We assessed ventilatory patterns and ventilatory responses to hypoxia (HVR) in high-altitude (HA) plateau pikas, repetitively exposed to hypoxic burrows, and control rats. We evaluated the role of neuronal nitric oxide synthase (nNOS) and dopamine by using S-methyl-l-thiocitrulline (SMTC) inhibitor and haloperidol antagonist, respectively. Ventilation (V̇i) was measured using a whole body plethysmograph in conscious pikas (n = 9) and low-altitude (LA) rats (n = 7) at different PiO2 (56, 80, 111, 150, and 186 mmHg) and in HA acclimatized rats (n = 9, 8 days at 4,600 m) at two different PiO2 (56 and 80 mmHg). The effects of NaCl, SMTC, and haloperidol on ventilatory patterns were assessed in pikas at PiO2 = 56 and 80 mmHg. We observed a main species effect with larger V̇i, tidal volume (VT), inspiratory time/total time (Ti/Ttot), and a lower expiratory time in pikas than in LA rats. Pikas had also a larger VT and lower respiratory frequency compared with HA rats in hypoxia. HVR of pikas and rats were not statistically different. In pikas, SMTC induced a significant increase in V̇i and VT for a PiO2 of 56 mmHg, but had no effect for a PiO2 of 80 mmHg, i.e., the living altitude of pikas. In pikas, haloperidol injection had no effect on any ventilatory parameter. Long-term ventilatory adaptation in pikas is mainly due to an improvement in respiratory pattern (VT and Ti/Ttot) with no significant improvement in HVR. The sensitivity to severe acute hypoxia in pikas seems to be regulated by a peripheral nNOS mechanism.
- control of breathing
long-term exposure of humans and animals to high altitude (HA) induces adaptative cardiopulmonary changes to maintain tissue homeostasis under hypoxic conditions. These changes occur along the four steps of oxygen transport from ambient air to the mitochondria: ventilation (V̇i), pulmonary diffusion, circulation, and tissue diffusion (50). However, evolutionary changes in the ventilatory control of HA-adapted species are not actually known. The plateau pika (Ochotona curzoniae) is a small lagomorph living in remote mountain areas at very HA (≈5,000 m). Pika fossil samples found on the north edge of the Qinghai-Tibetan plateau are ∼37 million years old, and this animal is considered to be fully adapted to HA. Therefore, the pika is a very suitable animal model for the study of adaptation mechanisms to a hypoxic environment. Previous studies about pikas have explored the effects of hypoxia on the liver (8), neuroendocrine system (12), pulmonary circulation (14), heart (45), or biological and genetic adaptations (30, 31). However, nothing is known about the hypoxic ventilatory response (HVR) and the long-term ventilatory adaptation to hypoxia (VAH) in this animal, i.e., changes in V̇i compared with sea level animals. It has been shown that pikas have a lower hemoglobin concentration than rats, whereas they are able to maintain a relatively high PaO2 at their living altitude (14). The two steps of oxygen transport relative to V̇i and pulmonary diffusion could be implied in this later adaptation. Therefore, we hypothesize that pikas have developed long-term ventilatory adaptation and have optimized their ventilatory pattern for life at HA (41). Moreover, pikas are burrowing mammals and it has been proposed that the mean FiO2 in the burrows of mammals could decrease between 15% to < 10% (26, 29, 56). These specific environmental conditions could have increased the pikas ventilatory adaptations to severe hypoxia.
Recently, some studies have assessed the role of neuronal nitric oxide synthase (nNOS) in the ventilatory response and acclimatization to hypoxia. Gozal et al. (16) have shown that S-methyl-l-thiocitrulline (SMTC), a selective nNOS inhibitor, reduces the late HVR (30 min) in nonacclimatized rats by a decrease in breathing frequency (fR) and tidal volume (VT). More recently, El Hasnaoui-Saadani et al. (13) observed an increase in V̇i after acclimatization in mice that was reduced after SMTC treatment, mainly through a decrease in VT. However, SMTC had no effect on acute HVR in the later study. These results suggest that nNOS could play an important role in HVR and/or VAH.
The role of dopamine in the modulation of ventilatory response to hypoxia is still discussed (3, 21, 37). The injection of haloperidol, an antagonist of D1 and D2 receptors, directly into the respiratory centers has no effect on HVR in conscious rats (3). However, some authors proposed that dopamine could modify the ventilatory drive to hypoxia. Normal animals exposed to acute hypoxia showed a decrease in the ventilatory drive after the injection of haloperidol that acts both on peripheral chemoreceptors and the central nervous system (21, 22, 37). However, a specific peripheral blockade of dopamine receptors by domperidone increased ventilatory drive from carotid bodies in hypoxia (21). Knockout mice with a deficient dopamine D2 receptor exposed to chronic hypoxia also showed a reduced carotid body sinus nerve activity probably counteracted by changes in other neurotransmitter systems, in peripheral chemoreceptors, and/or in the brainstem, allowing to them maintain HVR (44). More recently, a decrease in V̇i was found after haloperidol injection into hamsters during and following intermittent hypoxia (48).
Therefore, we evaluated the effects of hypoxia on V̇i in conscious pikas intermittently exposed to hypoxic burrows and control low-altitude (LA)- and HA-acclimatized rats. Then, assuming that nNOS and dopamine may play an important role in HVR and VAH, we hypothesized that SMTC (nNOS inhibitor) and haloperidol (dopamine antagonist) would decrease the V̇i of pikas at their living altitude and during a hypoxic challenge.
MATERIALS AND METHODS
Three experiments were done. In experiment A we assessed V̇i and HVR in pikas and LA rats at five different PiO2 (56 mmHg, 6,834 m; 80 mmHg, 4,611 m; 111 mmHg, 2,262 m; 149 mmHg, 0 m; 186 mmHg hyperoxia). This experiment was carried out in Xining (2,262 m, PiO2 = 111 mmHg, Qinghai Province, People's Republic of China). In experiment B we assessed the normal ventilatory response to hypoxia in pikas and HA rats acclimatized to the altitude of 4,611 m during 8 days. In experiment C we tested the effect of SMTC and haloperidol in pikas at two different PiO2 (56 and 80 mmHg). Experiments B and C were completed in the Hoh-Xil Station Laboratory (altitude, 4,611 m; Kekexili Reserve, Qinghai Province, People's Republic of China).
Wild pikas, weighing 100–150 g, were captured at an altitude between 4,600 and 4,750 m by traps in the Kekexili reserve (Hoh-Xil station) on the Tibetan Plateau, Tibet, People's Republic of China. The studies were conducted during the 7 days following the capture. The transfer from the Kekexili reserve to Xining was done by car and took one and a half days. During the travel the animals had food and water available ad libitum with few animals by cage. The male Wistar rats used for the experiments, weighing 150–180 g, were born and raised during 2 mo at Xining, Qinghai, People's Republic of China and, therefore, were moderately acclimatized to altitude. Kekexili reserve and Qinghai University authorities have given their agreement for all procedures conducted in animals. All the experiments were carried out following the Guiding Principles in the Care and Use of Animals (23).
V̇i was measured in conscious animals via a whole body, double-chamber plethysmograph. The system consists of two 1-liter high-density polyethylene, rigid and transparent, experimental chambers. Differential pressures between the experimental and reference chamber was measured with a differential pressure transducer (model TSD 160A; Biopac Systems, Goleta, CA). The rigid tube connections between plethysmographs and pressure transducer were 12.5-cm long. The pressure signal was sent to a demodulator (model DA100c; Biopac Systems), and data were recorded by a Biopac System model MP150. The pressure transducer was calibrated before each experiment with a manual manometer. Moreover, calibration pulses (0.2 ml) were generated by a gas-tight syringe and injection of air pulses into the plethysmograph at a rate similar to the animal's inspiratory duration to assess volume-pressure changes relationship. Barometric pressure was measured routinely before experiments, and temperature inside the chamber was kept stable and continuously monitored with a digital thermometer (Thermo Frigo OTAX). Relative humidity was monitored with a digital hygrometer. Rectal temperature was assessed before and after V̇i measurement using an electronic thermometer. On inspiration, the air entering the lungs is warmed and humidified, conducing an increase in volume, which, in turn, causes a rise in pressure. Therefore, breathing is measured from the change in pressure associated with the change in volume resulting from the warming and humidification of air during inspiration (10).
Each animal was placed in the chamber and allowed at least 30 min for familiarization before the assessment of V̇i. Baseline measurements were made when the animal was absolutely quiet but awake. Each data file was analyzed breath-by-breath throughout all baseline and experimental periods and was stored for offline analysis to determine fR (breaths/min), VT (ml/kg), inspiratory time (Ti), and the total time of the respiratory cycle (Ttot). VT calculations were based on the equation described by Bartlett and Tenney (2). Minute V̇i (ml·min−1·kg−1) was calculated as the product of fR and VT. Expiratory time (Te) was calculated by subtracting Ti from Ttot. The Ti-to-Ttot ratio, a measure of respiratory timing, was calculated. An index of inspiratory drive was also determined by calculating the VT-to-Ti ratio (35). The HVR was assessed in each animal by the changes in V̇i from high to low PiO2 (ΔV̇i).
V̇i measurements were done in Xining (PiO2 = 111.1 mmHg, 2,262 m) as described above. LA rats (n = 7, body wt = 161 ± 7 g) and pikas (n = 9, body wt = 141 ± 7 g, P < 0.05) were exposed to five different PiO2 (5 min each) and in the following order (in mmHg): 186, 150, 111, 80, and 56. O2 and N2 were mixed manually to create the desired gas mixtures. Animals were weighed and placed into the plethysmograph for the familiarization period. During this period, the plethysmograph was ventilated with 21% O2-0.04% CO2. O2 and CO2 levels within the plethysmograph were monitored using O2 and CO2 analyzers (models O2 100 c and CO2 100 c, respectively; Biopac Systems).
Measurements were performed in pikas (n = 7, body wt = 170 ± 5 g) and HA acclimatized rats (n = 9, body wt = 188 ± 7 g). Ventilatory patterns were recorded during 5 min in ambient conditions (PiO2 = 80 mmHg) and during acute hypoxic exposure (PiO2 = 56 mmHg) with the same material and according to the same general protocol previously described.
Pikas received an intraperitoneal injection of 1) NaCl vehicle, n = 6, body wt = 170 ± 7 g; 2) SMTC (acetate salt; Sigma; 10 mg/kg; 1.5 mg/ml of sterile 0.9% NaCl) , n = 6, body wt = 170 ± 7 g; 3) haloperidol (Sigma; 1 mg/kg, 0.15 mg/ml in dimethyl sulfoxide), n = 7, body wt = 160 ± 5 g; or 4) MK-801 [dizocilpine, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine, maleate salt (Sigma) 3 mg/kg and then 1.5 mg/kg, 0.5 mg/ml of sterile 0.9% NaCl]. The same animals received NaCl and SMTC injections after one washout day. Six other animals were used for haloperidol experiments. Only three animals were tested with MK-801 because of unexploitable data. This will be discussed later. The doses were chosen on the basis of previous experiments in which the effects of drugs on V̇i were examined on rat or mice (13, 37, 39). After an additional 30 min within the plethysmograph for a maximal drug action, the pikas were exposed to the gas concentrations as for control measurements.
Data are expressed as means ± SE. The normality of distribution was assessed by the Kolmogorov-Smirnov test. The effects of species (rats and pikas) and PiO2 were evaluated using repeated-measures MANOVA with, if necessary, Greenhouse and Geisser's adjustment. The effects of SMTC and haloperidol and of PiO2 on each ventilatory parameter were assessed by two-way ANOVAs. Newman-Keuls test was used for a post hoc test. All statistical analyses were done using the Statistica software (StatSoft, Tulsa, OK). Student 's t-test was done whenever appropriate. P < 0.05 was considered as a significant difference.
Comparison between LA and HA experiments showed that LA rats have higher Ti (P < 0.005) and Te (P < 0.005) and lower V̇i (P < 0.001), fR (P < 0.005), Ti-to-Ttot ratio (P < 0.05), and VT-to-Ti ratio (P < 0.01) than HA rats at PiO2 of 56 and 80 mmHg (Fig. 1). For pikas (Fig. 2), there was no significant influence of the descent from 4,611 m to 2,262 m on the ventilatory parameters measured at PiO2 of 56 and 80 mmHg, despite a slight tendency to hypoventilation during the LA experiment (−6% at PiO2 of 80 mmHg and −11% at PiO2 of 56 mmHg).
The results for the ventilatory response of pikas in hyperoxia, normoxia, and hypoxia are reported in Table 1. We observed a main effect of species with a larger V̇i (P < 0.005), VT (P < 0.005) and Ti/Ttot (P < 0.01) and a lower Te (P < 0.05) in pikas than in LA rats (Fig. 3). Moreover, we observed a main effect of PiO2 with higher V̇i, fR, and VT/Ti and lower Te and Ti for 56 (P < 0.05) and 80 mmHg (P < 0.001) compared with higher PiO2 for both species.
An interaction effect also showed that pikas have a larger fR compared with LA rats for a PiO2 of 56 mmHg (Fig. 4). Ti was significantly greater in pikas than in LA rats for PiO2 of 111, 150, and 186 mmHg. Ti decreased in pikas at PiO2 of 56 (P < 0.005) and 80 mmHg (P < 0.05) compared with 111, 150, and 186 mmHg. The Ti-to-Ttot ratio decreased significantly in pikas at PiO2 of 80 mmHg compared with 111 (P < 0.05) and at PiO2 of 80 mmHg compared with 111 (P < 0.05) or 150 mmHg (P < 0.05). The Ti-to-Ttot ratio remained always larger in pikas than in LA rats whatever the PiO2. The ΔV̇i was large in both species but not statistically different between pikas and LA rats (Fig. 5).
When we compared V̇i for pikas tested at PiO2 of 80 mmHg and 56 mmHg to HA acclimatized rats, we observed that pikas had larger VT and lower fR (Fig. 6).
Compared to the control NaCl group, SMTC injection in pikas induced a significant increase in V̇i (P < 0.05, main effect) and VT (P < 0.05, interaction) for a PiO2 of 56 mmHg but had no effect for a PiO2 of 80 mmHg, i.e., the living altitude of pikas (Fig. 7). There was no effect of SMTC on fR, VT/Ti, and Ti/Ttot (PiO2 = 56 mmHg: 0.49 ± 0.01 vs. 0.50 ± 0.01 and PiO2 = 80 mmHg: 0.49 ± 0.01 vs. 0.49 ± 0.01, for NaCl and SMTC, respectively). PiO2 had a main effect on all ventilatory parameters except on Ti/Ttot. The ventilatory response to PiO2 of 56 mmHg was greater after SMTC than NaCl injection (Fig. 8).
The ventilatory response to PiO2 of 56 mmHg was not changed after the haloperidol injection compared with the NaCl injection (80.6 ± 32.6 vs. 77.5 ± 21.3 ml·min−1·kg−1, respectively). The haloperidol injection also had no effect on any ventilatory parameter for PiO2 of 56 and 80 mmHg (Fig. 9). PiO2 had a main effect on V̇i, VT, and fR but not on VT/Ti or Ti/Ttot (PiO2 = 56 mmHg: 0.49 ± 0.01 vs. 0.47 ± 0.01 and PiO2 = 80 mmHg: 0.49 ± 0.01 vs. 0.48 ± 0.01, NaCl and haloperidol, respectively).
The main results of this study show that plateau pikas have developed specific adaptations with changes in ventilatory pattern compared with LA or HA acclimatized animals, even if the ventilatory response to hypoxia was not statistically different between pikas and rats. These adaptations are mainly due to an increase in VT and Ti in pikas leading to a better ventilatory efficiency. Moreover, we observed that nNOS and dopamine have no influence in pikas on the ventilatory adaptations to hypoxia at their living altitude. However, nNOS could act as a brake on V̇i in pikas exposed to acute severe hypoxia.
Ventilatory Response to Hypoxia in Pika
There is no difference between the HVR assessed in mammals adapted to HA (llama, yak, alpaca, etc.) and sea level animals born at HA (1, 6, 27, 36). Lahiri (27) observed no difference in V̇i between yaks and cows exposed at 3,800 m. The same result was observed on llamas with a minimal or even absent hyperventilation in well-adapted animals (1, 6). In this study, we observed that pikas have higher V̇i than LA-acclimatized rats for the same altitude (2,662 m). This effect is highly significant (+22%), despite a possible light ventilatory deacclimatization due to descent to lower altitude for pikas (4,611 to 2,262 m) (57) and despite a probable moderate ventilatory acclimatization in rats bread in Xining at 2,262 m used as reference animals. The same increase in V̇i was observed in guinea pigs raised at HA compared with LA (59). As VAH is defined as the time-dependent increase in V̇i that occurs with chronic hypoxic exposure of several hours to months (41), we can obviously say that pikas have developed VAH. Change in V̇i was nonstatistically different between species, even if slightly higher in pikas. Pikas displayed an increase in V̇i during the hypoxic challenge of ∼50% compared with 35% in our LA rats or ∼30% in guinea pigs (5, 47). These results suggest that pikas have almost a normal-to-elevated HVR compared with other mammals.
Pikas also demonstrated a significant increase in VT and Ti compared with rats, participating qualitatively to their adaptation to hypoxia. The first modification of ventilatory pattern toward an increase in VT is physiologically interesting in the way of ventilatory adaptation. Indeed, the increase in VT induces a successive improvement of alveolar V̇i (V̇A) and alveolar O2 pressure for a lower fR. Pikas showed two-thirds larger V̇A than nonacclimatized rats and one-sixth larger V̇A than acclimatized rats, with lower fR, according to previously published tracheal dead space values (25, 38). These adjustments in ventilatory pattern decrease the energetic cost of V̇i and lead to a better ventilatory efficiency in pikas and contribute to the VAH. This result has already been reported in birds with a greater VT in Bar-headed geese (submitted to very low PiO2 during their migration and summering on Tibetan plateaus) than in greylag geese (50). It is also possible that pikas display an increase in lung compliance, diffusive gas transport, and/or alveolar dimension as it has been shown in mammals raised at HA (18, 19, 34, 58).
Another way of adaptation to hypoxia has been observed in burrowing mammals (pocket gophers) living at HA with low minute V̇i despite normal alveolar O2 and CO2 concentration, probably because of a decrease in tracheal dead space optimizing alveolar V̇i (9). Pikas living on Tibetan plateaus at up to 5,000 m are also burrowing mammals. It has already been shown that the burrow atmosphere is actually different from the outside environment with a mean FiO2 from ∼15% to < 10% (26, 29, 56). Therefore, we can argue that pikas could be exposed to very low PiO2 in their burrows because of the additive effect of HA hypoxia and special burrowing environment. For example, for a living altitude of 4,611 m and a FiO2 of ∼15%, PiO2 would be ∼60 mmHg, corresponding to an altitude of 6,000 m. These animals would have therefore developed a specific ventilatory adaptation, such as tracheal dead space reduction. This probable adaptation could induce an additional increase in V̇A in pikas leading to the higher arterial Po2 observed in severe hypoxia (5,000 m) in this animal, compared with rats (49.1 ± 3.8 vs. 39.8 ± 2.7) (14). This effect, in parallel with the decrease in 2,3-diphosphoglycerate and the consecutive decrease of P50 (Po2 at which hemoglobin is 50% saturated) observed in pikas, must lead to a rise in arterial O2 saturation and the preservation of arterial O2 content in this animal well adapted to severe altitude, despite relatively low hemoglobin concentration (14).
It is also well known that acute hypoxia elicits complex time-dependent responses including rapid augmentation of inspiratory drive (VT/Ti) and shortening of inspiratory and expiratory durations (7, 33). In this study, the inspiratory drive, Ti/Ttot, and fR were higher in pikas than in LA-acclimatized rats, but the same or lower (fR) than HA-acclimatized rats. Only VT was systematically greater in pikas than in LA- or HA-acclimatized rats. These results suggest that pikas, for the same altitude, have a better VAH than nonacclimatized animals, but also than acclimatized animals. This could be due to the optimization of the ventilatory pattern caused by a probable increase in V̇A and a tendency toward an increase in the ventilatory drive for the same altitude.
Role of nNOS
We tried to evaluate the potential role of nNOS on HVR, VAH, and/or on long-term VAH. It has been shown previously that NO is involved both in the peripheral control of breathing in the carotid bodies (4) and in the regulation centers of V̇i (13, 49). First, NO is involved in the inhibition of the carotid body response to hypoxia (42, 43) due to the activation of NMDA receptors (51). Reid and Powell (46) showed a differential role of NMDA antagonist (MK-801) before (on fR) and after acclimatization (on VT), suggesting a probable change in the role of NO on ventilatory control during the acclimatization process. We tried to inject MK-801 in pikas to assess the role of NMDA receptors on VAH. However, MK-801 induced a large alteration in the motor control of pikas that prevented us from assessing correctly V̇i in quiet animals. Second, a recent study has proposed that NMDA receptors and nNOS could modify VAH through an increase in VT (13). NO could also play a role on HVR following chronic hypoxia (49). Therefore, we hypothesized that nNOS could act on ventilatory adaptations in pikas by modulating the ventilatory response to hypoxia. SMTC, a nNOS inhibitor, has no effect on the ventilatory adaptation in pikas according to the results obtained at their living altitude (4,611 m) on V̇i, VT, fR, or other ventilatory parameters. These results suggest that nNOS is not fundamentally involved in long-term ventilatory adaptation in this mammal.
Surprisingly, we observed a significant effect of SMTC on the HVR to a PiO2 of 56 mmHg: V̇i and VT increased systematically and significantly after SMTC injection compared with control values. These results suggest that nNOS in pikas could restrain the ventilatory response to acute severe hypoxia mainly by a diminution in VT. Indeed, it is now admitted that NO reduces the activity of carotid bodies (28, 55). In the present study, we can hypothesize that the increase in nNOS activity in the carotid body of pikas during acute hypoxic exposure (PiO2 = 56 mmHg) might have blunted the afferents to the respiratory centers and have limited V̇i through a decrease in VT. After SMTC injection in the same conditions, the “desinhibition” of the carotid body induced a significant increase in V̇i. This special adaptation could be linked to the very low PiO2 in the burrow of this animal and to the necessity of limiting the energetic cost of breathing in acute hypoxia. Gozal et al. (16), reported that only nonspecific NOS blockade NG-nitro-l-arginine methyl ester (l-NAME), and not SMTC, enhanced the early ventilatory response (1 min) of wakeful rats to mild hypoxia, via an increase in fR. The difference with our results could be due to the time of measurement (5 min vs. 1 min) and to a different time course in peripheral and central actions of nNOS. Indeed, they also observed a decrease in V̇i after 30 min of exposure to mild hypoxia, both after l-NAME and SMTC. It is therefore possible that longer exposure to severe hypoxia in pikas, as they experienced in their burrows, could activate central NO production and increase V̇i.
Effect of Dopamine
Contradictory results have been obtained after systemic injection of haloperidol with an increase (20, 52) or a decrease in the hypoxic hyperventilation (32, 53). It is well known that dopamine could act on the regulation of V̇i during hypoxia both in the carotid body (23, 43) and directly in the respiratory control centers (15, 17). In the present study, we report no effect of haloperidol during normal breathing, neither at living altitude of pikas nor at a simulated PiO2 of 80 mmHg. These results suggest that dopamine is not involved in long-term VAH or HVR in pikas. Powell (40) proposed that dopamine could act to maintain a normal O2 sensitivity in chronic hypoxia, restoring the normal (baseline) level of sensitivity (54). However, our data do not support the hypothesis of a role of dopamine on O2 sensitivity in carotid bodies of pikas. As we performed systemic haloperidol injection, we could expect a change in V̇i due to an effect on the central nervous system and particularly on the respiratory centers (nucleus tractus solitarius). Previous studies reported that dopamine could increase V̇i when animals are exposed to hypoxia (21, 22, 48). In our study, haloperidol had no effect on V̇i (VT, fR, or V̇i) of pikas in hypoxia. This suggests a weak role of dopamine on acute hypoxic ventilatory regulation in the central nervous system of pikas. Likewise, it could not be excluded that dopamine increases V̇i after a longer exposure to hypoxia. Another explanation concerning the lack of effect of the systemic haloperidol injection could be an opposite effect of dopamine receptors blockade on peripheral and central regulatory centers, which could mask a specific influence of dopamine on both sites.
Perspectives and Significance
Long-term ventilatory adaptation in pikas is mainly due to an improvement in V̇i, which is the consequence of an increase in VT, without change in the ventilatory response to hypoxia. Conversely to our initial hypothesis, the sensitivity to acute hypoxia in pikas seems to be limited via a nNOS-dependant mechanism, which could improve ventilatory efficiency in limiting V̇i during severe acute hypoxia occurring in burrows on HA Tibetan plateaus. Dopamine does not seem to have a significant effect on long-term ventilatory adaptation in this animal. Further studies are needed to unravel precisely the neurotransmitters implied in the peripheral and central long-term VAH in this very interesting model of plateau pika.
This work was supported by the National Basic Research Program of China (no. 2006CB504100), the National Natural Science Foundation of China (no. 30393133) (to RL Ge), by the Agence Nationale de la Recherche (no. 08-GENOPAT-029), and by the Bureau des Relations Internationales of the Paris 13 University.
We thank the officials of the Kekexili Reserve, the guards, the cooks, and the driver for their help during the high-altitude sojourn and experiments in Hoh Xil Station.
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