Critical behavior of a strongly interacting 2D electron system.

With decreasing density n(s) the thermopower S of a low-disorder two-dimensional electron system in silicon is found to exhibit a sharp increase by more than an order of magnitude tending to a divergence at a finite disorder-independent density n(t) consistent with the critical form (-T/S) is proportional to (n(s)-n(t))(x) with x=1.0±0.1 (T is the temperature). Our results provide clear evidence for an interaction-induced transition to a new phase at low density in a strongly interacting 2D electron system.

Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.

Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.

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 a3. The photo-reversible inhibition of oxygen sensing activity by CO accounts for at least 80% of the oxygen chemosensory activity of the carotid body.

Dynamics of carotid body responses in vitro in the presence of CO2-HCO3-: role of carbonic anhydrase.

The role of carbonic anhydrase (CNA) in the dynamics of carotid body (CB) function was tested by studying the effects of the membrane-permeable CNA inhibitor methazolamide on the chemosensory responses of the cat CB, perfused and superfused in vitro with cell-free and modified Tyrode solution at 36.5 +/- 0.5 degrees C in the presence of CO2-HCO3- (PO2 = 120 Torr, PCO2 = 32 Torr, pH = 7.40). The bulk of CO2 flow to the CB from the external milieu was overwhelmingly large relative to the metabolic production of CO2 in the CB. Accordingly, the relative contribution of the endogenous CO2 to the CB responses was small. The chemosensory nerve discharges were recorded from the whole desheathed carotid sinus nerve. The responses to acidic hypercapnia (PCO2 = 50-60 Torr, pH = 7.20-7.10), hypoxia (PO2 = 25 and 50 Torr), perfusate flow interruption, and bolus injections of sodium cyanide (20-40 nmol) were tested. To contrast, we also measured the effects of nicotine (2-4 nmol), which may act at sites other than those for O2 and CO2. Methazolamide (30 mg/l) in the perfusate at constant PCO2 and pH reduced the baseline activity and delayed the responses to step changes in PCO2 (and concomitantly pH) and PO2 and to cyanide but not to nicotine. The steady-state responses to these stimuli, measured as differences from control, were reduced, but not significantly. The initial overshoots seen with step changes in both high PCO2 and low PO2 were eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Cervical preganglionic sympathetic nerve activity and chemoreflexes in the cat.

The role of chemoreflexes originating from carotid body and central chemoreceptors in the regulation of cervical preganglionic sympathetic nerve (PSN) activity was studied in anesthetized and spontaneously breathing cats. PSN efferents which responded to hypoxia were selected for the study. The PSN activity, breath-by-breath inspiratory tidal volume, tracheal PO2 and PCO2, and arterial systemic blood pressure were recorded simultaneously. The responses of PSN efferents to transient changes in and steady-state levels of arterial PO2 and PCO2 and to graded bolus injections of intravenous sodium cyanide (50-100 micrograms), nicotine (50-100 micrograms), and dopamine hydrochloride (30-60 micrograms) were compared before and after bilateral section of carotid sinus nerves (CSN). CSN section raised the base-line PSN activity and practically eliminated the responses to brief pharmacological stimuli, but it did not eliminate the responses to transient changes in and steady-state levels of arterial PO2 and PCO2. However, CSN section diminished PSN responses and abolished ventilatory responses to hypoxia. Thus the PSN response to hypoxia was partly independent of peripheral chemoreflex and of respiratory drive. We conclude that carotid body chemoreflex elicits fast PSN responses and that a moderate decline in arterial PO2 causes an additional slow, direct excitation of sympathetic nervous system. The latter indicates O2 chemosensitivity of the system in the physiological range of arterial PO2. This O2-sensing property may allow sympathetic nervous system to initiate chemoreflex responses independent of the peripheral chemoreceptors.

Effects of acute hyperbaric oxygenation on respiratory control in cats.

We studied ventilatory responsiveness to hypoxia and hypercapnia in anesthetized cats before and after exposure to 5 atmospheres absolute O2 for 90-135 min. The acute hyperbaric oxygenation (HBO) was terminated at the onset of slow labored breathing. Tracheal airflow, inspiratory (TI) and expiratory (TE) times, inspiratory tidal volume (VT), end-tidal PO2 and PCO2, and arterial blood pressure were recorded simultaneously before and after HBO. Steady-state ventilation (VI at three arterial PO2 (PaO2) levels of approximately 99, 67, and 47 Torr at a maintained arterial PCO2 (PaCO2, 28 Torr) was measured for the hypoxic response. Ventilation at three steady-state PaCO2 levels of approximately 27, 36, and 46 Torr during hyperoxia (PaO2 450 Torr) gave a hypercapnic response. Both chemical stimuli significantly stimulated VT, breathing frequency, and VI before and after HBO. VT, TI, and TE at a given stimulus were significantly greater after HBO without a significant change in VT/TI. The breathing pattern, however, was abnormal after HBO, often showing inspiratory apneusis. Bilateral vagotomy diminished apneusis and further prolonged TI and TE and increased VT. Thus a part of the respiratory effects of HBO is due to pulmonary mechanoreflex changes.

Responses of ganglioglomerular nerve activity to respiratory stimuli in the cat.

We studied the responses of the ganglioglomerular nerve (GGN) efferents to brief periods of hypoxia and hypercapnia and to several levels of steady-state arterial PO2 and PCO2 and to intravascular injection of cyanide in thirteen anesthetized cats. The cats breathed spontaneously. A branch of the GGN which was cut close to the carotid body was divided into several filaments, and the activity of each filament was tested until clean and identifiable action potentials were obtained. The GGN efferent activity, breath-by-breath inspiratory volume, tracheal PO2 and PCO2 and arterial blood pressure were recorded simultaneously. We found that the GGN contained spontaneously active fibers which showed a range of responses to the respiratory stimuli. Fifty-eight percent of the filaments with dominant cardiovascular rhythm showed the least response to blood gas stimuli. Forty-two percent showed clear responses to hypoxia and hypercapnia. These responses developed slowly with the onset of the stimulus but decreased promptly with the withdrawal of the stimulus. These GGN efferents were also promptly stimulated by sodium cyanide. The steady-state response curve to hypoxia was hyperbolic and to hypercapnia it was linear. Some of these fibers showed stronger respiratory rhythms than others. The responses of these GGN efferents were associated with the respiratory responses to hypoxia and hypercapnia. For the same respiratory drive, however, the steady-state hypoxic stimulus elicited a greater GGN response than did hypercapnia.

Electrochemical detection of rapid DA release kinetics during hypoxia in perfused-superfused cat CB.

The hypothesis that hypoxic excitation is coupled to dopamine (DA) secretion was tested in perfused-superfused cat carotid bodies (CB). DA was electrochemically detected by an amperometric method (constant applied potential +150 mV) with Nafion polymer-coated recessed gold microsensors (tip diameter 3-8 microns) in 10 cat CBs. Neural discharge (ND) from the whole sinus nerve was measured simultaneously with DA changes during interruption of perfusate flow and during hypoxic perfusion (5% O2). A computer-controlled instrument using a chronoamperometric technique (+550-mV pulses) with a Nafion-coated carbon fiber microelectrode (tip diameter 35 microns) was used to detect DA changes in two CBs during similar hypoxic stimuli. Rapid DA release kinetics were measured during flow interruption with an initial rate of 1.05 +/- 0.15 (SE) microM/s within the first 10-15 s. At most measurement sites, the increase in DA preceded the rise in ND. After the initial increase, DA release slowed to 0.16 +/- 0.02 microM/s, reaching a maximum DA concentration of 20.7 +/- 2.6 microM above baseline after 90 s of flow interruption. Nicotine (10-micrograms bolus) caused a large increase in ND without a proportional increase in DA release. Spatially detailed time-resolved electrochemical measurements were able to discriminate between DA release during hypoxia and chemoexcitatory responses that do not involve DA release.

Carotid body chemosensory function in prolonged normobaric hyperoxia in the cat.

The effects of normobaric hyperoxia on carotid body chemosensory function in the cat were studied. The hypothesis was that carotid body chemosensory function would be affected by chronic exposure to 100% O2 at sea level. It was based on the assumptions that carotid body tissue is exposed to high PO2 because of its high blood flow and that its O2 chemosensing mechanism is sensitive to O2 radical-induced reactions. Twelve cats were exposed to 100% O2 for 60-67 h, and 10 control cats were maintained in room air at sea level. They were anesthetized with pentobarbital sodium (Nembutal), and chemosensory afferents from a cut carotid sinus nerve were isolated and identified. The responses of single or a few clearly identifiable chemoreceptor afferents to isocapnic hypoxia and hypercapnia during hyperoxia and to the bolus injections of cyanide, nicotine, and dopamine were studied. We found that chronic hyperoxia severely blunted or eliminated the O2-sensitive response of the carotid chemoreceptors while augmenting the hypercapnic response. The response to cyanide but not to nicotine and dopamine were attenuated. Thus the hypoxic and hypercapnic responses that normally interact were separable. The lack of the cyanide response was consistent with the lack of the hypoxic response, suggesting a possible shared mechanism of carotid chemoreceptor response. Qualitatively normal responses to dopamine and nicotine indicated that the respective receptors were relatively intact after chronic exposure to hyperoxia and that the sensory nerves themselves were not affected by the prolonged O2 exposure.

Dopamine, sensory discharge, and stimulus interaction with CO2 and O2 in cat carotid body.

It is hypothesized that carotid body chemosensory activity is coupled to neurosecretion. The purpose of this study was to examine whether there was a correspondence between carotid body tissue dopamine (DA) levels and neuronal discharge (ND) measured from the carotid sinus nerve of perfused cat carotid bodies and to characterize interaction between CO2 and O2 in these responses. ND and tissue DA were measured after changing from normoxic, normocapnic control bicarbonate buffer (PO2 >120 Torr, PCO2 25-30 Torr, pH approximately 7.4) to normoxic hypercapnia (PCO2 55-57 Torr, pH 7.1-7.2) or to hypoxic solutions (PO2 30-35 Torr) with normocapnia (PCO2 25-30 Torr, pH approximately 7.4) or hypocapnia (PCO2 10-15 Torr, pH 7.6-7.8). Similar temporal changes for ND and tissue DA were found for all of the stimuli, although there was a much different proportional relationship for normoxic hypercapnia. Both ND and DA increased above baseline values during flow interruption and normocapnic hypoxia, and both decreased below baseline values during hypoxic hypocapnia. In contrast, normoxic hypercapnia caused an initial increase in ND, from a baseline of 175 +/- 12 (SE) to a peak of 593 +/- 20 impulses/s within 4.6 +/- 0.9 s, followed by adaptation, whereas ND declined to 423 +/- 20 impulses/s after 1 min. Tissue DA initially increased from a baseline of 17.9 +/- 1.2 microM to a peak of 23.2 +/- 1.2 microM within 3.0 +/- 0.7 s, then declined to 2.6 +/- 1.0 microM. The substantial decrease in tissue DA during normoxic hypercapnia was not consistent with the parallel changes in DA with ND that were observed for hypoxic stimuli.

Chronic CO inhalation and carotid body catecholamines: testing of hypotheses.

The purpose of this study was twofold: one concerns carotid blood flow and tissue PO2 and the other the effect of chronic hypoxic hypoxia on enhanced catecholamine content. The rationale was that chronic CO inhalation would not mimic the effect of hypoxia on the carotid body if its tissue blood flow is sufficiently high to counteract the effect of CO on O2 delivery and, hence, on tissue PO2. The differential effects of CO on the carotid body and erythropoietin-producing tissue would also indicate that the effect of hypoxic hypoxia on the carotid body is the result of a direct action of a local low O2 stimulus rather than secondary to a systemic effect initiated by other O2-sensing tissues. To test these alternatives we studied the effects of chronic CO inhalation on carotid body catecholamine content and hematocrit in the rats, which were exposed to an inspired PCO of 0.4-0.5 Torr at an inspired PO2 of approximately 150 Torr for 22 days. The hematocrit of CO-exposed rats was 75 +/- 1.1% compared with 48 +/- 0.7% in controls. Dopamine and norepinephrine content of the carotid bodies (per pair) was 5.88 +/- 0.91 and 3.02 +/- 0.19 ng, respectively, in the CO-exposed rats compared with 6.20 +/- 1.0 and 3.29 +/- 0.6 ng, respectively, in the controls. Protein content of the carotid bodies (per pair) was 18.4 +/- 1.6 and 20.5 +/- 0.9 micrograms, respectively. Thus, despite a vigorous erythropoietic response, the CO-exposed rats failed to show any significant stimulation of carotid body in terms of the content of either catecholamine or protein. The results suggest that carotid body tissue PO2 is not compromised by moderate carboxyhemoglobinemia because of its high tissue blood flow and that the chronic effect of hypoxic hypoxia on carotid body is direct.

Peripheral chemoreceptors in respiratory oscillations.

The hypothesis that instability of cardiorespiratory control may depend on the response and sensitivity of carotid body chemoreceptors to arterial blood gases was studied in anesthetized cats under three different experimental conditions. 1) Following administration of the peripheral dopamine receptor blocker [domperidone (0.6-0.8 mg X kg-1, iv)], carotid chemoreceptor activity and its sensitivity to CO2 during hypoxia increased, leading to cardiorespiratory oscillations at low arterial PO2 in four of eight cats. Inhalation of 100% O2 promptly decreased chemoreceptor activity and eliminated the oscillations. Inhalation of CO2 stimulated the chemoreceptor activity and ventilation but did not eliminate the oscillations. Bilateral section of carotid sinus nerves abolished the cardiorespiratory oscillations. The implication is that the dopaminergic system in the carotid body keeps chemoreceptor responses to blood gas stimuli suppressed and hence cardiorespiratory oscillations damped. 2) Hypotension and circulatory delay induced by the partial occlusion of venous return led to cardiorespiratory oscillations at low but not at high arterial PO2. 3) A few cats developed cardiorespiratory oscillations without any particular experimental intervention. These oscillations were independent of arterial PO2 and chemoreceptor activity. Thus it is reasonable to conclude that the peripheral chemoreflex can play a critical role in developing cardiorespiratory oscillations in certain instances.

In vitro perfused-superfused cat carotid body for physiological and pharmacological studies.

An in vitro perfused carotid body preparation was developed to study its chemosensory responses to physiological and pharmacological stimuli. The carotid bifurcation with the carotid body was vascularly isolated and excised from pentobarbital sodium-anesthetized cats. The CB was perfused in a chamber by gravity (80 Torr) with modified Tyrode's solution (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-NaOH at pH 7.40) equilibrated at a given Po2 and superfused with the same medium at (Po2 of 20 Torr). The temperature was maintained at 35.5 +/- 0.5 degrees C. The frequency of chemosensory discharges (CD) was recorded from the whole carotid sinus nerve (n = 24), and the responses were tested by repeated interruptions of perfusate flow (SF), perfusion with hypoxic medium, and injections of nicotine and cyanide (0.1 nmol to 1 mumol) and hypercapnic medium. During hyperoxic perfusion, SF resulted in a sigmoidal increase in CD, reaching a maximum that was 23.6 +/- 4.4-fold greater than the basal activity. Restoration of flow returned CD promptly to basal values. After normoxic perfusion, SF led to a similar maximal activity more rapidly, but the duration was shorter. Reduction of the perfusate PO2 (Po2 from 450 Torr to 150, 30, and less than 10 Torr) caused a nonlinear increase in CD. CO2 stimuli (PCo2 38-110 Torr) resulted in a linear increase in CD. Nicotine or cyanide increased CD in a dose-dependent manner. The preparation retained its initial responsiveness for 2-3 h, making extensive experimental studies feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent effect of hypoxia on carotid body chemosensory function.

The time-dependent effects of hypoxia on the discharge rate carotid chemoreceptors were measured in anesthetized cats. Hypoxic exposure of two different durations were used: a short-term exposure (2-3 h) was used to measure the response of the same carotid chemoreceptors; and a long-term exposure (28 days at inspired PO2 of 70 Torr) to study carotid chemoreceptor properties in one group of cats relative to those of a control group. In the chronically hypoxic and control groups, determinations were made of the 1) steady-state responses to four levels of arterial PO2 (PaO2) at constant levels of arterial PCO2; 2) steady-state responses to acute hypercapnia during hyperoxia; and 3) maximal discharge rates during anoxia. We found that the acute responses of carotid chemoreceptor afferents to a given level of hypoxia (PaO2 = 30-40 Torr) did not significantly change within 2-3 h. After long-term exposure the carotid chemoreceptor responses to hypoxia significantly increased, with no significant changes in the hypercapnic response and in the maximal discharge rate during anoxia. We conclude that isocapnic hypoxia may not elicit a sufficient cellular response within 2-3 h in the cat carotid body to sensitize the O2 responsive mechanism, but hypoxia of longer duration will sensitize such a mechanism, thereby augmenting the chemosensory activity.

Effect of hypoxia on intracellular pH of glomus cells cultured from cat and rat carotid bodies.

To test the hypothesis that hypoxia may induce cellular acidification during chemotransduction in the carotid body, we compared the effects of hypoxia and of extracellular acidosis on intracellular pH (pHi) of glomus cells cultured from rat and cat carotid bodies. The cells were prepared and cultured for 2-7 days. The plated cells were loaded with a pH-sensitive fluorescent probe, SNARF-1-acetoxymethyl ester, and were placed in a closed chamber and superfused. The effects of lowering PO2 and pH in the superfusion medium containing CO2-HCO3- buffer on the glomus cell pHi were measured at 37 degrees C. The pHi was measured in a single or a few isolated cells with single excitation at 540 nm and dual emission at 590 and 640 nm, after the exposure to different PO2 levels from 132 to 43, 14, and 1-2 Torr for 10-12 min in the closed chamber. The resting pHi values were 7.263 +/- 0.008 for rat and 7.175 +/- 0.004 for cat carotid body glomus cells. For a decrease of PO2 from 132 Torr to 14 Torr, the change in pHi values, on average, for cat and rat glomus cells was 0.034 lower, and with PO2 decrease to 1-2 Torr for the cat glomus cells, the change in pHi values was 0.051 lower. On the other hand, when the perfusate pH values were decreased from 7.4 to 6.9 during normoxia, the reduction of change in pHi values were 0.327 for the rat and 0.397 for the cat. Thus glomus cell pHi change due to low PO2 exposure was not significant and was not commensurate with the large increases in the chemosensory activity.

Stimulus interaction between CO2 and almitrine in the cat carotid chemoreceptors.

The hypothesis that augmentation of the carotid chemoreceptor response to hypoxia by almitrine is due in part to an increased response to CO2 was tested by using single or few fiber preparation of carotid body chemosensory fibers in 12 cats anesthetized with alpha-chloralose. To differentiate between the plausible mechanisms of effects, we also tested the responsiveness of the afferents to cyanide and nicotine before and after almitrine. After a saturation dose of almitrine (1 mg.kg-1 followed by 0.5 mg.kg-1.h-1) the chemosensory responses to CO2 strikingly increased even during hyperoxia: the afferents showing an increased transient peak activity at the onset of hypercapnia, an augmented steady-state response to CO2 stimulus, and a decreased arterial PCO2 stimulus threshold. Thus, the effect of almitrine on carotid chemoreceptor response to hypoxia could be explained, at least in part, by its multiplicative stimulus interaction with CO2. After almitrine, the chemoreceptor response to cyanide, which is dependent on arterial PO2, was not particularly augmented relative to those of nicotine. Accordingly, the O2-sensing mechanism does not appear to be the primary site of almitrine effect. The results also indicate that the site of CO2 chemoreception resides downstream from those of hypoxia.

Adaptation to hypercapnia vs. intracellular pH in cat carotid body: responses in vitro.

The hypotheses that the chemosensory discharge rate parallels the intracellular pH (pHi) during hypercapnia and that the initial change in pHi (delta pHi) is always more than the stead-state delta pHi were studied by using cat carotid bodies in vitro at 36.5 degrees C in the absence and presence of methazolamide (30-100 mg/l). Incremental acidic hypercapnia was followed by an incremental initial peak response and a greater adaptation. A given acidic hypercapnia elicited a rapid initial response followed by a slower adaptation; isohydric hypercapnia produced an equally rapid initial response but of smaller magnitude that returned to near-baseline level; alkaline hypercapnia induced a similar rapid initial response but one of still smaller magnitude that decreased rapidly to below the baseline. Methazolamide eliminated the initial overshoot, which also suggested involvement of the initial rapid pHi in the overshoot. These results show that the initial delta pHi is always greater than the steady-state delta pHi and during hypercapnia. Also, the steady-state chemoreceptor activity varied linearly with the extracellular pH, indicating a linear relationship between extracellular pH and pHi.

Cobalt stimulates carotid body chemoreceptors.

Because cobalt administration is known to elicit erythropoietin response, it is a reasonable hypothesis that cobalt would also stimulate the O2-sensing process in the peripheral chemoreceptors. We tested this hypothesis by measuring the effects of cobalt chloride on carotid chemosensory fibers in pentobarbital-anesthetized cats that were paralyzed and artificially ventilated. Responses of carotid chemoreceptor afferents to graded doses of cobalt given by intra-arterial injections (0.08-2.10 mumols) were measured at constant blood gases. Responses of the same chemoreceptor afferents to hypoxia, before and after a saturation dose of cobalt, were measured. In two experiments carotid body tissue PO2 was also simultaneously measured. The chemosensory fibers showed prolonged excitation after a brief period of inhibition subsequent to cobalt administration. The stimulatory effect showed a dose-dependent saturation response. Cobalt augmented rather than blocked carotid chemoreceptor response to hypoxia. The effect of cobalt was not mediated by tissue PO2. These results are consistent with the hypothesis that cobalt stimulates the O2-sensing mechanism, although a direct effect of cobalt on the excitability of the chemosensory terminal remains a possibility.

Adaptive response of carotid body chemoreceptors to CO2.

Carotid body chemoreceptor responses to sudden changes in pETCO2 (end-tidal tracheal CO2 partial pressure) and paCO2 (arterial CO2 partial pressure) from one stable state to another at a constant level of PETO2 (end-tidal tracheal O2 partial pressure) and paO2 (arterial O2 partial pressure) were studied in 18 anesthetized cats. Chemoreceptor activity was recorded from single or pauci-fiber filaments of a cut sinus nerve. During a hypercapnic stimulus by CO2 inhalation the discharge rate rapidly increased to a peak and then adapted to a lower level in 20-30 s showing an overshoot in the response. Likewise, withdrawal of the hypercapnic stimulus was followed by an undershoot in chemoreceptor activity. Hypoxia decreased the latency of the response and increased the overshoot and stable state responses to hypercapnia. The responses to step paCO2 increases by blood perfusion were qualitatively similar but the latency and time to peak amplitude were shorter and the peak amplitude was larger at any given perfusate pO2. The stable state responses to a given paCO2 achieved by CO2 inhalation or by blood perfusion were similar. The transient overshoot and undershoot in the activity produced by the increase and decrease in paCO2 were blocked by acetazolamide, a carbonic anhydrase inhibitor. The results are best explained by postulating that in the carotid body tissue, H+ is generated from CO2 in one compartment in the presence of carbonic anhydrase and is transported to another containing the receptor site in a pO2 dependent way--a high pO2 attenuating and a low pO2 augmenting it.

K+-current modulated by PO2 in type I cells in rat carotid body is not a chemosensor.

According to the membrane channel hypothesis of carotid body O2 chemoreception, hypoxia suppresses K+ currents leading to cell depolarization, [Ca2+]i rise, neurosecretion, increased neural discharge from the carotid body. We show here that tetraethylammonium (TEA) plus 4-aminopyridine (4-AP) which suppressed the Ca2+ sensitive and other K+ currents in rat carotid body type I cells, with and without low [Ca2+]o plus high [Mg2+]o, did not essentially influence low PO2 effects on [Ca2+]i and chemosensory discharge. Thus, hypoxia may suppress the K+ currents in glomus cells but K+ current suppression of itself does not lead to chemosensory excitation. Therefore, the hypothesis that K+-O2 current is linked to events in chemoreception is not substantiated. K+-O2 current is an epiphemenon which is not directly linked with O2 chemoreception.