Endothelial function and nitric oxide production in rats adapted to intermittent hypoxia

Adaptation to intermittent hypoxic hypoxia did not affect the endothelium-dependent relaxation of the aorta in rats, but significantly increased the relaxation of their tail artery. Following the adaptation, the NO level fell in the liver, intestine, and kidneys and remained unchanged in the spleen. Adaptation to hypoxia presumably limits NO synthesis and/or release in the vascular endothelium or enhances the capacity of this oxide to bind in a physiologically active depot. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 11, pp. 495–498, November, 1995 Presented by Yu. A. Vladimirov, Member of the Russian Academy of Medical Sciences     

Role of ATP-sensitive K<Superscript>+</Superscript>-channels in antiarrhythmic and cardioprotective action of adaptation to intermittent hypobaric hypoxia

Mature Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 30 sessions). This mode of adaptation enhanced heart tolerance to the arrhythmogenic action of 45-min coronary occlusion, but does not affect the infarction size/risk area ratio. In some series, the rats were exposed to more severe intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) followed by 20-min coronary occlusion and 3-h reperfusion one day after the last hypoxia session. In this case, adaptation reduced the infarction size/risk area ratio and enhanced cardiac tolerance to the arrhythmogenic effect of reperfusion, but had no effect on the incidence of ventricular arrhythmia during ischemia. We found that the cardioprotective and antiarrhythmic effects of adaptation to an altitude of 7000 m and the antiarrhythmic effect of 5000-m adaptation were mediated via activation of K_ATP channels. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 395–398, April, 2008     

Exhaled nitric oxide is reduced upon chronic intermittent hypoxia exposure in well-acclimatized mine workers

The aim of this study was to assess how exhaled nitric oxide (NO) levels in healthy subjects changed upon exposure to intermittent hypoxia at high altitude. Eighty-one healthy subjects with a mean age of 31.8±6.7 years, well acclimatized at altitudes of 3800-4000m above sea level, and employed by a gold-mining company were recruited for the study. Baseline, altitude-corrected partial exhaled NO levels (PE(NO)) were measured in Bishkek, Kyrgyzstan (780m). Measurements were then taken on day 1 of the ascent to the mine, which is located at an altitude of 4000m, on day 3 and finally at the end of the 2- or 3-week shifts. The mean PE(NO) level was 9.49±3.66nmHg in Bishkek and was lower in females than in males (9.76±3.58nmHg vs. 7.03±3.71nmHg). When compared to the first day at altitude, exhaled NO was reduced by 17.2% on day 3 (p=0.001) and 29.6% by the end of the shift (p<0.001). In summary, this study of well-acclimatized high-altitude miners demonstrates that despite the absence of clinical signs of desadaptation, there is an apparent reduction in exhaled NO.     

Role of central nitric oxide in behavioral thermoregulation of toads during hypoxia

Nitric oxide (NO) is thought to play a key role in the development of hypoxia-induced anapyrexia in mammals, acting on the preoptic region of the anterior hypothalamus to activate autonomic heat loss responses. Regarding behavioral thermoregulation, no data exists for NO modulation/mediation of thermoregulatory behavior changes during hypoxia. Therefore, we tested the hypothesis that NO is involved in the preferred body temperature (Tb) reduction in the hypoxic toad Chaunus schneideri (formerly Bufo paracnemis), a primarily behavioral thermoregulator. Toads equipped with a temperature probe were placed in a thermal gradient chamber, and preferred Tb was monitored continuously. We analyzed the effect of intracerebroventricular injections of the nonselective NO synthase inhibitor l-NMMA (200, 400 and 800 microg per animal) or mock cerebrospinal fluid (mCSF, vehicle) on the preferred Tb of toads. No significant difference in preferred Tb was observed after l-NMMA treatments. Another group of toads treated with 2 mg kg(-1) (400 microg per animal) of l-NMMA or mCSF was submitted to hypoxia (3% inspired O(2)) for 8 h. The vehicle group showed a reduction of preferred Tb, a response that was inhibited by l-NMMA. A 3rd group of hypoxic animals was injected with Ringer or l-NMMA (2 mg kg(-1)) into the lymph sac and both treatments induced no change in the anapyretic response to hypoxia. These results indicate that NO acting on the central nervous system has an excitatory role for the development of hypoxia-induced anapyrexia in toads.     

Role of nitric oxide in isometric contraction properties of rat diaphragm during hypoxia

Hypoxia disturbs Ca²⁺ regulation and increases the intracellular Ca²⁺ concentration ([Ca²⁺]_i), which may in turn activate the nitric oxide synthase (NOS) regulated by [Ca²⁺]_i. Since nitric oxide (NO) reduces the isometric contractility of rat diaphragm in vitro, we hypothesized that NO contributes to the impaired force generation of an hypoxic diaphragm. The effects of different concentrations of the NOS inhibitor, N^G-monomethyl-L-arginine (L-NMMA), the NO scavenger haemoglobin (150 μmol·l^–1) and the NO donor spermine NONOate (Sp-NO; 1 mmol·l^–1) were determined on isometric contractility during hypoxia [partial pressure of oxygen, PO₂, about 7 kPa (about 54 mmHg)] and hyperoxia [PO₂ about 83 kPa (about 639 mmHg)]. Hypoxia significantly reduced maximal twitch force (F _t), and submaximal tetanic force (30 Hz, F ₃₀) in all L-NMMA groups. A low concentration of L-NMMA (30 μmol·l^–1) increased F ₃₀ but a high concentration (1,000 μmol·l^–1) reduced F ₃₀ during hypoxia. The effects of L-NMMA on force generation were more pronounced during hypoxia compared to hyperoxia. Peak increases in F ₃₀ and F _t were observed at a concentration of 30 μmol·l^–1 L-NMMA during hypoxia, but with 10 μmol·l^–1 L-NMMA during hyperoxia. The same concentration of haemoglobin increased F ₃₀ and F _t less during hypoxia compared to hyperoxia. The Sp-NO reduced F _t, F ₃₀ and maximal tetanic force (F ₀) during hypoxia; these effects were abolished in the presence of haemoglobin. The Sp-NO did not alter F _t, F ₃₀ and F ₀ during hyperoxia. We conclude that NO plays a more prominent role during hypoxia and that NO contributes to the depression of force generation in the hypoxic rat diaphragm in vitro. This change may be related to an elevated NO generation within the hypoxic diaphragm. Electronic Publication     

Role of nitric oxide in the gastro-protective effect of lithium.

Background and aim: Lithium is widely used for the management of neuropsychiatric symptoms in bipolar disorders. A few studies have shown that lithium has a protective effect against gastric damage with an unknown mechanism. Some of the actions of lithium are mediated through nitric oxide (NO), which has an important role in the regulation of gastric wall blood flow as well as gastric mucosal integrity. The aim of this study was to test the hypothesis if the gastro-protective effect of lithium is mediated through NO. Methods: Male Wistar rats were pre-treated with either a non-selective NO synthase inhibitor (N(G)-nitro-l-arginine, 10mg/kg), a selective inducible NO synthase inhibitor (aminoguanidine, 100mg/kg) or saline. Lithium carbonate (10, 20, 50 and 100mg/kg) was then administered intraperitoneally 1h before the induction of gastric mucosal damage. Gastric damage was induced by either water immersion stress or ethanol gavage in rats. Results: Lithium had a significant protective effect in both stress and ethanol-induced gastric damage, but it needed in ethanol-induced gastric damage a higher dose than in the stress induced lesion. Lithium carbonate doses 20 and 50mg/kg produced plasma concentrations that were in the range of human therapeutic Li levels (0.6-1.0muM). Pre-treatment of animals with N(G)-nitro-l-arginine (20 and 40mg/kg) reduced the protective effect of lithium against ethanol-induced gastric damage, but not in stress-induced damage. Aminoguanidine administration showed no effect on the damage reduction either in control or lithium treated rats. Conclusions: The results indicate that NO might play a role in the gastro-protective effect of lithium against ethanol-induced gastric damage in rats.     

Metabolic effects of trekrezan during adaptation of rats to intermittent hypoxic hypoxia

The animals were adapted to intermittent hypoxic hypoxia in a flow pressure chamber for 3 days. Each one-day training session consisted of 4 elevations to an altitude of 6000 m for 20 min (15 m/sec, 20-min intervals between assents). Trekrezan (25 mg/kg intraperitoneally) was injected immediately after the end of daily training over 3 days. We showed that trekrezan increased the degree of adaptive metabolic changes in the brain, heart, and liver of rats during adaptation to hypoxic hypoxia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 53–56, January, 2008     

Is nitric oxide involved in the adaptation to the stress-induced damage?

The iron dinitrosyl complex (a NO donor), adaptation to stress, and their combination suppress the stress-induced ulcer formation. Nω-nitro-L-arginine, a NO synthetase inhibitor, reduce the antistress effect of adaptation. Severe stress induces a sharp decrease in the NO production in the liver and brain. After adaptation to stress, the NO production in the liver and brain does not differ significantly from control levels. However, adaptation attenuates a decrease in the NO production in the liver caused by severe stress. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 9, pp. 274–277, September, 1998     

Increased α1-adrenoceptor activity of the rat heart during adaptation to intermittent hypoxia

Research Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Research Institute of Experimental Cardiology, All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 6, pp. 570–572, June, 1991.     

Effect of adaptation to intermittent normobaric hypoxia on the ultrastructure of cardiac myocytes in pregnant rats

A comparative ultrastructural study of organelles involved in supplying cardiac myocytes with energy (nucleus, mitochondria, microbodies, and lysosomes) in pregnant rats that had been exposed to intermittent normobaric hypoxia and in rats not so exposed showed no significant differences between these two groups of animals. In both groups, glycogen granules were present in the nucleus, mitochondria, lysosomes, and microbodies (peroxisomes) of cardiac myocytes, and many of their mitochondria had a dense matrix and appeared hyperplastic. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 6, pp. 597–602, June, 1995 Presented by A. V. Smol'yannikov, Member of the Russian Academy of Medical Sciences     

Blocked production of thermal shock proteins prevents the cardioprotective effect of adaptation to exercise

The resistance of isolated rat heart to ischemia and reperfusion increases after adaptation to exercise (swimming, 30 sessions 1 h/day), which correlated with accumulation of HSP70 cytoprotector proteins in the myocardium. Quercetin blockage of HSP70 production during adaptation prevents the development of adaptation defense of the heart. It was hypothesized that the accumulation of HSP70 in the myocardium is an important mechanism of local adaptation defense of the heart. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 9, pp. 299–301, September, 1998     

Contribution of nitric oxide to adaptation of tibetan sheep to high altitude

We examined the effects of endogenous nitric oxide synthase (NOS) inhibition on pulmonary hemodynamics in awake sheep living at low and high altitudes to evaluate the role of NO in adaptation to an hypoxic environment. Unanaesthetized male sheep in three places--Matsumoto, Japan (680 m above sea level), Xing, China (2300 m) and Maxin, China (3750 m)--were prepared for measurements of pulmonary artery (Ppa) and pulmonary vascular resistance (PVR) before and after the NOS inhibition. The non-selective NOS inhibitor, Nw-nitro-l-argine (NLA, 20 mg/kg) was used. Baseline Ppa became elevated with an increase in altitude. After NLA administration, PVR significantly increased in animals of all groups. However, the increase in PVR after NLA in tibetan sheep at 3750 m was significantly higher than those in other groups. We conclude that augmented endogenous NO production may contribute to regulating the pulmonary vascular tone in tibetan sheep (3750 m) adapted to high altitude.     

Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury

During cardiac ischemia-reperfusion (IR) injury, excessive generation of reactive oxygen species (ROS) and overload of Ca(2+) at the mitochondrial level both lead to opening of the mitochondrial permeability transition (PT) pore on reperfusion. This can result in the depletion of ATP, irreversible oxidation of proteins, lipids, and DNA within the cardiomyocyte, and can trigger cell-death pathways. In contrast, mitochondria are also implicated in the cardioprotective signaling processes of ischemic preconditioning (IPC), to prevent IR-related pathology. Nitric oxide (NO*) has emerged as a potent effector molecule for a variety of cardioprotective strategies, including IPC. Whereas NO* is most noted for its activation of the "classic" soluble guanylate cyclase (sGC) signaling pathway, emerging evidence indicates that NO can directly act on mitochondria, independent of the sGC pathway, affording acute cardioprotection against IR injury. These direct effects of NO* on mitochondria are the focus of this review.     

Energy metabolism of maternal and fetal tissues during adaptation to intermittent experimental normobaric hypoxia

Energy metabolism of maternal and fetal tissues in adaptation to intermittent normobaric hypoxia was studied in experiments on 72 female Wistar rats. During pregnancy the intensity of tissue respiration in myometry was more than twice that in a nonpregnant uterus. The rate of tissue respiration in vital organs (brain) remained at a high level irrespective of exposure to the effect of a gas hypoxic mixture containing 10% oxygen, i.e. the organism of the mother and fetus provides the developing brain with an optimum amount of oxygen even in its possible deficiency. Thus, adaptation of the maternal and fetal organism to GHM-10 is attended by some shifts in energy metabolism which maintain the aerobic oxidation metabolism in the studied tissues for a long duration through more effective consumption of oxygen in its lack.     

一氧化氮在失血性休克再灌注损伤中的作用及牛磺酸的影响

目的:探讨一氧化氮(NO)在失血性休克再灌注损伤中的作用及牛磺酸的影响。方法:新西兰种兔24只随机分为3组(n=8):对照组、休克组、牛磺酸治疗组。采用失血性休克-再灌注损伤模型。连续观察休克前、休克1.5h、再灌注1h、2h、3h时血浆一氧化氮合酶(NOS)活性、一氧化氮代谢产物(NO^-₂／NO^-₃)含量、超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量、乳酸脱氢酶(LDH)活性的动态变化。结果:①休克组再灌注各时限血浆NOS活性、NO^-₂／NO^-₃含量、MDA含量、LDH活性显著高于休克前及休克1.5h;SOD活性显著低于休克前及休克1.5h。②休克组再灌注3h时心、肺组织NOS活性、NO^-₂／NO^-₃含量、MDA含量显著高于对照组;SOD活性显著低于对照组。③牛磺酸(40mg·kg^-1, iv)可减轻再灌注各时限上述指标的变化。④血浆、心肺组织中NO^-₂／NO^-₃含量与MDA含量均呈正相关。结论:NO介导了休克再灌注损伤, 大量释放的NO参与休克再灌注损伤的脂质过氧化反应, 牛磺酸的拮抗作用可能与减少NO的生成、抗脂质过氧化有关。     

Role of nitric oxide in inflammation.

A number of laboratories have sought to elucidate the role of nitric oxide (NO) in both acute and chronic inflammatory diseases. It is now well appreciated that NO can influence many aspects of the inflammatory cascade ranging from its own expression to recruitment of leucocytes to the effected tissue. With the advent of mice selectively deficient in the various isoforms of nitric oxide synthase (NOS), the role that NO may play in various disease states can now be examined in vivo. One such syndrome that has gained much attention in recent years is ischaemia and reperfusion-induced tissue injury. Ischaemia-reperfusion (I/R) injury is an important clinical consideration in situations such as transplantation, trauma, liver or bowel resection and haemorrhagic shock. A hallmark of I/R is the production of reactive oxygen species (ROS) during the reperfusion phase and it is thought that the production of ROS mediate much of the post-ischaemic tissue injury. This review will examine the current state of knowledge regarding the regulatory mechanisms by which NO can influence various aspects of the inflammatory cascade as well as its role in a model of I/R injury in vivo.     

Effect of adaptation to continuous and intermittent hypoxia on heart resistance to ischemic and reperfusion arrhythmias

The effect of adaptation to intermittent hypoxia in a pressure chamber (5.000 m daily for 6 hours for 30 days) on arrhythmias occurring in occlusion of the coronary artery and subsequent reperfusion in rats was compared with the effect of adaptation to continuous hypoxia at middle-mountain altitudes. Adaptation to intermittent hypoxia reduced the duration of severe ventricular arrhythmias in acute ischemia and reperfusion to a great measure. Adaptation to continuous hypoxia at middle-mountain altitudes has a similar effect only in ischemic arrhythmias but at the same time promotes the development of reperfusion arrhythmias. The possible mechanisms of these effects are discussed.     

Thermal adaptation activates HSP70 synthesis, inhibits overproduction of nitric oxide, and protects the body from acute hypotension during heat shock

The role of HSP70 and nitric oxide in antihypotensive effects of thermal adaptation was studied. Western blot analysis and electron paramagnetic resonance were used to determine the contents of HSP70 and nitric oxide. Protective effect of adaptation was evaluated by the limitation of blood pressure drop after heat shock. The formation of protective effects, accumulation of HSP70, and development of the ability to decrease nitric oxide overproduction had similar dynamic patterns and appeared at the same period. Quercetin, an inhibitor of HSP70 synthesis, prevented the development of protective effects. The data suggest that HSP70 accumulated during adaptation prevents heat shock-induced hypotension by restricting NO over-production and interfering with its cytotoxic effects. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 11, pp. 507–510, November, 1999