Medical use of stepwise adaptation to hypoxia

The paper outlines N. N. Sirotinin's concept of the use of stepwise adaptation to diminished inspired air pO2 as a non-drug agent for the prevention and treatment of diseases whose pathogenesis hypoxia and their subsequent rehabilitation play a definite role in. A comprehensive study of the impact of reduced pO2 on man and animals has defined the magnitude of its ambient air changes under which a human being may adapt himself to hypoxia, it characterized five stages of hypoxic hypoxia and concluded that an adaptative process is effective in subcompensated and compensated hypoxia. The paper describes the stepwise adaptation proposed by N. N. Sirotinin to treat diseases chiefly caused by hypoxia and his three identified stages of adaptation-a process considered by N. N. Sirotinin and his pupils as a natural response of the respiratory functional system to the changing magnitude of the usually acting stimuli-reduced arterial blood oxygen and carbon dioxide tension. The mechanisms responsible for the favourable impact of stepwise hypoxic adaptation, which are the basis for its wide use in medicine, occupational hygiene, and sports are presented. Data on the development of N. N. Sirotinin's idea and its medical application in Russia and foreign countries are given.     

Carotid body adaptation to hypoxia: cellular and molecular mechanisms in vitro

Chronic hypoxia in vivo promotes long-term changes in the carotid body (CB) response to low PO2. By exposing cultured rat CB chemoreceptors (glomus cells) to 6% O2 for 1-3 weeks, we are investigating the cellular and molecular mechanisms of hypoxic adaptation. Recent studies have uncovered a series of plastic changes in glomus cells including hypertrophy, differential regulation of Na+, Ca2+, and K+ currents, and upregulation of the 'plasticity protein', GAP-43. We have also identified cyclic AMP as a possible intracellular mediator of at least some of these effects of chronic hypoxia. Associated with the changes in ionic currents, glomus cells become electrically more excitable. However, a complete understanding of the physiological response of chronically hypoxic glomus cells to chemostimuli will require more detailed knowledge of the specific alterations in the sensing and signaling pathways, including modifications in neurotransmitter (e.g. catecholamine) functions.     

Alterations in alpha 1-adrenergic receptor-mediated phosphatidylinositol turnover in hypoxic cardiac myocytes

The purpose of these studies was to examine the effects of hypoxia on alpha 1-adrenergic receptor (alpha 1AR) mediated phosphatidylinositol (PI) turnover in cultured neonatal rat cardiac myocytes. Cells were pre-labeled with [3H]-inositol and incubated for 1 h in either normoxia or hypoxia. Phenylephrine, an alpha 1AR agonist, was added at various time intervals (0-60 min) before termination of the incubation. There was a time-dependent release of radioactivity from the lipid fraction to the aqueous fraction with alpha 1AR stimulation. alpha 1AR-mediated PI turnover was biphasic in normoxic cells and monophasic in hypoxic cells. Using ion-exchange chromatography, radioactivity in the inositol trisphosphate (IP3) peak was increased with acute phenylephrine stimulation (5 min) in the normoxic cells, while inositol phosphate (IP) and inositol bisphosphate (IP2) were increased with chronic stimulation (60 min). After 5 min of alpha 1AR stimulation, hypoxia did not alter total aqueous radioactivity when compared to normoxia, but there was a significant increase in IP2. However, there was decreased PI turnover in chronically stimulated (30-60 min) hypoxic cells when compared to normoxic cells. Hypoxia had no effect on radioactivity in the IP3 fraction with either 0, 5, or 60 min of alpha 1AR stimulation, but there was a significant increase in [1,4,5]-IP3 in hypoxic cells with 30 s alpha 1AR stimulation. With hypoxia, there was no difference in radioactivity in the phosphatidylinositols with either 0 or 5 min stimulation when compared to normoxia. However, after 60 min of alpha 1AR stimulation, hypoxia resulted in increased PI and PIP, when compared to normoxic cells, but PIP2 radioactivity was unchanged. There was no effect of pertussis toxin on either the acute or chronic phase of PI turnover, negating involvement of Gi or G(o). These data suggest that alpha 1AR stimulation in neonatal rat cardiac myocytes is biphasic, and that hypoxia produces a slower monophasic response during extended alpha 1-agonist exposure as would be found with ischemia.     

Hypoxia decreases calcium influx into rat proximal tubules

Renal ischemia results in adenosine triphosphate (ATP) depletion, particularly in cells of the proximal tubule (PT), which rely heavily on oxidative phosphorylation for energy supply. Lack of ATP leads to a disturbance in intracellular homeostasis of Na+, K+ and Cl-. Also, cytosolic Ca2+ levels in renal PTs may increase during hypoxia [1], presumably by a combination of impaired extrusion and enhanced influx [2]. However, Ca2+ influx was previously measured using radiolabeled Ca2+ and at varying partial oxygen tension [2]. We have now used to Mn2(+)-induced quenching of fura-2 fluorescence to study Ca2+ influx in individual rat PTs during normoxic and hypoxic superfusion. Normoxic Ca2+ influx was indeed reflected by the Mn2+ quenching of fura-2 fluorescence and this influx could be inhibited by the calcium entry blocker methoxyverapamil (D600; inhibition 50 +/- 2% and 35 +/- 3% for 10 and 100 mumol, respectively). La3+ completely blocked normoxic Ca2+ influx. Hypoxic superfusion or rat PTs did not induce an increase in Ca2+ influx, but reduced this influx to 79 +/- 3% of the normoxic control. We hypothesize that reducing Ca2+ influx during hypoxia provides the cell with a means to prevent cellular Ca2+ overload during ATP-depletion, where Ca2+ extrusion is limited.     

Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia

1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC50: 7.12 +/- 0.19, maximum: 72.1 +/- 0.2.0%) compared to their age-matched controls (pIC50: 5.77 +/- 0.15, maximum: 28.2 +/- 2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7. These results demonstrate that control rat preparations showed greatest sensitivity for ET-1 when set at the lower tension, equivalent to the pressure expected in vivo (approximately 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET(B2) receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.     

Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia

Failure to autoresuscitate by hypoxic gasping during prolonged sleep apnea has been suggested to play a role in sudden infant death. Furthermore, maternal smoking has been repeatedly shown to be a risk factor for sudden infant death. The present experiments were carried out on newborn rat pups to investigate the influence of perinatal exposure to nicotine (the primary pharmacological and addictive agent in tobacco) on their time to last gasp during a single hypoxic exposure and on their ability to autoresuscitate during repeated exposure to hypoxia. Pregnant rats received either nicotine (6 mg. kg-1. 24 h-1) or vehicle continuously from day 6 of gestation to days 5 or 6 postpartum via an osmotic minipump. On days 5 or 6 postpartum, pups were exposed either to a single period of hypoxia (97% N2-3% CO2) and their time to last gasp was determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea was determined. Perinatal exposure to nicotine did not alter the time to last gasp, but it did impair the ability of pups to autoresuscitate from primary apnea. After vehicle, the pups were able to autoresuscitate from 18 +/- 1 (SD) periods of hypoxia, whereas, after nicotine, the pups were able to autoresuscitate from only 12 +/- 2 periods (P < 0.001) of hypoxia. Thus our data provide evidence that perinatal exposure to nicotine impairs the ability of newborn rats to autoresuscitate from primary apnea during repeated exposure to hypoxia, such as may occur during episodes of prolonged sleep apnea.     

Effect of hypoxia on the proliferation of retinal microvessel endothelial cells in culture

BACKGROUND: To determine if hypoxia stimulates the proliferation of retinal microvessel endothelial cells in culture. METHODS: Bovine retinal microvessel endothelial cells were cultured in normoxic (95% air, 5% CO2) and hypoxic (2% O2, 5% CO2, 93% N2) conditions. Endothelial cells were identified by acetylated LDL and Factor VIII-related antigen immunocytochemical staining. Cells from passages three to eight were used in these experiments. Proliferation assays included cell counts by hemocytometer and autoradiographic analysis of incorporated 3H-thymidine (3H-TdR). RESULTS: At day 4, cell counts of endothelial cells in hypoxia showed a 133% increase over those grown in normoxic conditions (N = 25, P < 0.01). Cell counts per day for 5 days were 121-181% greater in hypoxia. Autoradiography of endothelial cells exposed to 3H-TdR and counted every 12 hours for 60 hours exhibited labeling indices 112-118% higher in hypoxic conditions (P < 0.0001). Endothelial cells cultured under hypoxic conditions were smaller and spindle-shaped, whereas those grown under normoxic conditions were larger and more polygonal. CONCLUSIONS: Hypoxia increases DNA synthesis and stimulates proliferation of retinal microvessel endothelial cells in vitro and induces alterations in morphology. These results may be relevant to microvessel angiogenesis, which occurs in vivo under ischemic conditions.     

The influence of hypoxia on the cytotoxicity of concomitant KW-2149 and ionizing irradiation in Chinese hamster fibroblasts

7-N-((2-((2-(gamma-L-glutamylamino)ethyl)dithio)ethyl))-mitomycin C (KW-2149) is a newly synthesized water-soluble mitomycin C (MMC) analog. Preclinical testing showed an interesting activity profile and a superior hematological tolerance in murine models. The aim of this study was to investigate the interaction of this compound with ionizing radiation, both under normoxic and hypoxic conditions, in Chinese hamster fibroblasts (V79). V79 cells were irradiated both under normoxic conditions and after a 1 h period of hypoxia. Paired irradiation dose-response curves confirmed the significance of radioresistance under hypoxia with an oxygen enhancement ratio of approximately 3. In contrast to MMC, KW-2149 showed no increased cytotoxic effect on hypoxic V79 cells. The cytotoxic effect of KW-2149 increased with increasing concentration, irrespective of the ambient oxygen pressure. When KW-2149 was combined with irradiation under hypoxic conditions, cytotoxicity was significantly enhanced under these conditions. The difference in survival between normoxic and hypoxic conditions was statistically significant (p < 0.004). These data suggest a radiosensitizing effect of KW-2149, more pronounced under hypoxic conditions. This effect increases with radiation dose. It also corroborates earlier suggestions of a different mode of action of KW-2149 as compared to MMC.     

Mechanisms of relaxation of coronary artery by hypoxia

This study was designed to clarify the dependency of hypoxic coronary vasodilation (HCD) on the endothelium and the role of the K+ channels on HCD in the rabbit coronary artery. HCD was investigated in an isolated left circumflex coronary artery precontracted with prostaglandin F2 alpha. Vascular rings were suspended for isometric tension recording in an organ chamber filled with Krebs-Henseleit (KH) solution. Hypoxia was induced by gassing the chamber with 95% N2 + 5% CO2 and was maintained for 15 approximately 25 min. Hypoxia elicited a vasodilation in the precontracted coronary artery with and without endothelium. There was no difference between the amplitude of the HCD induced by two consecutive hypoxic challenges and the effects of 20% O2 + 5% CO2 + 75% N2 and 95% O2 + 5% CO2 control K-H solution of subsequent responses to hypoxia. Inhibition of the cyclooxygenase pathway by treatment with indomethacin had no effect on HCD. Blockades of the tetraethylammonium chloride-sensitive K+ channel abolished HCD. Apamin, a blocker of the small conductance Ca(2+)-activated K+ (KCa) channel, and iberiotoxin, a blocker of the large conductance KCa channel had no effect on HCD, respectively. Glibenclamide, a blocker of the ATP-sensitive K+ (K+ATP) channel, reduced HCD. Cromakalim, an opener of the K+ATP channel, relaxed the coronary artery precontracted with prostaglandin F2 alpha. The degree of relaxation by cromakalim was similar to that by hypoxia while glibenclamide reduced both hypoxia- and cromakalim-induced vasodilatations. In conclusion, these results suggest that HCD is independent on endothelium and HCD is considered to be induced by activation of K+ATP channel.     

Renal hemodynamics and renal O2 uptake during hypoxia in the anesthetized rabbit

The effects of hypoxic hypoxia on renal hemodynamics and metabolism have been studied in anaesthetized mechanically ventilated rabbits. Acute hypoxa (FIO2 = 0.10, PaO2 = 35 torr) induces at constant mean arterial pressure a 45% decrease in RBF, GFR, TNa and RVO2 whereas free water clearance increases. These alterations were still apparent 50 min after resuming normal arterial oxygenation. In order to assess the role of the stimulation of catecholamine release in these observations, two other sets of experiments were performed: 1) the animals were ventilated with the same hypoxic gas mixture but after alpha adrenergic blockade (phentolamine: 0.2 mg - kg - min-1 i.v.), 2) hypoxia was induced by ventilating the animals with CO (FICO = 0.002) at constnat PaO2. Increase in renal vascular resistance and reduction of renal O2 uptake were still observed. This indicates that adrenergic stimulation cannot fully explain the renal vasoconstriction encountered in hypoxia. The role of a local vasoactive factor, especially that of the renin angiotensin system is discussed. The apparent O2 cost of Na reabsorption was not greatly modified by any type of hypoxia and the Na: O2 ratio remained close to the value observed in normoxic animals. This indicates that the kidney may adapt to hypoxia by reducing its O2 demand keeping unaltered its tubular function and basal O2 needs.     

Ramiprilat attenuates hypoxia/reoxygenation injury to cardiac myocytes via a bradykinin-dependent mechanism

Isolated rat neonatal cardiac myocytes were subjected to immersion in hypoxic (PO2 < 2 mm Hg), glucose-free Tyrode's solution for 5 h followed by concomitant reoxygenation and staining with the membrane-impermeant fluorophore, propidium iodide, in normoxic (PO2 > 150 mm Hg), serum-free culture media for 15 min in order to assess sarcolemmal damage indicative of myocyte viability due to hypoxia/reoxygenation injury. Prior to hypoxic exposure, cells were pretreated for 90 min with the angiotensin-converting enzyme inhibitor cyclopenta[b]pyrrole-2-carboxylic acid, 1-[2-[(1-carboxy-3-phenylpropyl)amino]-l-oxopropyl]octahydro-[2S-[1[R* (R*)]2 alpha, 3a beta, 6a beta]] (ramiprilat), concomitantly with ramiprilat and H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (bradykinin B2 receptor antagonist HOE 140), the bioactive peptide Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (bradykinin) or concomitantly with bradykinin and HOE 140. Hypoxia/reoxygenation injury to untreated control cardiac myocytes was characterized by a significant loss of sarcolemmal integrity measured at 75 +/- 4% of total cell fluorescence (mean +/- S.E., n = 42 cultures). Compared to propidium iodide staining of the above untreated control myocytes, those pretreated with 30 or 100 microM ramiprilat showed a significant reduction of propidium iodide staining to 45 +/- 9% and 40 +/- 8% (n = 9, P < 0.05) of untreated controls, respectively. Pretreatment with the protective concentrations of ramiprilat concomitant with 10 microM HOE 140 abolished the significant reduction in propidium iodide staining observed with ramiprilat alone. Similarly, pretreatment with 10 or 100 nM bradykinin significantly reduced propidium iodide staining to 35 +/- 5% and 60 +/- 10% (n = 6, P < 0.05) of the untreated hypoxic controls, respectively. In addition, concomitant pretreatment with protective concentrations of bradykinin and 10 microM HOE 140 also abolished the significant reduction in propidium iodide staining observed with bradykinin alone. The results indicate that the angiotensin-converting enzyme inhibitor ramiprilat has a protective effect on isolated cardiac myocytes exposed to hypoxia/reoxygenation and that this effect is most likely related to a local action of bradykinin on the cardiac myocyte via the activation of the kinin B2 receptor.     

Decreased ventilation response to hypoxia in children with asthma

We measured the ventilation and inspiratory muscle activity responses to hypoxia and hypercapnia in 18 children with asthma. Ventilation was less efficient in the asthmatic children in that more inspiratory muscle activity per liter of ventilation was required than in normal children. Asthmatic and healthy children had similar ventilation responses to hypercapnia; at all levels of end-tidal Pco2, the inspiratory muscle activity was greater in those with asthma. However, during progressive isocapnic hypoxia, asthmatic patients did not increase their inspiratory muscle activity at a rate greater than normal. Thus, because of inefficient ventilation, they had significantly decreased ventilatory responses to hypoxia. Neither ventilation nor inspiratory muscle activity response to hypoxia was correlated with duration of illness or with the degree of airways obstruction present. These results demonstrate that children with chronic asthma have decreased hypoxic responsiveness and suggest that neither long-term airways obstruction nor intermittent hypoxia associated with asthma is necessary to diminish hypoxic response in asthmatic patients. An asthmatic child with depressed hypoxic responsiveness may be at increased risk of hypoxic complications or respiratory failure during acute asthma.     

Screening of potential cancer-preventing chemicals for inhibition of induction of ornithine decarboxylase in epithelial cells from rat trachea

A 10 min exposure of rat hippocampal slices to hypoxic/hypoglycemic medium decreased tissue adenosine 5'-triphosphate (ATP) levels. Hypoxia/hypoglycemia also caused an anoxic depolarization and essentially no recovery of the synaptically evoked population spike from CA1 region recorded 30 min after re-introduction of normoxic/normoglycemic medium. Removal of Ca2+ or the addition of either the non-competitive N-methyl-D-aspartate antagonist dizocilpine maleate, the inorganic Ca2+ channel antagonist Co2+; or the Na+ channel blocker tetrodotoxin to hypoxic/hypoglycemic medium improved recovery of the evoked population spike upon re-oxygenation. Dizocilpine maleate, Co2+, and tetrodotoxin spared ATP during exposure to hypoxia/hypoglycemia. In contrast, Ca(2+)-free medium facilitated recovery of the population spike but did not preserve ATP during hypoxia/hypoglycemia. Dizocilpine maleate, Co2+ or dantrolene, when added to Ca(2+)-free medium, did not preserve ATP. Tetrodotoxin, when added to Ca(2+)-free medium, was effective in sparing ATP in hypoxic/hypoglycemic medium. To determine the effect of anoxic depolarization on ATP levels, hippocampal slices were collected just before and after the depolarization. There appeared to be an abrupt drop in ATP associated with the anoxic depolarization. We conclude that Na+ influx plays a relatively larger role in ATP consumption during hypoxia/hypoglycemia than Ca2+ influx. In addition, the anoxic depolarization imposes a large and rapid drop in ATP levels.     

Mitochondrial free calcium regulation in hypoxia and reoxygenation: relation to cellular injury

The role of mitochondria in myocardial ischemic and hypoxic injury is discussed. Increases in mitochondrial Ca content and ionized Ca2+ concentration are observed during and after ischemic and hypoxic exposure and have traditionally been considered to impair mitochondrial function. New data are discussed in which it is shown that increases in mitochondrial [Ca2+] do not necessarily reflect irreversible myocyte injury. Further, it is shown that irreversible cellular injury may occur in hypoxic myocytes in association with increases in mitochondrial [Ca2+] that would ordinarily be considered to fall within a physiologic range. The significance of these observations is considered in context with observations relating to the assessment of post-hypoxic mitochondrial function.     

IL-10-mediated suppression of TNF-alpha production is independent of its ability to inhibit NF kappa B activity

It is hypothesized that carotid body chemosensory activity is coupled to neurosecretion. The purpose of this study was to examine whether there was a correspondence between carotid body tissue dopamine (DA) levels and neuronal discharge (ND) measured from the carotid sinus nerve of perfused cat carotid bodies and to characterize interaction between CO2 and O2 in these responses. ND and tissue DA were measured after changing from normoxic, normocapnic control bicarbonate buffer (PO2 >120 Torr, PCO2 25-30 Torr, pH approximately 7.4) to normoxic hypercapnia (PCO2 55-57 Torr, pH 7.1-7.2) or to hypoxic solutions (PO2 30-35 Torr) with normocapnia (PCO2 25-30 Torr, pH approximately 7.4) or hypocapnia (PCO2 10-15 Torr, pH 7.6-7.8). Similar temporal changes for ND and tissue DA were found for all of the stimuli, although there was a much different proportional relationship for normoxic hypercapnia. Both ND and DA increased above baseline values during flow interruption and normocapnic hypoxia, and both decreased below baseline values during hypoxic hypocapnia. In contrast, normoxic hypercapnia caused an initial increase in ND, from a baseline of 175 +/- 12 (SE) to a peak of 593 +/- 20 impulses/s within 4.6 +/- 0.9 s, followed by adaptation, whereas ND declined to 423 +/- 20 impulses/s after 1 min. Tissue DA initially increased from a baseline of 17.9 +/- 1.2 microM to a peak of 23.2 +/- 1.2 microM within 3.0 +/- 0.7 s, then declined to 2.6 +/- 1.0 microM. The substantial decrease in tissue DA during normoxic hypercapnia was not consistent with the parallel changes in DA with ND that were observed for hypoxic stimuli.     

Effects of exposure to hypoxia on the signal-averaged electrocardiogram in healthy subjects

The effects of hypoxia on the signal-averaged ECG (SAECG) were investigated in 26 healthy active subjects with no suggestion of cardiac disease. The SAECG was recorded in each resting subject in normoxic and hypoxic normobaric conditions (inspired O2 fraction 20.7 vs 10.0%) which lowered resting arterial O2 saturation from 98.6 +/- 0.6% to 77.7 +/- 8%. Recordings from four subjects (three men) met the definition of abnormal late potentials at baseline; in all these subjects but one, who exhibited an improved but still abnormal QRS duration, these parameters returned to normal in hypoxic conditions. The duration of the filtered QRS was significantly reduced (from 107.6 +/- 13.2 to 101.6 +/- 11.3 ms, P < 0.01), the duration of the low amplitude signals in the terminal portion of the QRS < 40 microV (LAS) significantly decreased (from 26.5 +/- 9.5 to 22.7 +/- 7.9 ms, P < 0.05) and the root mean square voltage in the last 40 ms (Term-RMS) increased non-significantly (from 55.8 +/- 40.2 to 69.1 +/- 38.3 microV, P = 0.058). Hypoxia determined a higher (P < 0.05) heart rate increase in subjects with abnormal records than in normal subjects. These data could be related to a sympathic discharge. They suggest that: (1) variation in heart rate could affect the SAECG; (2) exposure to hypoxia improves SAECG parameters in healthy subjects, possibly related to sympathetic discharge; (3) abnormal records collected during sinus bradycardia could represent a type of false-positive expression of late potentials in young active adults.     

Hypoxia inhibits gastric emptying and gastric acid secretion in conscious rats

This study examines the effects of hypoxia in the gastric function in conscious rats which adapted to a meal-feeding schedule, that allowed free access to a high protein (HP) diet (550 g casein/kg diet, Exp.1,2 and 4), a normal protein (NP) diet (200 g casein/kg diet, Exp.3) or a nonpurified rat (NPR) diet (Exp. 5 and 6) for 4 h every day for 2 wk. In Exp. 1, after 4 h of consuming the HP diet, rats were exposed to 7.6 or 10.5% O2 normobaric hypoxia. Hypoxia delayed the excretion of urinary urea for 12 h. In Exp.2 and 3, when rats were exposed to 7.6%O2 after 4 h of consuming the HP diet and exposed to 10.5% O2 after 4 h of consuming the NP diet, respectively, a significant delay in gastric emptying was found in the hypoxic rats. In Exp. 4, when rats were exposed to 7.6 O2 hypoxia after 4 hr of eating the HP diet, the plasma gastrin concentration in the 7.6% O2 hypoxic rats was 2.3-fold that of the normoxic rats after 6 h of hypoxia. Furthermore, when rats that did not consume any HP diet on the day of the experiment were exposed to 7.6 or 10.5% O2 hypoxia, the plasma gastrin concentration was higher in both hypoxic groups than in the normoxic group after 3 and 6 of hypoxia. In Exp. 5, rats that were not fed the NPR diet on the day of study were exposed to 7.6 or 10.5% O2 hypoxia for 3 h after pylorus ligation. Hypoxia inhibited the secretion of gastric acid and elevated the plasma gastrin concentration. In Exp. 6, unfed rats that had been consuming the NPR diet were exposed to 7.6% O2 hypoxia for 3 h after pylorus ligation and were orally administered HCl. The rise of the gastrin concentration due to hypoxia was completely inhibited by oral HCl. These results demonstrate that hypoxia inhibits gastric emptying and gastric acid secretion and that the inhibitory effect of hypoxia on gastric acid secretion stimulates gastrin release through positive feedback regulation.     

Impaired posthypoxic relaxation in single cardiac myocytes: role of intracellular pH and inorganic phosphate

OBJECTIVE: The aim was to examine the effects of alterations in intracellular pH and inorganic phosphate concentration (known to influence myofilament kinetics and to change rapidly during hypoxia) on cell contraction, relaxation, and the Ca2+ transient in normoxic and hypoxic myocytes. METHODS: Single adult rat ventricular myocytes were electrically stimulated (0.2 Hz) and cell length (photodiode array), intracellular Ca2+ (indo-1 fluorescence), or intracellular pH (SNARF-1 fluorescence) measured. Hypoxia was induced in a special open chamber in which a laminar layer of argon prevented the back diffusion of atmospheric oxygen. RESULTS: Electrically stimulated contraction was preserved during exposure to hypoxia. At reoxygenation 10 minutes later the time from the stimulus to the peak of contraction (TPK) increased by 30(SEM 9)% and the time from the peak of contraction to 50% recovery of cell length (RT50) increased by 59(13)% relative to prehypoxic values (n = 8). These changes were not accompanied by a change in the kinetics of the Ca2+ transient. pHi fell from a baseline of 7.33(0.04) to 7.25(0.03) during hypoxia and then overshot to 7.44(0.03) at reoxygenation (n = 5). Since an intracellular alkalosis can slow myofilament relaxation, proton extrusion routes were blocked to examine posthypoxic relaxation in the absence of an alkalosis. Despite inhibition of the pHi overshoot, posthypoxic relaxation remained impaired. Intracellular inorganic phosphate levels were manipulated in two protocols (2-deoxyglucose to "trap" phosphate and Tris(hydroxymethyl)-aminomethane to buffer phosphate) and both TPK and RT50 increased in normoxic cells. Having established that these two interventions, which would be expected to decrease intracellular inorganic phosphate, result in a slowing of relaxation, myocytes were first phosphate loaded (exposed to 5.0 mM phosphate) and then made hypoxic and reoxygenated after 10 min to blunt the expected fall in phosphate accompanying reoxygenation. This led to a reduction in the slowing of contraction and relaxation following reoxygenation [TPK increased by 7(5)% and RT50 by 17(9)%, n = 8; p < 0.05 v cells studied in control buffer]. CONCLUSIONS: Impaired posthypoxic relaxation is not the result of changes in pHi but is attenuated by phosphate loading of cells and may be due to a rapid decrease in intracellular phosphate accompanying the resynthesis of high energy phosphates at reoxygenation.