Brain stem NO modulates ventilatory acclimatization to hypoxia in mice.

The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.

Time course of ventilatory acclimatisation to hypoxia in a model of anemic transgenic mice.

We questioned the assumption that polycythemia is essential for adaptation to chronic hypoxia. Thus, the objective of our study was to determine if anemic Epo-TAg(h) mice could survive in hypoxia despite low oxygen carrying capacity. We explored the possibility that ventilatory acclimatisation is involved in the strategy used by anemic transgenic mice to adapt to chronic hypoxia. Epo-TAg(h) and Wild Type mice were exposed during 2 weeks at a barometric pressure of 450 Torr. After 1, 5 and 14 days of exposure, ventilation at different inspired oxygen fraction was measured in both groups. Ventilation during acclimatisation to hypoxia was significantly greater in Epo-TAg(h) than in Wild Type. The difference was mainly due to a higher tidal volume that could explain a higher arterial PO2 in Epo-TAg(h) mice. Epo-Tag(h) mice did not develop right ventricle hypertrophy after 2 weeks of exposure to hypoxia while Wild Type did. Hemoglobin concentration was 60% lower in anemic mice versus Wild Type after acclimatisation. In conclusion, ventilatory acclimatisation contributed to the adaptation of Epo-Tag(h) mice in chronic hypoxia despite low arterial oxygen carrying capacity.

Characterisation of the ventilatory response to hypoxia in a model of transgenic anemic mice.

Both polycythemia and the increase in hypoxic ventilatory response (HVR) are considered as important factors of acclimatization to hypoxia. The objective of this study was to characterise the ventilation pattern at different inspired oxygen fraction in a model of chronic anemic mice. These mice have a targeted disruption in the 5' untranslated region of the Epo gene that reduces Epo expression such that the homozygous animal is severely anemic. Ventilation in normoxia in Epo-TAg(h) mice was significantly greater than in wild type, and the difference was mainly due to a higher tidal volume. HVR was higher in Epo-TAg(h) mice at every FIO2 suggesting a higher chemosensitivity. Resting oxygen consumption was maintained in anemic mice. Maximal oxygen consumption was 30% lower while hemoglobin was 60% lower in anemic mice compared to wild type. This small decrease in maximal oxygen consumption is probably due a greater cardiac output and/or a better tissue oxygen extraction and would allow these anemic mice to acclimatize to hypoxia in spite of low oxygen carrying capacity. In conclusion, Epo-TAg(h) anemic mice showed increased ventilation and hypoxic ventilatory response. However, whether these adaptations will contribute to acclimatization in chronic hypoxia remains to be determined.

Cerebrovascular responses to hypoxia and hypocapnia in high-altitude dwellers.

Cerebral blood flow is known to increase in response to hypoxia and to decrease with hypocapnia. It is not known, however, whether these responses are altered in high-altitude dwellers who are not only chronically hypoxic and hypocapnic, but also polycythaemic. Here we examined cerebral blood flow responses to hypoxia and hypocapnia, separately and together, in Andean high-altitude dwellers, including some with chronic mountain sickness (CMS), which is characterized by excessive polycythaemia. Studies were carried out at high altitude (Cerro de Pasco (CP), Peru; barometric pressure (P(B)) 450 mmHg) and repeated, following relief of the hypoxia, on the day following arrival at sea level (Lima, Peru; P(B) 755 mmHg). We compared these results with those from eight sea-level residents studied at sea level. In nine high-altitude normal subjects (HA) and nine CMS patients, we recorded middle cerebral artery mean blood flow velocity (MCAVm) using transcranial Doppler ultrasonography, and expressed responses as changes from baseline. MCAVm responses to hypoxia were determined by changing end-tidal partial pressure of oxygen (P(ET,O2)) from 100 to 50 mmHg, with end-tidal partial pressure of carbon dioxide clamped. MCAVm responses to hypocapnia were studied by voluntary hyperventilation with (P(ET,O2)) clamped at 100 and 50 mmHg. There were no significant differences between the cerebrovascular responses of the two groups to any of the interventions at either location. In both groups, the MCAVm responses to hypoxia were significantly greater at Lima than at CP (HA, 12.1 +/- 1.3 and 6.1 +/- 1.0%; CMS, 12.5 +/- 0.8 and 5.6 +/- 1.2%; P < 0.01 both groups). The responses at Lima were similar to those in the sea-level subjects (13.6 +/- 2.3%). The responses to normoxic hypocapnia in the altitude subjects were also similar at both locations and greater than those in sea-level residents. During hypoxia, both high-altitude groups showed responses to hypocapnia that were significantly smaller at Lima than at CP (HA, 2.17 +/- 0.23 and 3.29 +/- 0.34% mmHg(-1), P < 0.05; CMS, 1.87 +/- 0.16 and 3.23 +/- 0.24% mmHg(-1); P < 0.01). The similarity of the results from the two groups of altitude dwellers suggests that haematocrit is unlikely to greatly affect cerebrovascular reactivity to hypoxia and hypocapnia. The smaller vasodilatation to hypoxia and larger vasoconstriction to hypoxic hypocapnia at high altitude suggest that cerebrovascular responses may be impaired at the high altitude, i.e. a maladaptation. The changes in the responses within less than 24 h at sea level indicate that this impairment is rapidly reversible.

Cardiovascular responses to orthostatic stress in healthy altitude dwellers, and altitude residents with chronic mountain sickness.

High altitude (HA) dwellers have an exceptionally high tolerance to orthostatic stress, and this may partly be related to their high packed cell and blood volumes. However, it is not known whether their orthostatic tolerance would be changed after relief of the altitude-related hypoxia. Furthermore, orthostatic tolerance is known also to be influenced by the efficiency of the control of peripheral vascular resistance and by the effectiveness of cerebral autoregulation and these have not been reported in HA dwellers. In this study we examined plasma volume, orthostatic tolerance and peripheral vascular and cerebrovascular responses to orthostatic stress in HA dwellers, including some with chronic mountain sickness (CMS) in whom packed cell and blood volumes are particularly large. Eleven HA control subjects and 11 CMS patients underwent orthostatic stress testing, comprising head-up tilting with lower body suction, at their resident altitude (4338 m) and at sea level. Blood pressure (Portapres), heart rate (ECG), brachial and middle cerebral artery blood velocities (Doppler) were recorded during the test. Plasma volumes were found to be similar in both groups and at both locations. Packed cell and blood volumes were higher in CMS patients than controls. All subjects had very good orthostatic tolerances at both locations, compared to previously published data in lowland dwellers. In CMS patients responses of forearm vascular resistance to the orthostatic stress, at sea level, were smaller than controls (P < 0.05). Cerebral blood velocity was less in CMS than in controls (P < 0.01) and, at sea level, it decreased more than the controls in response to head-up tilting (P < 0.02). Cerebral autoregulation, assessed from the relationship between cerebral pressure and velocity, was also impaired in CMS patients compared to HA controls, when examined at sea level (P < 0.02). These results have shown that the good orthostatic tolerance seen in high altitude dwellers at altitude is also seen at sea level. There was no difference in orthostatic tolerance between CMS patients, with their exceptionally large blood volumes, and the HA controls. This may be because peripheral vascular and cerebrovascular responses (at least at sea level) are impaired in the CMS patients relative to HA controls. Thus, the advantage of the large blood volume may be offset by the smaller vascular responses.

Avian embryos in hypoxic environments.

Avian embryos at high altitude do not benefit of the maternal protection against hypoxia as in mammals. Nevertheless, avian embryos are known to hatch successfully at altitudes between 4,000 and 6,500 m. This review considers some of the processes that bring about the outstanding modifications in the pressure differences between the environment and mitochondria of avian embryos in hypoxic environments. Among species, some maintain normal levels of oxygen consumption ( VO2) have a high oxygen carrying capacity, lower the air cell-arterial pressure difference ( PAO2 - PaO2 ) with a constant pH. Other species decrease VO2, increase only slightly the oxygen carrying capacity, have a higher PAO2 - PaO2 difference than sea-level embryos and lower the PCO2 and pH. High altitude embryos, and those exposed to hypoxia have an accelerated decline of erythrocyte ATP levels during development and an earlier stimulation of 2,3-BPG synthesis. A higher Bohr effect may ensure high tissue PO2 in the presence of the high-affinity hemoglobin. Independently of the strategy used, they serve together to promote suitable rates of development and successful hatching of high altitude birds in hypoxic environments.

Orthostatic tolerance and blood volumes in Andean high altitude dwellers.

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives.

To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6 +/- 1.3% and 5.4 +/- 0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EE than in controls (83.7 +/- 0.3% versus 85.6 +/- 0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0 +/- 0.8% in EE and to 82.8 +/- 0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction in oxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for the increase in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.

High-altitude pulmonary hypertension: a pathophysiological entity to different diseases.

Pulmonary hypertension is a hallmark of high-altitude pulmonary oedema (HAPE) and of congestive right heart failure in subacute mountain sickness (SMS) and chronic mountain sickness (CMS) in the Himalayas and in the end-stage of CMS (Monge's disease) in the Andes. There are studies to suggest that transmission of excessively elevated pulmonary artery pressure and/or flow to the pulmonary capillaries leading to alveolar haemorrhage is the pathophysiological mechanism of HAPE. In the Himalayas, HAPE was successfully prevented by extending the acclimatisation period from a few days to 5 weeks, however, this did not prevent the occurrence of congestive right heart failure after several weeks of stay at 6,000 m. This leads to the concept that rapid remodelling of the small precapillary arteries prevents HAPE but not the development of right heart failure in SMS and CMS. Unresponsiveness of pulmonary hypertension to oxygen at high altitude and its complete resolution only after weeks of stay at low altitude suggest that structural rather than functional changes are its pathophysiological mechanism. Since pulmonary hypertension at high altitude is the driving force leading to high-altitude pulmonary oedema and "high-altitude right heart failure" in newcomers and residents of high altitude, the authors propose to adjust current terminology accordingly.

Effect of domperidone on ventilation and polycythemia after 5 weeks of chronic hypoxia in rats.

Chronically hypoxic humans and some mammals have attenuated ventilatory responses, which have been associated with high dopamine level in carotid bodies. Alveolar hypoventilation and blunted ventilatory response have been recognized to be at the basis of Chronic Mountain Sickness by generating arterial hypoxemia and polycythemia. To investigate whether dopamine antagonism could decrease the hemoglobin concentration by stimulating resting ventilation (VE) and/or hypoxic ventilatory response, 18 chronically hypoxic rats (5 weeks, PB=433 Torr) were studied with and without domperidone treatment (a peripheral dopamine antagonist). Acute and prolonged treatment significantly increased poikilocapnic ventilatory response to hypoxia (RVE ml/min/kg=VE at 0.1 FI(O(2))-VE at 0.21 FI(O(2))), from 506+/-36 to 697+/-48; and from 394+/-37 to 660+/-81, respectively. In addition, Domperidone treatment decreased hemoglobin concentration from 21.6+/-0.29 to 18.9+/-0.19 (P<0.01) in rats chronically exposed to hypobaric hypoxia. Our study suggests that the stimulant effect of D(2)-R blockade on ventilatory response to hypoxia seems to compensate the low hypoxic peripheral chemosensitivity after chronic exposure and the latter in turn decrease hemoglobin concentration.

Autonomic cardiovascular function in high-altitude Andean natives with chronic mountain sickness.

We evaluated autonomic cardiovascular regulation in subjects with polycythemia and chronic mountain sickness (CMS) and tested the hypothesis that an increase in arterial oxygen saturation has a beneficial effect on arterial baroreflex sensitivity in these subjects. Ten Andean natives with a Hct >65% and 10 natives with a Hct <60%, all living permanently at an altitude of 4,300 m, were included in the study. Cardiovascular autonomic regulation was evaluated by spectral analysis of hemodynamic parameters, while subjects breathed spontaneously or frequency controlled at 0.1 and 0.25 Hz, respectively. The recordings were repeated after a 1-h administration of supplemental oxygen and after frequency-controlled breathing at 6 breaths/min for 1 h, respectively. Subjects with Hct >65% showed an increased incidence of CMS compared with subjects with Hct <60%. Spontaneous baroreflex sensitivity was significantly lower in subjects with high Hct compared with the control group. The effects of supplemental oxygen or modification of the breathing pattern on autonomic function were as follows: 1) heart rate decreased significantly after both maneuvers in both groups, and 2) spontaneous baroreflex sensitivity increased significantly in subjects with high Hct and did not differ from subjects with low Hct. Temporary slow-frequency breathing may provide a beneficial effect on the autonomic cardiovascular function in high-altitude natives with CMS.

Effect of intermittent hypoxia on cardiovascular function, adrenoceptors and muscarinic receptors in Wistar rats.

The usual model of intermittent hypoxia (sleep apnoea) corresponds to repeated episodes of hypoxia from a few seconds to a few hours interspersed with episodes of normoxia. The aim of this study was to evaluate in rats the effect of two periods of intermittent exposure for 2 months to hypoxia (IHX1, 24 h in hypoxia (428 Torr), 24 h in normoxia; IHX2, 48 h in hypoxia (428 Torr), 24 h in normoxia) as a new model of hypoxia simulating intermittent exposure to high altitude experienced by Andean miners. We assessed the haematological parameters, time course of resting heart rate and systolic blood pressure. We also evaluated the expression of adrenergic and muscarinic receptors. IHX1 and IHX2 produced an increase in haematocrit, haemoglobin concentration and mean corpuscular volume as previously seen in most hypoxic models. IHX1 and IHX2 induced a similar sustained elevation of systolic blood pressure (132 +/- 2 and 135 +/- 3 mmHg, respectively, vs. the control level of 121 +/- 16 mmHg) after 10 days of exposure without change in heart rate. Right ventricular (RV) hypertrophy (225 +/- 13 and 268 +/- 15 mg g(-1), vs. 178 +/- 7 mg g(-1) and downregulation of alpha1-adrenoceptor (RV: 127 +/- 21 and 94 +/- 16 fmol mg(-1) vs. 157 +/- 8 fmol mg(-1); left ventricle (LV): 141 +/- 5 and 126 +/- 9 fmol mg(-1) vs. 152 +/- 5 fmol mg(-1)) have been found in both groups, with right ventricular hypertrophy being greater and alpha1-adrenoceptor density being lower in IHX2 than in HX1 groups. These data indicate that both parameters are related to the time of exposure to hypoxia. IHX1 and IHX2 produced the same magnitude of upregulation of muscarinic receptors (LV, 60%; RV, 40%), and no change in beta-adrenoceptors. In conclusion, exposure to intermittent hypoxia led to polycythaemia and RV hypertrophy as observed in other types of hypoxia. A specific cardiovascular response was seen, that is an increase in blood pressure without change in heart rate, which was different from the one observed in episodic and chronic hypoxia. Furthermore, this model involved specific modifications of alpha1-adrenergic and muscarinic expression.

Oxygen saturation and heart rate in healthy school children and adolescents living at high altitude.

This study was conducted to establish reference values for percent oxygen saturation of hemoglobin (SaO2, %) and heart rate (HR, bpm) in children living at high altitude (4,100 m) and to relate possible differences in the variables with ethnic origin. Healthy children from a mine-located school (Tintaya, n = 417), a nearby school (Marquiri, n = 474), and a rural Andean community (Nuñoa, n = 373) were investigated. The samples included different ethnic combinations, with the Nuñoa children having a predominant Quechua ancestry. Mean SaO2 for all ages was substantially lower in all high altitude children compared to values considered normal for sea level. Among the three samples, SaO2 was higher (91.3 +/- 2.7) and HR was lower (84.8 +/- 13.6) in Nuñoa than in Tintaya (SaO2, 89.8 +/- 2.5; HR, 91.7 +/- 14.9) and Marquiri (SaO2, 89.6 +/- 3.1; HR, 88.5 +/- 12.9) (P < 0.05). There was no sex difference and only a weak age-dependent trend for SaO2. Values considered abnormal at sea level were observed in all healthy high-altitude children. Higher SaO2 and lower HR in Nuñoa children may suggest a better degree of acclimatization to altitude.

Ventilatory and cardiovascular responses to hypoxia and exercise in Andean natives living at sea level.

This study was designed to determine in subjects born at high altitude who move to sea level (HA-SL: born at 3500 m or above; n = 25) whether their cardiorespiratory responses to hypoxia and exercise are similar to those of sea level natives (SL,n = 25). The average age (39 +/- 7.3 yr), weight (72 +/- 7.3 kg), and height (1.71 +/- 0.01 m) did not differ between the SL and HA-SL subjects. All subjects were studied at rest or during exercise (60 W on cycle ergometer) while breathing room air (F(IO2) = 0.21 and P(B) = 760) or hypoxia (F(IO2) = 0.115 and PB = 760) in the following order: (1) normoxia at rest (NX-Rs), (2) hypoxia at rest (HX-Rs, 11.5% O(2)), hypoxia at exercise (HX-Ex), and normoxia at exercise (NX-Ex). Each period lasted 5 min. In absolute values, HA-SL showed significantly higher ventilation (V(E), L/min) during exercise in both normoxia and hypoxia and higher oxygen saturation (Sa(O2), %) during hypoxia both at rest and in exercise. They also had lower end-tidal CO(2) values (P(ETCO2), torr) at rest in both normoxia and hypoxia, but a higher P(ETCO2) in hypoxic exercise. Heart rate (HR, beats/min) was lower at rest in both normoxia and hypoxia, but higher in exercise. With acute hypoxia, Sa(O2) decreased less in the HA-SL than in the SL at rest (HA-SL, 9.2 +/- 0.8; SL, 12.0 +/- 0.82) and during exercise (HA-SL, 18.3 +/- 1.1; SL, 21.2 +/- 1.2). In conclusion, this study shows that HA-SL natives have increased ventilation and heart rate during exercise once their lifelong hypoxia is relieved.

Circadian patterns in men acclimatized to intermittent hypoxia.

Six men, normally working shifts of 7 days at high altitude (HA, 3800 m, approximately 480 mm Hg barometric pressure) followed by 7 days of rest at sea level (SL), were studied during the last days of their HA and SL shifts with a 24-h constant routine protocol of sustained wakefulness and minimal activity. The amplitude of the circadian oscillations of oxygen consumption, breathing rate, thoracic skin temperature and diastolic pressure did not differ between HA and SL. At HA, the amplitude of the tympanic and calf temperature oscillations, were, respectively, lower and higher than at SL. End-tidal P(CO2) and systolic pressure had larger amplitude oscillations at HA than at SL. Hence, also in humans, as previously shown in animals, hypoxia can affect some circadian patterns, including those involved in thermoregulation. These effects of hypoxia could contribute to sleep disturbances at HA and in patients with cardiorespiratory diseases.

Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m.

Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal CO(2) (PET(CO(2)), Torr) and end-tidal O(2) (PET(O(2)), Torr), arterial oxygen saturation (Sa(O(2)), %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26--62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower PET(O(2)) (48 +/- 4 vs. 53 +/- 2 Torr, P = 0.005) and Sa(O(2)) levels (82 +/- 12 vs. 88 +/- 12%, P < 0.005) and higher PET(CO(2)) (34 +/- 2 vs. 29 +/- 3 Torr, P = 0.005) and Hb concentration (19 +/- 1 vs. 14 +/- 2 g/dl, P < 0.005). In addition, plasma progesterone was negatively correlated with PET(CO(2)) and positively correlated with PET(O(2)) and Sa(O(2)). No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle.

Differential alterations in cardiac adrenergic signaling in chronic hypoxia or norepinephrine infusion.

Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg. kg(-1). h(-1)) for 21 days. Because NE treatment resulted in left ventricular (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, alpha(1)-adrenergic receptors (AR) density increased by 35%, only in the LV. In NE, alpha(1)-AR density decreased by 43% in the RV. Both hypoxia and NE decreased beta-AR density. No difference was found in receptor apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of G(i) and G(s) proteins in cardiac membranes were assessed by incubation with pertussis toxin (PT) and cholera toxin (CT). PT had an important effect in abolishing the decrease in isoproterenol-induced stimulation of adenylate cyclase in hypoxia; however, pretreatment of the NE ventricle cells with PT failed to restore this stimulation. Although CT attenuates the basal activity of adenylate cyclase in the RV and the isoproterenol-stimulated activity in the LV, pretreatment of NE or hypoxic cardiac membranes with CT has a less clear effect on the adenylate cyclase pathway. The present study has demonstrated that 1) NE does not mimic the effects of hypoxia at the cellular level, i.e., hypoxia has specific effects on cardiac adrenergic signaling, and 2) changes in alpha- and beta-adrenergic pathways are chamber specific and may depend on the type of stimulation (hypoxia or adrenergic).

Hematological parameters in high altitude residents living at 4,355, 4,660, and 5,500 meters above sea level.

There have been a number of reports describing the hematological indicators of Andean residents living at altitudes above 4,000 m, but several confounding factors have made the published results difficult to interpret. To clear up the effect of hypoxia on hemoglobin concentration (Hb, g/dL), hematocrit (Hct, %) and red blood cell concentration (RBC, cells/microL), this publication describes and analyzes these variables in children, men, and women from three large and homogeneous populations living at 4,355 m (n = 151), 4,660 m (n = 400), and 5,500 m (n = 273) in the Southern Peruvian Andes. Hb, Hct, and RBC increase with age in men (p < 0.001), as well as in women (p < 0.001) at the three altitudes of the study. In children (boys and girls) living at 5,500, Hb increases 11% when compared with children living at 4,355 m, and in adults, Hb increases 9.6% when comparing the same altitudes. The maximum percentage increase in Hb with age was 5.6% at 5,500 m, in men and 3.2% at 4,355 m, in women. The average percentage of difference for the Hb concentration between adult men and women is 6.6% at 4,355 m, 9.8% at 4,660 m, and 11.6% at 5,500 m. The differences in Hb concentration between men and women can only be seen after puberty. Finally, Hb is higher in older than younger women, which confirms the role of menopause in the development of erythremia. The result of this analysis reinforces the notion that Hb and Hct seem to be stable and useful parameters for acclimatization only at moderate altitudes; with aging or with increasing altitude, they may become excessive and lose their efficiency to protect the venous oxygen pressure.

Heart rate variability in 1-day-old infants born at 4330 m altitude.

In fetuses and newborn infants heart rate variability changes in conditions of acute and chronic hypoxia; we therefore asked whether heart rate variability of infants born at high altitude differed from that of low-altitude infants. Short-term recordings (4-5 min) of inter-beat intervals were obtained in 19 infants in Lima (50 m altitude) and in 15 infants in Cerro de Pasco (4330 m, barometric pressure approximately 450 mmHg, inspired oxygen pressure approximately 94 mmHg) during quiet rest in warm conditions (ambient temperature, Ta, approximately 35 degrees C). In 12 infants from each group recordings were also obtained during cooling (Ta approximately 26 degrees C). Heart rate variability was evaluated from 512 consecutive inter-beat intervals, with analysis based on time-domain and frequency-domain methods. At warm Ta, heart rate variability did not differ between the two groups. During cooling, heart rate increased only in the low-altitude group. As in the warm, during cooling most parameters of heart rate variability did not differ between the two groups. The only exception was the inter-beat interval power of the high-frequency range of the spectrum (0.15-0.4 Hz), which, at least in adults, is believed to be a reflection of vagal activity, and was greater in the high-altitude group. It is concluded that gestation at high altitude, despite its blunting effects on fetal growth, does not have a major impact on heart rate variability of the newborn. Nevertheless, the possibility that differences in response to cooling may reflect some limitation in heart rate control needs to be examined further.