractus solitarius neurons during baroreceptor stimulation.

The reflex effects of arterial chemoreceptor activation are attenuated as arterial pressure is elevated and augmented as arterial pressure is decreased. This study was designed to test the hypothesis that excitatory arterial chemoreceptor inputs to neurons in the nucleus tractus solitarius (NTS) are inhibited by arterial baroreceptors. In pentobarbital sodium-anesthetized, mechanically ventilated, paralyzed cats, extracellular recordings were obtained from NTS neurons, which were excited after brief activation of ipsilateral carotid body chemoreceptors. During increases in arterial pressure, carotid sinus nerve (CSN)-evoked discharge was 45-112% of the control-evoked discharge at the prevailing level of arterial pressure (n = 70). Inhibition of CSN-evoked discharge during increased arterial pressure was significant when evoked discharge was < 90% of control (n = 31; 67 +/- 2%, mean percent of control-evoked discharge +/- SE; P < 0.01, Wilcoxon signed-rank test). The inhibition of CSN-evoked discharge was reduced after section of both vagi, both aortic nerves, and the contralateral CSN (n = 5, P < 0.05). These results demonstrate that activation of arterial baroreceptors attenuates excitatory chemoreceptor inputs to a subpopulation of NTS neurons. The inhibition appears to be mediated by disfacilitation. The results indicate that baroreceptor modulation of arterial chemoreflexes occurs at an early stage of the reflex arc, within the NTS. The results also suggest that sympathoinhibition evoked by baroreceptors might include, as a component, reduced sympathoexcitatory, i.e., chemoreceptor, drive.

Absence of respiration modulation of carotid sinus nerve inputs to nucleus tractus solitarius neurons receiving arterial chemoreceptor inputs

The reflex responses to activation of the arterial chemoreceptors are dependent upon when in the respiratory cycle the chemoreceptor stimulus is given. To determine if the respiratory modulation of the chemoreflex occurs within the nucleus tractus solitarius (NTS), intracellular recordings were obtained in pentobarbital-anesthetized, paralyzed and mechanically ventilated cats, from 22 non-respiratory NTS cells which were depolarized following activation of the ipsilateral carotid body chemoreceptors (by close arterial injection of <100 μ1 CO 2 saturated bicarbonate). Activation of the ipsilateral carotid body chemoreceptors evoked depolarizations with amplitudes of 2.9–4.6 mV and durations of 2.1–5.9 s. Three of these cells also received a convergent excitatory input from the carotid sinus baroreceptors. Carotid sinus nerve (CSN) stimulation evoked either an excitatory post-synaptic potential (EPSPs) ( n = 14, 8 monosynaptic) or an excitatory/inhibitory sequence (EPSP/IPSPs) ( n = 8, 1 monosynaptic). CSN evoked PSPs were separately averaged (25–50 sweeps) during periods of phrenic nerve activity and phrenic nerve silence and during periods when the lungs were inflated and when the lungs were deflated. No parameter of the CSN evoked PSPs (latency, peak amplitude, duration) was altered during periods of phrenic nerve activity or lung inilation (all P values > 0.12, Wilxocon signed-rank test). The results suggest that there is no respiratory modulation of arterial chemoreceptor inputs by either central respiratory drive or lung stretch receptor afferent inputs at this early stage of the reflex arc.

Baroreflex control of arterial blood pressure during involuntary diving in ducks (Anas platyrhynchos var.).

The dynamic role of arterial baroreceptors in control of mean arterial blood pressure (MAP), heart rate (HR), cardiac output (CO), hindlimb vascular (HLVR) and total peripheral (TPR) resistance responses to forced dives was investigated in acutely and chronically barodenervated ducks. To activate the baroreflex, the proximal end of one aortic nerve was stimulated electrically with bipolar electrodes that had been implanted under pentobarbital sodium anesthesia. Predive nerve stimulation caused CO to fall (by reducing HR; stroke volume remained constant), producing a decrease in MAP to half the prestimulation level. During diving (for 2.5-min periods) nerve stimulation did not affect HR and MAP after the first minute of submersion. Neither HLVR nor TPR contributed to the fall in MAP during aortic nerve stimulation before or during diving. The effects of nerve stimulation on HR and MAP were maintained to the end of dives in animals given 100% O2 to breathe before diving. In separate experiments, increasing arterial chemoreceptor input by perfusing one vascularly isolated carotid body with venous blood caused a reduction in the effects of aortic nerve stimulation on MAP. Arterial baroreceptors may thus act on HR to alter MAP early in the dive, but as the dive progresses the baroreflex is attenuated by an increase in peripheral chemoreceptor drive.

Role of dopamine and arterial chemoreceptors in thermal tachypnea in conscious cats

In mammals submitted to a warm environment, intracerebral injection of dopamine (DA) produces no change or an increase in body temperature accompanied by an increase in metabolic heat production, but its effect on heat loss mechanisms such as vasodilation and tachypnea is not clear. Because the principal mechanism of heat loss in the conscious cat is thermal tachypnea, we studied the influence of DA on thermal tachypnea in response to heat stress (ambient temperature = 33-36 degrees C) in five conscious cats. We first studied the steady-state response to a DA agonist, apomorphine, which crosses the blood-brain barrier. Intravenous injection of apomorphine greatly reduced thermal tachypnea by decreasing respiratory frequency (from 94.9 to 52.5 breaths/min) and increasing tidal volume (from 13.2 to 20.4 ml). The subsequent injection of the DA antagonist haloperidol, which also crosses the blood-brain barrier, restored the initial tachypnea. To further investigate the mechanism involved in thermal tachypnea, we studied the influence of peripheral chemoreceptors by transiently stimulating or inhibiting carotid body (CB) activity during tachypneic breathing. CB stimulation by intravenous injection of NaCN or domperidone reduced thermal tachypnea mainly by decreasing the respiratory frequency, whereas CB inhibition by DA tended to increase frequency and thus tachypnea. It is concluded that 1) in a warm environment, central DA receptors are also greatly involved in heat loss mechanisms, 2) arterial chemoreceptor input appears to counteract this tachypneic breathing, and 3) thermal and hypoxic tachypnea may be controlled by the same mechanism in which a DA-like system has a key role.