K+ channel activation with minoxidil stimulates nasal-epithelial ion transport and blunts exaggerated hypoxic pulmonary hypertension

Increased pulmonary capillary pressure and inhibition of alveolar Na+ transport putatively contribute to the formation of pulmonary edema in alveolar hypoxia such as at high altitude. Since both events might be linked to the inhibition of K+ channels, we studied whether in vivo application of minoxidil, a stimulator of ATP-gated K channels (K+ ATP channel activator) prevents both effects. In a double- blind, placebo-controlled crossover study on 17 volunteers with no known susceptibility to high altitude pulmonary edema, we tested whether a single dose of minoxidil (5 mg) prevents pulmonary hypertension and inhibition of nasal-epithelial Na+ transport in normobaric hypoxia (12% O2, 2 h). In hypoxia, arterial SO2 was decreased to about 80%, and systolic pulmonary artery pressure (PAP) measured by Doppler echocardiography increased significantly from approximately 25 mmHg (normoxia) to approximately 38 mmHg (hypoxia; range 22 to 61 mmHg). Minoxidil decreased PAP in hypoxia in those individuals who had the highest increase in PAP in hypoxia when taking placebo. Nasal potentials decreased by about 10% in hypoxia. Although minoxidil had no effect on nasal potentials in normoxia, it increased nasal potentials significantly above normoxic control values after 2-h hypoxia. These results show that the K+ ATP activator minoxidil prevents the decrease in nasal-epithelial potential by hypoxia and seems to blunt an exaggerated increase in PAP in acute hypoxia.     

Reduced pulmonary vascular reactivity after cold exposure to acute hypoxia: a role of nitric oxide (NO)

Exposure to high altitude causes pulmonary hypertension and alterations in pulmonary vascular reactivity. Among the environmental factors, cold exposure has been suggested to be involved in the development of pulmonary hypertension. However, little information is available about pulmonary vascular reactivity after cold exposure. We examined whether cold exposure can cause changes in pulmonary vascular reactivity to acute hypoxia and the possible participation of endogenous nitric oxide. We measured mean systemic (Psa) and pulmonary artery pressures (Ppa) in conscious rats after 1-week cold exposure (3.5 +/- 1.0 degrees C). Subsequently, we investigated hypoxic pulmonary vasoconstriction (HPV) with and without endogenous NO inhibition using N(G)-nitro-L-arginine methyl ester (3 mg/kg) or 7-nitroindazole (1 mg/kg). Cold exposure for 1 week caused a small but significant increase in Ppa, but not in Psa. Neither Ppa nor Psa showed significant changes after both NO inhibitions in rats exposed to cold. However, cold exposure caused a blunted HPV and an increase in plasma nitrite-nitrate concentration compared with rats kept in a neutral environment (24.0 +/- 1.0 degrees C). In addition, NO inhibition by N(G)-nitro-L-arginine methyl ester partially restored the blunted HPV in rats exposed to cold, but not 7-nitroindazole, a selective inhibitor of neuronal NO synthase. We concluded that cold exposure alters pulmonary vascular reactivity to acute hypoxia, and augmented endothelial NO bioactivity plays a counterregulatory role in response to acute hypoxia during cold exposure in rats.     

血管钠肽对低氧性肺动脉高压和肺动脉平滑肌细胞增殖的影响

目的：研究血管钠肽（VNP）对慢性低氧性肺动脉高压（HPH）大鼠的治疗作用和肺动脉平滑肌细胞（PASMC）增殖的影响,并与C型钠尿肽（CNP）和心房钠尿肽（ANP）作比较。方法：采用整体静脉给药、离体血管灌流和PASMC培养等方法,测定肺血流动力学参数、离体肺动脉的等长张力和PASMC增殖的变化。结果：（1）VNP、CNP和ANP都能有效降低HPH大鼠的平均肺动脉压（mPAP),P＜0．05－0．01,除CNP外,VNP和ANP并能明显降低肺血管阻力（PVR）,P＜0．05－0．01,其中VNP降低mPAP和PVR的作用明显大于CNP和ANP。（2）VNP对离体肺支 浓度依赖性舒张作用,该作用不受内皮细胞的影响;但在浴槽内预先加入格列苯脲或普萘洛尔可显著降低肺动脉对VNP和CNP的最大舒张反应（Rmax),P＜0．05－0．01,而对ANP却无明显影响 。（3）VNP能明显抑制低氧介导的PASMC的增殖及DNA合成,其作用明显大于CNP和ANP。结论：VNP对HPH具有显著的治疗作用,它是一个新型、强效、非内皮依赖性的血管松弛多肽和细胞增殖负调控因子。     

热休克蛋白70与加速度应激

现代高性能战斗机产生的高G值持续性正加速度可导致脑缺血、缺氧,继而引起脑功能障碍。热休克蛋白70（heat shock protein 70,HSP70）是生物体中广泛存在的一种蛋白质,其表达与脑缺血中的应激反应有重要关系,与神经细胞的缺血性损伤密切相关,目前大多数研究认为应激时HSP70的表达对神经元有保护作用。本文综述了HSP70的生物学特性及其在脑缺血后对细胞保护作用,并阐述了HSP70的表达与＋Gz暴露强度的关系。     

L—精氨酸对慢性间断性缺氧大白鼠肺循环和体循环的影响

目的：本研究通过大鼠在慢性间断性缺氧状态下，持续给予Ｌ－精氨酸灌饲，动态观察其以大鼠肺循环和体循环的影响；方法：将大鼠随机分为三组；单纯缺氧组、缺氧给药组与正常组。用微导管插管分别各组大鼠的肺动脉与体循环的收缩压和舒张压；结果：单纯缺氧组一缺呀 的肺动脉压 高于正常     

脂多糖对复合培养的肺微血管内皮细胞和肺动脉平滑肌细胞生长周期的影响

以脂多糖（LPS）处理复合培养的大鼠肺微血管内皮细胞（LMVEC）和肺动脉平滑肌细胞（PASMC），利用流式细胞仪检测LMVEC和PASMC细胞周期的变化。结果发现，单独培养和复合培养时，LPS均能使G1期细胞减少，S G2/M期细胞增多；LPS处理16h后，复合培养组LMVEC和PASMC较单独培养组G1期细胞增多，S G2/M细胞数减少；LPS可使单独培养的LMVEC S期细胞增多。说明LPS可促进LMVEC和PASMC分裂、增殖，二者复合培养可减轻LPS引起的LMVEC和PASMC增殖作用；LMVEC和PASMC在细胞增殖方面存在着复杂的调节关系。     

Pulmonary artery pressure increases during commercial air travel in healthy passengers

BACKGROUND: It is not known whether the mild hypoxia experienced by passengers during commercial air travel triggers hypoxic pulmonary vasoconstriction and increases pulmonary artery pressure in flight. Insidious pulmonary hypertensive responses could endanger susceptible passengers who have cardiopulmonary disease or increased hypoxic pulmonary vascular sensitivity. Understanding these effects may improve pre-flight assessment of fitness-to-fly and reduce in-flight morbidity and mortality. Methods: Eight healthy volunteers were studied during a scheduled commercial airline flight from London, UK, to Denver, CO. The aircraft was a Boeing 777 and the duration of the flight was 9 h. Systolic pulmonary artery pressure (sPAP) was assessed by portable Doppler echocardiography during the flight and over the following week in Denver, where the altitude (5280 ft/1610 m) simulates a commercial airliner environment. Results: Cruising cabin altitude ranged between 5840 and 7170 ft (1780 to 2185 m), and mean arterial oxygen saturation was 95 +/- 0.6% during the flight. Mean sPAP increased significantly in flight by 6 +/- 1 mmHg to 33 +/- 1 mmHg, an increase of approximately 20%. After landing in Denver, sPAP was still 3 +/- 1 mmHg higher than baseline and remained elevated at 30 +/- 1 mmHg for a further 12 h. Conclusions: Pulmonary artery pressure increases during commercial air travel in healthy passengers, raising the possibility that hypoxic pulmonary hypertension could develop in susceptible individuals. A hypoxia altitude simulation test with simultaneous echocardiography ('HAST-echo') may be beneficial in assessing fitness to fly in vulnerable patients.     

Redistribution of pulmonary blood flow during hypoxic exercise.

Pulmonary blood flow (PBF) distribution was studied at rest and during exercise in rats acclimatized to chronic hypoxia (barometric pressure [PB] 370 Torr for 3 weeks, A rats) and non-acclimatized (NA) littermates. Both A and NA rats exercised in hypoxia (inspired O2 pressure [PIO2] approximately 70 Torr) or in normoxia (PlO2 approximately 145 Torr). PBF distribution was determined using fluorescent-labeled microspheres injected into the right atrium. The lungs were cut into 28 samples to determine relative scatter of specific PBF ([sample fluorescence intensity/sample dry weight)/(total lung fluorescence intensity/total lung dry weight]). Exercise produced redistribution of PBF both in NA and A rats, and this effect was larger in hypoxia than in normoxia, with minimal redistribution occurring during normoxic exercise in NA rats. The pattern of distribution varies considerably among individual animals. As a result of distribution, the previous high flow areas would be overperfused during hypoxic exercise in some rats. The results support the concept that hypoxic pulmonary vasoconstriction is not uniform and suggest that the combination of hypoxia and exercise may lead to overperfusion and capillary leak in some individuals.     

金纳多与茶多酚对缺氧诱导血管内皮细胞分泌内皮素的保护作用比较

目的观察缺氧对血管内皮细胞（VEC）分泌内皮素（ET）的影响及金纳多和茶多酚的保护作用。方法将VEC分为空白对照组、单纯缺氧组、缺氧＋金纳多组、缺氧＋茶多酚组。除空白对照组外,其他各组置于低压舱内进行缺氧暴露。用放免法测定各组缺氧前和缺氧后0．5、6、24h ET含量。结果（1）缺氧可促进VEC分泌ET增加（P〈0．01）。（2）同单纯缺氧组比较,在缺氧后0．5、6、24h时,金纳多组的ET含量明显低于缺氧组（P〈0．01）。（3）同单纯缺氧组比较,在缺氧后0．5h,茶多酚组的ET含量无显著性差异（P〉0．05）。在缺氧后6h和24h时,茶多酚组的ET含量明显低于缺氧组（P〈0．01）。（4）金钠多组与茶多酚组比较,金纳多组ET浓度在缺氧后0．5h较茶多酚组显著降低（P〈0．01）。在6h和24h两组比较无显著性差异（P〉0．05）。结论缺氧可显著增加VEC分泌ET;金纳多和茶多酚具有抑制缺氧促VEC分泌ET的作用。     

Effect of muscle tensing on cerebral oxygen status during sustained high +Gz

BACKGROUND: Successful monitoring of oxyhemoglobin during +Gz exposure was recently achieved using near-infrared spectroscopy (NIRS). To assess the effects of muscle tensing on sustained +Gz tolerance, we measured muscle activity and cerebral oxygen status (COS) during anti-G straining maneuvers at sustained high +Gz. METHOD: We exposed 21 male pilots wearing CSU-13/P anti-G suit to two different centrifuge profiles: 1) short-term repeated exposure (5 to 20 s) at 4, 5, 6, 5.5, or 7 Gz; 2) sustained exposure to a + 7Gz plateau for 30 s. During the Gz exposures, surface electromyographic (EMG) measurements were taken from the vastus medialis (VM) and rectus abdominis (RA) muscles. At the same time, the COS was recorded from the left forehead area using a commercial NIRS system. Mean muscular tensing for each muscle was calculated as a percentage of maximal voluntary contraction (% MVC). RESULTS: Oxyhemoglobin (O2Hb) and total hemoglobin (sum of O2Hb and deoxyhemoglobin) were decreased during both short-term and sustained +Gz exposure. RA muscle tensing was positively correlated with changes in the concentration of O2Hb during sustained + 7Gz exposure (r = 0.540, p < 0.05). RA tensing ranged from 6.2 to 36.8%MVC, and O2Hb ranged from -41.3 to -7.28 micromol x L(-1) during the exposures. No significant correlation was observed between VM tensing and O2Hb. CONCLUSION: NIRS measurements confirmed that a muscle straining maneuver increases G tolerance. Higher RA muscle tensing helps preserve brain blood volume during sustained high +Gz.     

低氧时蛋白激酶C对内皮细胞表达血管内皮生长因子的调节作用

目的探讨低氧培养大鼠肺动脉血管内皮细胞生长因子 (VEGF)表达变化与蛋白激酶C(PKC)活性的关系。方法培养大鼠肺动脉血管内皮细胞 ,观察低氧 ( 1 %O2 )培养 0、1、3、6、1 2h大鼠肺动脉血管内皮细胞PKC活性和VEGFmRNA水平变化 ;同时对培养液中VEGF蛋白水平进行测定。培养基中加入PKC抑制剂 (staurosporine)后 ,立即进行低氧培养 ,测定低氧培养不同时间点上述指标的变化。 结果低氧培养 1hPKC活性首先明显升高 (P >0 .0 5 ) ,至 3hVEGFmRNA表达明显升高 (P <0 .0 1 ) ,6h培养液中VEGF蛋白水平显著升高 (P <0 .0 1 )。而加入PKC抑制剂后 ,低氧培养的内皮细胞PKC活性与 0h比较明显下降 (P <0 .0 1 ) ,相应各时间点的VEGFmRNA及蛋白水平与 0h比较无明显变化 (P >0 .0 5 )。结论低氧能够刺激大鼠肺动脉血管内皮细胞VEGF表达升高 ,低氧时PKC活性升高是调节VEGF表达升高的重要因素之一     

Degradation of visual pursuit during sustained +3 Gz acceleration.

BACKGROUND: During positive acceleration, there is a diminished flow of blood to all regions above the heart. This is manifested by the commonly described loss of peripheral vision, greyout and blackout, which have been investigated extensively. The ability to select appropriate scanning patterns and to efficiently process visual information is one of the important determinants of scan effectiveness. This study investigates the performance of the smooth pursuit system under sustained +3 Gz before any signs of loss of vision. METHODS: Eleven subjects with no known oculomotor and vestibular anomalies participated in the study. Horizontal and vertical pursuit at amplitudes of 10 and 20 degrees were investigated in each of the subjects over 4 separate days. During each test session, pursuit targets of a predictable sine wave, oscillating at 0.2, 0.4, 0.8, 1.2 and 1.6 Hz were presented to the subjects in a random order. Horizontal and vertical eye movements were recorded using the El-Mar eye tracking system. The subjects were tested in 4 trials: 1) at 1 G before exposure to increased acceleration; 2) during sustained +3 Gz; 3) immediately after the +3 Gz exposure; and 4) 5 min after the +3 Gz exposure. RESULTS: Breakdown in smooth pursuit in response to horizontal and vertical sinusoidal stimuli during +3 Gz is indicated by a statistically significant decrease in gain and an increase in phase lag (p < 0.01). This is most obvious when the stimulus frequency is greater than 0.4 Hz. Qualitatively, the pursuit response during acceleration was ataxic and disorganized in appearance. CONCLUSION: It is postulated that degradation of pursuit gain and phase could be due to central hypoxia, and that the increase of G loading on the vestibular system could affect the neural integration of the pursuit signal in the vestibular nuclei with its direct output to the oculomotor system.     

缺氧时肺动脉内皮细胞分泌血管舒缩因子的变化

目的　探讨肺动脉内皮细胞在缺氧性肺动脉高压和肺水肿发生机制中的作用。　方法　利用离体培养的猪肺动脉内皮细胞 (PAEC)为实验模型 ,通过放免分析方法检测了缺氧过程中PAEC分泌到培养液中的收缩因子内皮素 (ET- 1)及舒张因子前列环素 (PGI2 )的变化。　结果　在缺氧过程中 ,PAEC分泌 ET- 1的水平与对照组比较均明显增加 (P<0 .0 5 ) ;PAEC分泌 PGI2 的水平在缺氧开始 (12 h)时出现一过性的增加 ,但随缺氧时间的延长 (2 4h) ,PGI2 含量明显降低 (P<0 .0 5 )。　结论　缺氧过程中 PAEC分泌功能的变化可能导致肺血管收缩 ,形成缺氧性肺动脉高压 ,以及血管完整性的破坏和通透性的增加 ,形成缺氧性肺水肿。     

Circulatory response to acute hypobaric hypoxia in conscious dogs.

Hemodynamics were studied in seven conscious dogs during acute hypobaric stress at 14,000 ft simulated altitude. Silastic catheters were chronically implanted in the pulmonary artery, left atrium, and aorta. Pulmonary and central aortic pressures, cardiac output, and pulmonary blood volume were determined under conditions of normoxia and acute hypoxia in a hypobaric chamber maintained at 446 mm Hg pressure (14,000 ft). Altitude resulted in significant increases in heart rate, cardiac output, pulmonary blood volume, and pulmonary artery pressure. Left atrial pressure and calculated systemic vascular resistance decreased during hypobaric hypoxia while stroke volume, stroke work index, arterial pressure and pulmonary vascular resistance remained unchanged. Arterial blood PO2 decreased markedly at altitude, and all animals hyperventilated with resultant systemic hypocarbic alkalosis. The combination of elevated pulmonary arterial pressure and increased pulmonary blood volume may by an etiologic factor in the development of high-altitude pulmonary edema.     

持续高+Gx对猴肺组织病理学影响的初步观察

目的 观察模拟航天器应急返回过程中持续高 Gx对猴肺组织的影响。方法 以雄性猕猴(共9只)为对象，随机分为4组，对照组在动物离心机上承受 1Gx、300s的作用；实验组根据承受Gx峰值的大小分为3个亚组，分别为 15Ga、200s， 18Gx、165s， 21Gx、140s。经离心机运转后，即刻处死，观察高 Gx对猴肺组织病理学的影响。结果 实验组肉眼可见肺表面有出血点，肺背面可见淤血，胸面可见气肿。镜检肺实质部分出现肺泡扩张、肺泡隔断裂；部分肺组织实变、肺泡塌陷、不张，肺间质充血。肺组织损伤程度与Gx值呈现出较明显的相关性。对照组未见明显的病理学改变。结论模拟航天器应急返回的高 Gx可引起猴肺组织明显损伤。     

Reflex heart rate response to variable onset +Gz

Rapid onset high sustained +Gz is a frequent requirement in air combat maneuvering. The cardiovascular response is inadequate to fully compensate for this rapid +Gz change. The rate of change in heart rate (HR) during gradual (0.1 G.s-1, GOR), rapid (1.0 G.s-1, ROR), and very high (6.0 G.s-1, VHOG) onset acceleration exposures to sustained (15 s) +7Gz, +8Gz, and +9Gz levels was measured in 81 healthy male subjects in a human centrifuge. The time (s) to reach maximum heart rate (T7) was measured as the time for the preacceleration exposure resting heart rate (RHR) to reach maximum heart rate (MHR). The change in heart rate upon reaching maximum +Gz level (delta HRA) from rest was calculated along with the change in HR from rest to the maximum heart rate achieved before maximum +Gz level was attained. During the ROR and VHOG runs, MHR was not achieved until after maximum +Gz level was attained. The change in heart rate from resting HR (immediately prior to acceleration) to the heart rate achieved at the onset of maximum +Gz level (delta HRA), decreased by 50% as the onset rate increased from GOR to ROR and VHOG. The delta HRB for very high onset rates exposures was significantly greater than that for ROR and GOR exposures. Acceleration exposure to levels of +7Gz and above (+7Gz, +8Gz and +9Gz) exhibited similar HR responses. VHOG to sustained +Gz stress levels of +7 to +9Gz for 15 s did not provide a sufficient length of time to allow maximum cardiovascular response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ionizing non-fatal whole-body irradiation inhibits Ca2+-dependent K+ channels in endothelial cells of rat coronary artery: possible contribution to depression of endothelium-dependent vascular relaxation

PURPOSE: The goal of this study was to evaluate the influence of ionizing irradiation on large conductance Ca2+-dependent potassium (BKCa) channels in rat coronary endothelial cells. MATERIALS AND METHODS: Rats were exposed to a 6 Gy dose from a cobalt60 source. Experimental design of this study comprised recording of contractile force using isolated rat aortic rings and whole-cell patch clamp techniques to study whole-cell potassium currents in isolated rat coronary artery endothelial cells. RESULTS: It has been shown that outward potassium currents in endothelial cells 9 days after irradiation appear to be suppressed or even totally abolished. The reversal potential for these currents in irradiated cells was shifted to more positive values. Paxilline (500 nM), an inhibitor of BKCa channels, had no or only a negligible effect on irradiated cells. The experiments using isolated aortic rings demonstrated that both paxilline and irradiation significantly shifted the acetylcholine dependent concentration-relaxation response curve to the right. Irradiated tissues were insensitive to paxilline. CONCLUSION: The results suggest that non-fatal, whole-body gamma-irradiation suppresses large conductance, calcium-activated potassium channels, which control the driving force for Ca2+ entry and therefore Ca2+ dependent nitric oxide (NO) synthesis in endothelial cells. This may contribute, in part, to radiation-induced endothelium dysfunction and an increase in arterial blood pressure.     

Altitude-related hypoxia: risk assessment and management for passengers on commerical aircraft

BACKGROUND: Individuals with pulmonary and cardiac disorders are particularly at risk of developing hypoxemia at altitude. Our objective is to describe the normal and maladaptive physiological responses to altitude-related hypoxia, to review existing methods and guidelines for preflight assessment of air travelers, and to provide recommendations for treatment of hypoxia at altitude. DATA SYNTHESIS: Falling partial pressure of oxygen with altitude results in a number of physiologic adaptations including hyperventilation, pulmonary vasoconstriction, altered ventilation/perfusion matching, and increased sympathetic tone. According to three guideline statements, the arterial pressure of oxygen (PaO2) should be maintained above 50 to 55 mm Hg at all altitudes. General indicators such as oxygen saturation and sea level blood gases may be useful in predicting altitude hypoxia. More specialized techniques for estimation of altitude PaO2, such as regression equations, hypoxia challenge testing, and hypobaric chamber exposure have also been examined. A regression equation using sea level PaO2 and spirometric parameters can be used to estimate PaO2 at altitude. Hypoxia challenge testing, performed by exposing subjects to lower inspired FIO2 at sea level may be more precise. Hypobaric chamber exposure, the gold standard, mimics lower barometric pressure, but is mainly used in research. CONCLUSION: Oxygen supplementation during air travel is needed for individuals with an estimated PaO2 (8000 ft) below 50 mmHg. There are a number of guidelines for the pre-flight assessment of patients with pulmonary and/or cardiac diseases. However, these data are based on small studies in patients with a limited group of diseases.     

The fetal llama versus the fetal sheep: different strategies to withstand hypoxia

The pregnant llama (Lama glama) has walked for millions of years through the thin oxygen trail of the Andean altiplano. We hypothesize that a pool of genes has been selected in the llama that express efficient mechanisms to withstand this low-oxygen milieu. The llama fetus responds to acute hypoxia with an intense peripheral vasoconstriction that is not affected by bilateral section of the carotid sinus nerves. Moreover, the increase in fetal plasma concentrations of vasoconstrictor hormones, such as catecholamines, neuropeptide Y, and vasopressin, is much greater in the llama than in the sheep fetus. Furthermore, treatment of fetal llamas with an alpha-adrenergic antagonist abolished the peripheral vasoconstriction and resulted in fetal cardiovascular collapse and death during acute hypoxia, suggesting an indispensable upregulation of alpha-adrenergic mechanisms in this high altitude species. Local endothelial factors such as nitric oxide (NO) also play a key role in the regulation of fetal adrenal blood flow and in the adrenal secretion of catecholamines and cortisol. Interestingly, in contrast to the human or sheep fetus, the llama fetus showed a small increase in brain blood flow during acute hypoxia, with no increase in oxygen extraction across the brain, and thereby a decrease in brain oxygen consumption. These results suggest that the llama fetus responds to acute hypoxia with hypometabolism. How this reduction in metabolism is produced and how the cells are preserved during this condition remain to be elucidated.