The earliest histopathological response to hypobaric hypoxia in rabbits in the rifugio torino (3370 M) on Monte Bianco

Twelve Dutch rabbits were kept on Monte Bianco at an altitude of 3370 m. Half of the animals were killed after 3 months, the remainder after 6 months, and a further six animals maintained at sea-level acted as controls. The carotid bodies of all the rabbits were processed for light and electron microscopy and examined qualitatively and quantitatively. The lungs were processed for light microscopical assessment of small pulmonary arterial vessels; the thickness of the pulmonary trunks and aortas were measured; and the hearts were dissected to obtain ratios of the ventricular weight. There was a slight increase in the right ventricular weight in the hypoxic rabbits but no change in the thickness of the pulmonary trunk compared with that of the aorta. In particular, there was no hypoxic remodelling of the pulmonary vasculature such as muscularization of pulmonary arterioles or intimal longitudinal muscie in pulmonary arteries. The earliest histopathological response to hypoxia occurred in the carotid bodies in the form of an increase in the count of the dark variant of chief cell after 3 months which returned to normal after 6 months. It is concluded that the carotid body of the rabbit responds with a change in its population of dark chief cells to a level of hypoxia which is insufficient to affect the pulmonary arterioles. Changes in the cardiopulmonary system can no longer be considered to be the earliest histopathological response to hypobaric hypoxia.     

高原低氧大鼠肺组织超微结构及其低氧诱导因子1α的表达

背景：低氧诱导因子1α可介导哺乳动物细胞适应低氧环境。 目的：观察高原低氧对大鼠肺组织超微结构的影响及其低氧诱导因子1α表达变化。 方法：将SD大鼠分别为进行高原低氧干预1,2,3和30 d,并设置对照组。4个高原低氧组由海拔5 m的西安地区途中耗时1 d带到海拔2 700 m的青海格尔木地区、途中耗时2 d带到海拔5 000 m的唐古拉地区,途中耗时3,30 d分别带到海拔4 500 m的西藏那曲地区。 结果与结论：光镜及电镜观察显示,急性高原低氧2 d组肺组织出现明显的高原肺水肿,急性高原低氧30 d组低氧诱导因子1α mRNA的表达明显增高(P < 0.01),高原肺水肿现象则明显减轻。结果证实,低氧习服后肺组织低氧诱导因子1α mRNA表达的提高有利于减轻高原肺水肿。     

A quantitative morphological study of the carotid bodies of rats living at a simulated altitude of 4300 metres.

A quantitative histological study was carried out on the carotid bodies of 10 normal rats and 10 rats living in a hypobaric chamber at a pressure of 460 mm Hg from 25 to 96 days. In the chronically hypoxic rats there was a four-fold increase in the mean combined volume of the carotid bodies. Morphometric analysis disclosed a three-fold increase in the mean volume of specialised glomic cells and a ten-fold increase in the mean volume of capillaries, although the proportion of glomic cells was actually significantly decreased. In all our hypoxic rats there was evidence of both right and left ventricular hypertrophy. However, there was no linear relation between total carotid body volume or volume of glomic cells on one hand and the right and left ventricular weight, on the other hand. Although there was no linear relation between combined total carotid body volume and duration of hypoxia, the linear relation between glomic cell volume and duration of hypoxia was significant at the 5 per cent. level. The increase in vascularity of the hypoxic carotid body may be a mechanism to increase blood flow and thus oxygen transport to a hypoxic organ with increased metabolic activity. Small quantities of an amorphous hyaline material of unknown nature were found in relation to capillaries and type I cells in all the hypoxic rats.     

In vitro recording of chemoreceptor activity in catecholamine-depleted rabbit carotid bodies

Carotid bodies, together with Hering's nerves, were excised from anesthetized rabbits 24, 48 or 72 h after single reserpine injections (5 mg kg-1, i.v. or i.p.) and were superfused in vitro. Some carotid bodies were processed for formaldehyde-induced fluorescence microscopy to assess catecholamine depletion. Twenty-four hours after reserpine treatment, most of the type I cell islets had lost their fluorescence and the number of spontaneously active chemoafferent units was dramatically reduced. Forty-eight hours after reserpine injection, both the fluorescence of type I cells had partially recovered and the number of chemoreceptor units was almost normal. A significant reduction of both the normoxic and hypoxic frequencies of discharge was demonstrated in carotid bodies examined 24 or 48 h after reserpine pretreatment. Superfusions with dopamine (1, 10, 100 microM) transiently restored the response to hypoxia. It is proposed that catecholamines contained in type I cells play a prominent role in the genesis of chemoafferent activity and in the chemoreceptor response to hypoxia.     

Effects on the rabbit carotid body of stimulation by almitrine, natural high altitude, and experimental normobaric hypoxia

Rabbits were given intraperitoneal injections of almitrine in ascending doses for 5 weeks. They were compared with a control group and with a group of rabbits which had been exposed from birth to the natural hypobaric hypoxia found at Cerro de Pasco (433 m) in the Peruvian Andes. A further group of animals was placed in an experimental normobaric chamber for either 3 or 6 months to subject them to the same degree of hypoxia as that occurring in Cerro. The carotid bodies of the rabbits in all these groups were processed for light and electron microscopy, and examined both qualitatively and quantitatively. The carotid bodies in the group given almitrine showed no changes in their size or in the population of their glomic cells when compared with controls. In contrast, the carotid bodies of Peruvian rabbits were greatly enlarged with a disproportionate increase in the population of the light variant of chief cell. Rabbits from the hypoxic chamber also had enlarged carotid bodies but those killed after 3 months showed an increase in the dark variant of chief cell, whereas after 6 months this cell was reduced in number. There was also intense cytoplasmic vacuolation. Election microscopy confirmed these changes and revealed that dark cells had larger, more pleomorphic granules than the light variant. Vacuolation of the granules in light cells was most pronounced in Peruvian rabbits, but was uncommon in animals exposed to hypoxia for 3 months. We suggest that the dark cell responds to the early stages of hypoxia but later matures into the light variant of chief cell.     

Comparative pathology of the enlarged carotid body

A histological study was made of the carotid bodies of man and various animal species from low and high altitudes. The animals studied were the alpaca, llama, cattle, guinea-pig, rabbit, dog, rat and man. As well as a qualitative microscopic study, a differential cell count was carried out to determine the percentage of the light and dark variants of chief cells and of sustentacular cells present. The investigation showed that the carotid bodies enlarge in cattle, guinea-pigs and rabbits living in the hypobaric hypoxia of high altitude to which they have to acclimatize. The carotid bodies are not enlarged in llamas and alpacas which show Darwinian adaptation to high altitude. There is no single histopathological appearance to be found with enlargement of the carotid body; on the contrary, there appears to be a characteristic histological reaction for different species. Thus, man shows hyperplasia of sustentacular cells, cattle show focal dark cell proliferation and rabbits, guinea-pigs, and dogs show striking hyperplasia and vacuolation of chief cells. In the rat, the enlargement of the carotid body is not characterized by the differential proliferation of any specific element and, as a result, it does not appear to be a good model for the human organ. In man and rat, carotid body enlargement occurs in response to systemic hypertension as well as to chronic hypoxaemia and the histological response to the 2 stimuli is the same, depending on the species. The normal rabbit carotid body is more reminiscent of that of man but, in this species, the reaction of glomic tissue differs from that of human glomic tissue.     

Long-term exposure to intermittent hypoxia results in increased hemoglobin mass,reduced plasma volume,and elevated erythropoietin plasma levels in man

While it is well established that highlanders have optimized their oxygen transport system, little is known about the acclimatization of those who move between different altitudes. The purpose of this study was to establish whether the acclimatization to long-term intermittent hypoxic exposure in members of the Chilean Army who frequently move from sea level to 3,550 m altitude is correlated with acute acclimatization or chronic adaptation to hypoxia. A group of officers was exposed intermittently to hypoxia for about 22 years (OI, officers at intermittent hypoxia) and a group of soldiers for 6 months (SI, soldiers at intermittent hypoxia). Both groups were compared to residents at altitude (RA) and to soldiers at sea level (SL). When compared to SL, we observed an 11% increase in total hemoglobin mass (tHb) as well as a corresponding increase in red cell volume (RCV), hemoglobin concentration and hematocrit in all three groups at altitude. Plasma volume (PV) and blood volume (BV) decreased at altitude but increased when OI and SI returned to sea level. Moreover, intermittent hypoxic exposure of OI and SI resulted in increased plasma erythropoietin (Epo) levels, which peaked on day 2 at high altitude followed by decreasing levels during the successive days, and reaching pre-altitude values in SI even when staying at altitude. In conclusion, with regard to tHb and RCV, the acclimatization to long-term intermittent hypoxia resembles the adaptation to chronic hypoxia, while PV and BV regulation mimicked acclimatization to acute hypoxia. Remarkably, finely controlled regulation of Epo expression still occurs after up to 22 years of weekly exposure to altitude. Electronic Publication     

Ultrastructural features of the carotid body afterin vitro experiments: Correlation with physiological results

Summary We have studied the ultrastructure and physiological properties of the rabbit carotid body superfusedin vitro. After 3 h superfusion, the ultrastructural features of the carotid body cells, nerve fibres and nerve endings are similar to those observed afterin vivo perfusion with fixative. After 5 h superfusion, the fluorescence of type I cells and sympathetic post-ganglionic nerve fibres appears normal, as demonstrated by the Falck method. After 6 h superfusion, some type I cells are characterized by a highly vacuolated cytoplasm whereas most of the nerve fibres and nerve endings still show a normal ultrastructure. Damaged cells are not more abundant in the centre of the organ than in the surface layer. Recordings from chemoafferent units demonstrate the possibility of superfusing the carotid body with an air-equilibrated medium without any noticeable excitation. Large and reproducible responses to hyperoxic and hypoxic superfusions are recorded. It is concluded that thein vitro superfused rabbit carotid body is a reliable and useful preparation for studying the mechanism of chemoreceptor excitation.     

Stimulus-specific signaling pathways in rabbit carotid body chemoreceptors

The carotid body is an arterial chemosensory organ which responds to multiple natural and pharmacological stimuli, including hypoxia and nicotine. Numerous studies have investigated the initial molecular events which activate chemosensory type I cells in the carotid body, but less attention has been focused on later steps in the transduction cascade, which mediate neurotransmitter release from type I cells and excitation of chemoreceptor afferent fibers in the carotid sinus nerve. In the present study, we examined the effects of a highly specific inhibitor of calcium/calmodulin-dependent kinase II, KN-62, and a calmodulin inhibitor, trifluoperazine, on carotid sinus nerve activity and catecholamine release evoked from rabbit carotid bodies superfused in vitro. KN-62 did not alter sinus nerve activity and catecholamine release evoked by hypoxia, but this agent significantly reduced nerve activity and neurotransmitter release evoked by 100 microM nicotine. Trifluoperazine (10 microM), likewise inhibited activity evoked by nicotine, as well as hypoxia. Basal levels of nerve activity and catecholamine release (established in superfusate equilibrated with 100% O2) were unaffected by all drug treatments. Separate biochemical experiments showed that Ca2+/calmodulin-dependent incorporation of 32P into carotid body particulate proteins is significantly reduced following incubation of intact carotid bodies in nicotine, but not following exposure to hypoxia. Our observations suggest that excitation of the carotid body by diverse stimuli may involve the activation of distinct, stimulus-specific transduction pathways. Furthermore, these data correlate with our previous findings which showed that hypoxia, on the one hand, and nicotine on the other, evoke the preferential release of either dopamine or norepinephrine, respectively, from carotid bodies incubated in vitro.     

The effect of chronic hypoxia on the number and nuclear diameter of type I cells in the carotid bodies of rats.

We measured the number and nuclear diameter of type I cells in the carotid bodies of 10 normal rats and in 10 rats living in a hypobaric chamber at a pressure of 460 mm Hg for 25 to 96 days. In normal rats, the number of type I rats, the number ranged from 15.92 to 30.77 times 10-3 with a mean of 40.79 times 10-3 which differed significantly from that in the control group. In 5 hypoxic rats the number of type I cells was less than the highest figure in the control group. The mean diameter of the nuclei of type I cells of hypoxic rats (5.5 mu) was greater than that of the controls (5.0 mu). The largest type I nuclei were seen in those rats which had been subjected to hypoxia for the shortest time.     

Enhanced chemosensitivity after intermittent hypoxic exposure does not affect exercise ventilation at sea level

The purpose of the present study was to test the hypothesis that the ventilatory response to exercise at sea level may increase after intermittent hypoxic exposure for 1 week, accompanied by an increase in hypoxic or hypercapnic ventilatory chemosensitivity. One group of eight subjects (hypoxic group) were decompressed in a chamber to 432 torr (where 1 torr=1.0 mmHg, simulating an altitude of 4,500 m) over a period of 30 min and maintained at that pressure for 1 h daily for 7 days. Oxygen uptake and pulmonary ventilation (V_E) were determined at 40%, 70%, and 100% of maximal oxygen uptake at sea level before (Pre) and after (Post) 1 week of daily exposures to hypoxia. The hypoxic ventilatory response (HVR) was determined using the isocapnic progressive hypoxic method as an index of ventilatory chemosensitivity to hypoxia, and the hypercapnic ventilatory response (HCVRSB) was measured by means of the single-breath carbon dioxide method as an index of peripheral ventilatory chemosensitivity to hypercapnia. The same parameters were measured in another group of six subjects (control group). In the hypoxic group, resting HVR increased significantly (P<0.05) after intermittent hypoxia and HCVRSB increased at Post, but the change was not statistically significant (P=0.07). In contrast, no changes in HVR and HCVRSB were found in the control group. There were no changes in either V_E or the ventilatory equivalent for oxygen during maximal and submaximal exercise at sea level throughout the experimental period in either group. These results suggest that the changes in resting hypoxic and peripheral hypercapnic chemosensitivities following short-term intermittent hypoxia have little effect on exercise ventilation at sea level. Electronic Publication     

Carotid baroreflex regulation of vascular resistance in high-altitude Andean natives with and without chronic mountain sickness

We investigated carotid baroreflex control of vascular resistance in two groups of high-altitude natives: healthy subjects (HA) and a group with chronic mountain sickness (CMS), a maladaptation condition characterized by high haematocrit values and symptoms attributable to chronic hypoxia. Eleven HA controls and 11 CMS patients underwent baroreflex testing, using the neck collar method in which the pressure distending the carotid baroreceptors was changed by applying pressures of -40 to +60 mmHg to the chamber. Responses of forearm vascular resistance were assessed from changes in the quotient of blood pressure divided by brachial artery blood velocity. Stimulus-response curves were defined at high altitude (4338 m) and within 1 day of descent to sea level. We applied a sigmoid function or third-order polynomial to the curves and determined the maximal slope (equivalent to peak gain) and the corresponding carotid pressure (equivalent to 'set point'). The results showed that the peak gains of the reflex were similar in both groups and at both locations. The 'set point' of the reflex, however, was significantly higher in the CMS patients compared to HA controls, indicating that the reflex operates over higher pressures in the patients (94.4 +/- 3.0 versus 79.6 +/- 4.1 mmHg; P < 0.01). This, however, was seen only when subjects were studied at altitude; after descent to sea level the curve reset to a lower pressure with no significant difference between HA and CMS subjects. These results indicate that carotid baroreceptor control of vascular resistance may be abnormal in CMS patients but that descent to sea level rapidly normalizes it. We speculate that this may be explained by CMS patients having greater vasoconstrictor activity at altitude owing to greater hypoxic stimulation of chemoreceptors.     

高原低氧对大鼠心肺组织超微结构的影响

背景：研究表明快速进入高原地区时,机体不可避免地会受到不同程度的损伤,以心肺损伤较显著。 目的：观察低氧习服对高原低氧大鼠心肺组织的超微结构影响。 方法：将SD大鼠分别为进行高原低氧干预1,3和30 d,并设置对照组。3个高原低氧组由海拔5 m的西安途中耗时1 d带到海拔2 700 m的青海格尔木地区、途中耗时3,30 d分别带到海拔4 500 m的西藏那曲地区,观察各时间点心肺标本的组织学变化。 结果与结论：急性高原低氧1,3 d组肺组织显微和超微结构出现明显的间质性肺水肿和肺泡性肺水肿,其心脏组织光镜下大鼠各室壁心肌细胞均可见不同程度的浊肿、空泡变性、溶解坏死及间质水肿等,电镜下可见心肌细胞线粒体肿胀,肌浆网扩张,肌原纤维溶解,细胞内外水肿等,急性高原低氧3 d上述改变右室壁较左室壁明显,而低氧习服后高原低氧30 d组间质性水肿和则肺水肿明显减轻。结果证实,高原急性缺氧可造成大鼠间质性肺水肿和肺泡型肺水肿,并引起以右心室为主的全心性损伤,经过高原低氧习服后心肺组织病变明显减轻。     

Stimulus-specific signaling pathways in rabbit carotid body chemoreceptors

The carotid body is an arterial chemosensory organ which responds to multiple natural and pharmacological stimuli, including hypoxia and nicotine. Numerous studies have investigated the initial molecular events which activate chemosensory type I cells in the carotid body, but less attention has been focused on later steps in the transduction cascade, which mediate neurotransmitter release from type I cells and excitation of chemoreceptor afferent fibers in the carotid sinus nerve. In the present study, we examined the effects of a highly specific inhibitor of calcium/calmodulin-dependent kinase II, KN-62, and a calmodulin inhibitor, trifluoperazine, on carotid sinus nerve activity and catecholamine release evoked from rabbit carotid bodies superfused in vitro. KN-62 did not alter sinus nerve activity and catecholamine release evoked by hypoxia, but this agent significantly reduced nerve activity and neurotransmitter release evoked by 100 μM nicotine. Trifluoperazine (10 μM), likewise inhibited activity evoked by nicotine, as well as hypoxia. Basal levels of nerve activity and catecholamine release (established in superfusate equilibrated with 100% O₂) were unaffected by all drug treatments. Separate biochemical experiments showed that Ca²⁺/calmodulin-dependent incorporation of ³²P into carotid body particulate proteins is significantly reduced following incubation of intact carotid bodies in nicotine, but not following exposure to hypoxia.Our observations suggest that excitation of the carotid body by diverse stimuli may involve the activation of distinct, stimulus-specific transduction pathways. Furthermore, these data correlate with our previous findings which showed that hypoxia, on the one hand, and nicotine on the other, evoke the preferential release of either dopamine or norepinephrine, respectively, from carotid bodies incubated in vitro.     

低氧和低氧游泳大鼠心肌糖原含量与右室功能的变化

目的：观察慢性低氧及低氧游泳大鼠心肌糖原含量的变化，探讨其与右心舒缩功能升降的关系。方法：采用低压舱模拟海拔5000 m连续低氧及低氧游泳大鼠模型，用比色法测定其心肌糖原含量；用右心导管法经RM-6000生理多导记录仪记录右心舒缩功能指标。结果：大鼠心肌糖原含量在低氧早期即显著下降，随低氧时间的延长，呈较明显进一步下降的趋势，而右心功能则逐渐增强；低氧游泳组大鼠右心功能明显增强，其心肌糖原含量接近平原对照水平，显著高于单纯低氧组。结论：大鼠在低氧条件下适量作功（游泳），可能有利于机体的低氧适应。     

低压缺氧延迟预适应对小鼠海马神经元的保护作用研究

目的：了解低压缺氧预处理是否能够诱导小鼠海马神经元产生延迟预适应，增强神经元耐缺氧能力。 方法： 将近交系Babl/c小鼠放入减压舱，模拟海拔7 000 m高度减压2.5 h/d，连续3 d。第3次减压毕36 h后，观察严重低压缺氧(12 000 m 4 h)、严重缺血(双侧颈总动脉阻塞18 min)、缺血合并低压缺氧 (结扎右侧颈总动脉后，低压缺氧8 000 m 4 h)对低压缺氧预处理及正常对照小鼠海马神经元的损伤情况。 结果： 7 000 m 2.5 h低压缺氧预处理对小鼠海马神经元无显著损伤，能够诱导其产生延迟预适应，显著增强海马神经元耐受严重低压缺氧、严重缺血、缺血合并低压缺氧损伤的能力。 结论: 本研究所采用的低压缺氧预处理方法能够诱导海马神经元产生延迟预适应，增强其抗缺血缺氧能力。     

Intact and sympathectomized carotid bodies of long-term hypoxic rats: a morphometric ultrastructural study

Summary The ultrastructure of the carotid body after exposure to hypoxia (10% O₂) for one, two or three weeks was investigated morphometrically. The study was performed on rats after unilateral removal of the superior cervical ganglion. The normally occurring bimodal distribution of type I cells, representing cells with small vesicle profile diameters (SVC) and large vesicle profile diameters (LVC) respectively, changed after one week of hypoxia into a unimodal population. After one or two weeks of hypoxia the diameter range of dense-cored vesicle (DCV) profiles in type I cells was not different from that of DCV profiles in control LVC. After three weeks of hypoxia the DCV vesicle size was intermediate between those of control SVC and LVC. The volume density of DCV decreased after one week but returned to initial values after two and three weeks of hypoxia. At two or three weeks of hypoxia, however, the total cell volume was increased about 1.4 times which should reflect an increase of the total content of DCV at these times of exposure to hypoxia. An increased mean area of cell profiles indicates a hypertrophy of the type I cells, but no signs of hyperplasia could be detected. The ganglionectomy did not cause any remarkable changes compared to the intact carotid body except for a higher volume density of DCV during the early periods of hypoxia.It is inferred from the study that the increased total mass of type I cell tissue during long-term hypoxia is due to a hypertrophy of the cells. Furthermore, the type I cells can increase their storage capacity for catecholamines during hypoxia by an increase in the size and number of DCV.     

Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca(2+)-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K(+) channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K(+) channel activators; NS-1619 as a Ca(2+)-sensitive K(+) channel activator; and halothane as a TASK-like background K(+) channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.     

A quantitative study of some ultrastructural features of the type I cells in the carotid bodies of rats living at a simulated altitude of 4300 metres

Summary A quantitative study was carried out on the ultrastructure of the type I cells of the carotid bodies of three normal rats and three rats living in a hypobaric chamber at an atmospheric pressure of 460 mm Hg for 27, 28 and 35 days. Point-counting methods were performed on electron micrographs of randomly selected cross-sections of type I cells. These sections always included the nucleus of the cell. The same electron micrographs were used to determine the number of mitochondrial cross-sections and electron-dense core vesicles appearing in each type 1 cell profile. The morphometric analysis disclosed that the mean cross-sectional area of the type I cells was 41.35 m³ in the untreated rats and 82.03 m³ in the rats exposed to chronic hypoxia. Assuming that this area of cross-section was in direct proportion to the volume of the cell, this result indicates an approximately three-fold increase in volume of the type I cells of the carotid bodies in hypoxaemic rats. There was no change in the volume proportion of the type I cells occupied by the mitochondria. However, as the cells had increased in volume in hypoxaemic rats, it was concluded that the number of mitocondria in each type I cell was increased. The concentration of electron-dense core vesicles was 21.9/m³ cytoplasm in the type I cells of untreated rats and 7.3/m³ in the hypoxaemic rats. The dense-core vesicles were increased in diameter in states of chronic hypoxia. Their mean diameter was 102.3 nm in normal rats and 117.0 nm in hypoxaemic rats. The enlargement of the type I cells and the increase in the number of mitochondria within each cell suggests that this depletion is more likely to be due to an increased rate of release of dense-core vesicles, than to a reduced rate of their synthesis.     

Hyperplasia of the carotid body

The histopathology of hyperplasia of the carotid bodies was studied in 6 cases of hypoxaemia and right ventricular hypertrophy secondary to pan-acinar emphysema, and in five cases of systemic hypertension with left ventricular hypertrophy. The features of the hyperplasia were the same in the two groups. There was proliferation of sustentacular (type II) cells and compression of central cores of chief (type I) cells. It is speculated that the hyperplasia of sustentacular cells is associated in some way with the prevention of retention of sodium ions and water which characterises hypoxic cor pulmonale in "blue bloaters", systemic hypertension, and ascent to high altitude with the complications of acute mountain sickness, and pulmonary and cerebral oedema.