S. Lahiri

Stimulus interaction in the responses of carotid body chemoreceptor single afferent fibers.

The characteristics of steady-state responses of single afferent fibers of carotid chemoreceptors to independent changes in arterial Po2, and Pco2 were investigated in cats. The arterial blood pressure was maintained within the normal limits (115-130 torr). Single chemoreceptor afferent fibers responded to changes both in arterial Po2 and Pco2. The relationship between the activity of chemoreceptors and changes in arterial Pco2 was linear at a constant arterial Po2. The two stimuli showed multiplicative interaction. The activity approached zero (threshold) as arterial Pco2 was decreased at a constant arterial Po2; a decrease in arterial Po2 decreased the arterial Pco2 threshold. These response characteristics of a single fiber suggest that the sensory receptor may be activated through a single mechanism by the two stimuli. The data fit into an idea that the mechanism may involve a conformational change in the membrane-bound polymeric chromophore group which reacts with O2 reversibly and shows a Bohr-shift.

Dependence of high altitude sleep apnea on ventilatory sensitivty to hypoxia

Respiration in man exposed to 5400 m was studied during sleep over a period of 6-8 h at night. Subjects were adult males, and belonged to distinct groups: one was Sherpa high altitude residents of the Himalayas and the other consisted of causasian sojourners from near sea level. All the volunteers had spent at least 32 days at or above 5400 m before the study. The subjects were instrumented for the measurements of breath-by-breath ventilation, SaO2%, eye-movement and heart rate. Nasal prongs were secured for the administration of mixtures of O2, N2 or CO2. Also, ventilatory sensitivity to hypoxia was studied in the awake state by the transient N2 and O2 tests. The lowlanders who showed high respiratory sensitivity to hypoxia also manifested periodic breathing with apnea during sleep. A raised PIO2 and SaO2% decreased ventilation, raised PACO2, attenuated respiratory oscillations and eliminated apnea in the sojourners. CO2 inhalation in air also eliminated apnea but not the periodicity, indicating that respiratory alkalosis caused apnea but periodic breathing was independent of central stimulation by CO2-H+. None of the Sherpa highlanders with low ventilatory sensitivity to hypoxia showed any sustained periodic breathing with apnea. The large breathing oscillations and periodic apnea correlated well with the ventilatory sensitivity to hypoxia (r = 0.85), supporting the hypothesis that a high gain of the peripheral chemoreflex is conductive to periodic breathing. Sherpas by attenuating chemoreflexes have reduced instability as well as cost of breathing at high altitude.

Ventilatory responses to transient hypoxia and hypercapnia in man

Abstract The contribution of the peripheral (arterial) chemoreceptors to the ventilatory response to acute hypoxia and hypercapnia in intact unanesthetized man has been evaluated by methods which assume that ventilatory responses to transient stimuli reflect their effects upon the arterial chemoreceptors while responses to steady-state stimuli reflect their effects upon both arterial chemoreceptors and the central nervous system. Transient eucapneic hypoxia was produced by inhalation of several breaths of N 2 while breathing room air; transient hypercapneic hypoxia was produced by inhalation of several breaths of N 2 with CO 2 added while breathing CO 2 enriched air. Transient euoxic hypercapnia was produced by inhalation of single breaths of from 6 to 20% CO 2 in 21 % O 2 while the subject breathed air; transient hypoxic hypercapnia was produced by inhalation of single breaths of CO 2 enriched hypoxic gas while the subjects breathed a similarly hypoxic gas mixture. The ventilatory responses to transient hypoxia were qualitatively similar to the responses to steady-state hypoxia although they were quantitatively significantly greater by an average of 18%. The responses to transient euoxic hypercapnia averaged approximately one-third the responses to steady-state euoxic hypercapnia. Responses to transient hypercapnia were much less enhanced by hypoxia than were responses to steady-state hypercapnia. The findings suggest that: (1) A slight. centrally mediated, depressant effect of hypoxia may be present in unanesthetized man; (2) The peripheral chemoreceptors are responsible for approximately one-third of the overall (steady-state) ventilatory response to hypercapnia; (3) The phenomenon of stimulus interaction (enhancement of ventilatory response to hypercapnia by hypoxia) occurs at both the peripheral chemoreceptors and within the central nervous system but the central effect is the predominant one.

The primary oxygen sensor of the cat carotid body is cytochrome a3 of the mitochondrial respiratory chain

Carbon monoxide was shown to be competitive with O2 in oxygen sensing by perfused carotid bodies isolated from cats, afferent electrical activity increasing with either decreasing O2 or increasing CO. The CO‐induced increase in afferent activity was fully reversed by bright light. At submaximal light intensities the extent of reversal, after correcting to equal light intensity of light quanta at each wavelength, was maximal for light of 432 ± 2 and 590 ± 2 nm, with a ratio (432/590) of approximately 6. This spectrum is characteristic of the CO compound of mitochondrial cytochrome a 3. The photo‐reversible inhibition of oxygen sensing activity by CO accounts for at least 80% of the oxygen chemosensory activity of the carotid body.

Relationship between carotid chemoreceptor activity and ventilation in the cat.

The steady-state stimulus-response relations between arterial P02 and PCO2 and the mean activity of carotid chemoreceptors (single and multi-fiber) and ventilation were simultaneously recorded in 48 anesthetized cats. The carotid chemoreceptor activity varied linearly with the increase of arterial PCO2, below and above the normal value, at any given level of arterial P02. A decrease in arterial P02 increased the activity of the carotid chemoreceptors and increased its sensitivity to changes in arterial PCO2, showing multiplicative stimulus interaction. The authors also found that the response in ventilation during hypoxia to changes in arterial PCO2 below the normal value was smaller than that to changes above it, unlike the response of carotid chemoreceptors. This arterial PCO2 quasi-threshold for ventilation was, therefore, not due to a corresponding threshold for the activity of the carotid chemoreceptors but to a central mechanism. Above the central PaCO2 threshold, the ventilatory response to changes in PaCO2 and Pa02 resembled that of chemoreceptors but the ventilation dependent on hypoxia was greater than that could be directly accounted for by the activity of peripheral chemorecepors. A multiplicative interaction between the activity of peripheral chemoreceptors and central CO2 excitation appears to play a role in the regulation of ventilation.

Hypoxia and hypercapnia as respiratory stimulants and depressants.

Abstract The effect of wide variations in arterial O2 and CO2 tensions on phrenic nerve activity was evaluated in anesthetized dogs which were paralyzed so that the physical properties of the lung and chest wall could not influence respiratory neuron response. The techniques used allowed the effects of hypoxia and hypercapnia to be assessed either separately or in combination. The results showed that hypoxia enhanced the stimulating effects of hypercapnia on respiratory neuron response by (1) decreasing the arterial CO2 tension at which phasic phrenic activity begins and by (2) increasing the change in phrenic nerve activity produced by a given rise in arterial CO2 tension. However, hypoxia also augmented the depressing effect of hypercapnia by (1) decreasing the arterial CO2 tension at which peak phrenic nerve activity occurred and by (2) reducing the range of arterial CO2 tensions over which progressive hypercapnia increased phrenic nerve activity. The results suggest that the usual steady state methods of evaluating hypoxic response may be measuring opposing effects of hypoxia on ventilation; a stimulating effect of hypoxia at the peripheral chemoreceptor; and a depressing central effect of hypoxia.

Mice lacking in gp91 phox subunit of NAD(P)H oxidase showed glomus cell [Ca2+]i and respiratory responses to hypoxia

The hypothesis that NAD(P)H oxidase may serve as an oxygen sensor was tested using the mice deficient (knock-out) in gp91phox subunit of NAD(P)H oxidase enzyme complex and compared with wild-type (C57BL/6J) strain measuring the ventilatory and glomus cell intracellular calcium ([Ca(2+)](i)) responses of carotid body to hypoxia. The hypoxic ventilatory responses as well as the [Ca(2+)](i) were preserved in the NAD(P)H oxidase knock-out mice. NAD(P)H oxidase, though a major source of oxygen radical production, is not the oxygen sensor in mice carotid body.

Nitric oxide-related inhibition of carotid chemosensory nerve activity in the cat.

The hypothesis that endogenous nitric oxide may play a physiological role in the regulation of carotid chemosensory activity was tested in this study. The nitric oxide synthase (NOS) inhibitors, L-nitro-arginine-methyl ester (L-NAME, 25-200 microM) and NG-monomethyl-L-arginine acetate (L-NMMA, 50 and 100 microM) were used to study its effects on the chemosensory activity of perfused and superfused cat carotid bodies (n = 21) in vitro at 37-37 degrees C. L-NAME elicited slow excitation of the sensory activity as did L-NMMA. The peak-response was dose-dependent, and approached saturation around 200 microM. The excitation by L-NAME showed the following characteristics (mean +/- SEM): latency of response, 2.2 min +/- 0.3 min; time to peak response, 5.5 min +/- 1.0 min and the peak response increased to 407 +/- 42 imp/sec from 88 +/- 13 imp/sec. The peak response was significantly different (P < 0.05) from the baseline activity. L-arginine (50-500 microM) only briefly reversed the stimulation. Hypoxia enhanced the excitation by L-NAME. On the other hand, sodium nitroprusside (SNP, 0.5-10 microM) which supplies NO, terminated the excitatory effect of L-NAME. The results provide evidence in favor of an inhibitory role of endogenous NO in the carotid body, and exogenous application of NO confirms the inhibitory effect.

Regulation of oxygen sensing in peripheral arterial chemoreceptors

The carotid bodies are a small pair of highly vascularized and well perfused organs located at each carotid artery bifurcation, strategically situated to sense oxygen in arterial blood as it leaves the heart. Carotid body glomus cells are identified as the primary oxygen sensors, which respond to changes in blood P(O(2)) within milliseconds. Acute hypoxia causes a rapid increase in carotid sinus nerve (CSN) activity, providing afferent signals to the respiratory center in the brainstem. Glomus cells secrete numerous neurotransmitters that modulate CSN firing rates. This review will discuss major hypotheses that have emerged regarding acute oxygen sensing by glomus cells. In contrast, chronic responses to hypoxia are much slower, involving cytosolic reactions that take place over several minutes and nuclear reactions which occur over several hours. Converging concepts from different areas of research in oxygen sensing cells and tissues (including the carotid body) have been combined to describe molecular and biochemical changes that take place in the carotid body with chronic hypoxia. These include oxygen dependent proteolytic processes in the cytosol and gene transcription in the nucleus. In addition, cellular and nuclear responses to chronic hypoxia will be discussed.

Arterial PO2 and PCO2 stimulus threshold for carotid chemoreceptors and breathing

The PaO2 and PaCO2 stimulus thresholds for activity of carotid chemoreceptors and for ventilation were investigated in twenty anesthetized adult cats at sea level. Over the range studied PaCO2 threshold for carotid chemoreceptors decreased with increasing intensity of hypoxia showing stimulus interaction. Once begun, the carotid chemoreceptor activity increased gradually at a rate that was inversely related to initial PaO2. The greater the initial hypoxia the greater was the carotid chemoreceptor activity at which the first inspiration occurred, apnea was shorter and inspiratory PaCO2 threshold lower. Hypoxia per se depressed the central mechanism for the resumption of inspiration. We conclude that (1) carotid chemoreceptor PaO2-PaCO2 stimulus thresholds are largely interdependent; (2) these receptors are activated at a lower PaO2-PaCO2 stimulus strength than ventilation is; (3) an increased input from peripheral chemoreceptors initiates breathing at a lower PaCO2 indicating that central chemoreceptor threshold is lower than the PCO2 threshold for inspiration; (4) a finite total input from the receptors is needed to start ventilation.