Types Of Hypoxia Research Articles

Hepatoprotective Efficacy of Pyrimidine Derivatives in Acute Dichloroethane Intoxication

The paper presents the results of a study of the antioxidative and hematoprotective properties of pyrimidine derivatives: 1,3,6-trimethyl-5-hydroxyuracil and 3,6-dimethyl-5-hydrpxyuracil versus the synthetic antioxidant tonarol, а-tocopherol acetate, and the antihypoxant ethomerzole. In model systems of varying complexity, the antiradical activity of pyrimidines and their effects on spontaneous, ascorbate- and NADPH-dependent lipid peroxidation processes, as well as their protective activity were studied in different types of hypoxia. The pyrimidine derivatives were found to have the high antioxidative activity comparable with that of ionol. 1,3,6-trimethyl-5-hydroxyuracil has antihypoxic activity. Dichloroethane induced acute toxic hepatitis whose major manifestations were cytolysis, cholestasis, lipid metabolic disturbances, and an activated lipid peroxidation response. 1,3,6-trimethyl-5-hydroxyuracil limits the cytotoxic and cholestatic activity of dichloroethane, stabilizes lipid metabolism and lipid peroxidation reactions, and increases life span and survival in rats.

Hypoxic adaptation of the rat carotid body.

Three types of hypoxia with different levels of carbon dioxide (hypocapnic, isocapnic, and hypercapnic hypoxia) have been called systemic hypoxia. The systemic hypoxic carotid bodies were enlarged several fold, but the degree of enlargement was different for each. The mean short and long axes of hypocapnic and isocapnic hypoxic carotid bodies were 1.6 (short axis) and 1.8-1.9 (long axis) times larger than normoxic control carotid bodies, respectively. Those of hypercapnic hypoxic carotid bodies were 1.2 (short axis) and 1.5 (long axis) times larger than controls, respectively. The rate of enlargement in hypercapnic hypoxic carotid bodies was lower than in hypocapnic and isocapnic hypoxic carotid bodies. The rate of vascular enlargement in hypercapnic hypoxic carotid bodies was also smaller than in hypocapnic and isocapnic hypoxic carotid bodies. Thus, the enlargement of hypoxic carotid bodies is mainly due to vascular dilation. Different levels of arterial CO2 tension change the peptidergic innervation during chronically hypoxic exposure. The characteristic vascular arrangement was under the control of altered peptidergic innervation. During the course of hypoxic adaptation, the enlargement of the carotid bodies with vascular expansion began soon after the start of hypoxic exposure. During the course of recovery, the shrinking of the carotid bodies with vascular contraction also started at a relatively early period after the termination of chronic hypoxia. These processes during the course of hypoxic adaptation and during the course of recovery were under the control of peptidergic innervation. These findings may provide a standard for further studies of hypoxic carotid bodies.

Carotid body dysfunction: The possible etiology of non-insulin dependent diabetes mellitus and essential hypertension

Carotid bodies are monitors of oxygen and glucose delivery to the brain. Faced with the threat of hypoxia or hypoglycemia carotid bodies initiate responses to counter the threat. General corrective action is to improve the perfusion by increasing the arterial blood pressure. Specific corrective actions are to stimulate ventilation to improve oxygen availability or to induce insulin resistance to raise blood glucose levels. Inappropriateness of response caused by misreading of hypoxia as hypoglycemia and hypoglycemia as hypoxia is observed experimentally and clinically. The response to all four types of hypoxia, namely, hypoxic, anemic, histotoxic and ischemic (or stagnant) hypoxia, is stimulation of ventilation and elevation of blood pressure. Ischemia produced by narrowing of the artery to the carotid body activates the carotid bodies. The activation produces hypertension, stimulation of ventilation and insulin resistance that manifests as non-insulin dependent diabetes mellitus. There is epidemiologic and necropsy evidence for the onset of atherosclerotic changes in childhood. Early atherosclerotic changes occurring in the region of carotid arteries and their bifurcation narrows the lumen of the arteries to the carotid bodies and produce hypo-perfusion of the carotid bodies. This ischemic hypoxia is a causative, or at least a permissive factor for hypertension and/or non-insulin dependent diabetes mellitus. It is suggested that neither non-insulin dependent diabetes mellitus causes hypertension nor hypertension causes diabetes mellitus, but both are caused by dysfunctional carotid bodies.

Tissue oxygenation and capacity to deliver O 2 do the two go together?

Oxidative phosphorylation is the most important source of energy in mammals. Oxygen capture, convective and diffusive oxygen transport as well as the final intracellular oxygen utilization within the mitochondria represent highly refined mechanisms, supervised by a variety of physiological control systems. Any disease process interfering with the delivery of oxygen to tissue will ultimately lead to an impairment of cellular energy production. Generally, cellular hypoxia may result from either reduced oxygen uptake (hypoxic hypoxia), reduced convective and diffusive oxygen transport (circulatory and anemic hypoxia), impaired oxygen consumption (histotoxic hypoxia), or a combination of these states. To effectively treat any of these conditions, it is mandatory to recognize the underlying specific alterations of oxidative metabolism. Identification of the various types of hypoxia as well as contemporary treatment surveillance strategies depend primarily on measuring oxygen partial pressure in inspiratory gas, blood (arterial, mixed-venous) and tissue (extracellular fluid), next to monitoring of various circulatory parameters. This review focuses (a) on the diagnostic value of different techniques used to monitor blood and tissue oxygenation and (b) on the effects of impaired capacity to deliver O 2 on tissue oxygen delivery and consumption. The potential value of multiparametric monitoring in guiding specific treatment measures to improve oxygen delivery to tissue is highlighted.

Mechanisms underlying hypoxia development in tumors.

The purpose of this review is to critically evaluate physiologic mechanisms that lead to hypoxia in tumors. This review will challenge some of the current paradigms and present an alternative view. There are two types of hypoxia, as described radiobiologically. Long intercapillary distances between microvessels are believed to be causal fordiffusion limited or chronic hypoxia.Intermittent vascular stasis is commonly believed to be responsiblefor perfusion limited or acute hypoxia.If one considers the multitude of factors that could influence oxygen transport, it becomes clear that these two classifications are gross oversimplifications of a more complex process. Factors that are known to affect delivery include microvessel density, vessel orientation, red cell flux, hemoglobin saturation and blood viscosity, to name a few. One must also consider the oxygen consumption rate, which can be influenced by cell proliferation rate and other factors, such as inflammation. This review will present a comprehensive model including factors governing oxygen transport in tumors that provides a testable mechanistic underpinning for future research on this subject. The increased interest in tumor hypoxia because of its influences on gene expression and selection for more aggressive phenotype further emphasizes the need for more detailed study.

The Effect of Hypoxic Hypoxia on the Systemic and Myocardial Pharmacokinetics and Dynamics of Lidocaine in Sheep

It was hypothesized that the increased myocardial blood flow known to occur during some types of hypoxia may alter the kinetics and dynamics of cardio-active drugs such as lidocaine that act directly on the myocardium. In a randomized cross-over design, iv lidocaine (100 mg over 2 min) was administered to conscious instrumented sheep in a control state (C) or when the sheep were rendered hypoxic (H) by the addition of nitrogen to their inspired air (average Pa(O2) = 26 mmHg). Hypoxia caused a significant increase in myocardial blood flow (193% of control, SD = 37%, p < 0.05), a nonsignificant increase in cardiac output, and unchanged heart rate and blood pressure. Peak arterial lidocaine concentrations were unchanged, but peak concentrations in coronary sinus blood (effluent from the myocardium) were increased (maximum 201% of control, SD = 63%, p < or = 0.05), suggesting more rapid uptake of lidocaine into the myocardium in hypoxia. There was a linear relationship between coronary sinus lidocaine concentrations and reductions in myocardial contractility. However, the higher myocardial concentrations associated with H were not associated with overall greater reductions in contractility, as baseline contractility was elevated by H. Thus, hypoxia was not detrimental with respect to this adverse effect of lidocaine on the myocardium.

Carbogen Breathing after Irradiation Enhances the Effectiveness of Tirapazamine in SiHa Tumors but not SCCVII Tumors in Mice

The penetration of anticancer agents into tumor tissue has recently attracted considerable attention. This study examines the effect of carbogen breathing on the antitumor activity of tirapazamine combined with radiation. Our hypothesis is based on the observation that the diffusion of tirapazamine through tissue is dependent on oxygen tension. We postulated that carbogen breathing might enhance the ability of tirapazamine to diffuse to hypoxic cells located distal to functional blood vessels in tumors. We first determined that carbogen breathing caused no significant change in the pharmacokinetics of tirapazamine, suggesting that any effect of carbogen breathing on the activity of tirapazamine is not attributable to modulation of pharmacokinetics. Cell survival in SCCVII and SiHa tumors after 10 Gy X rays alone was similar. However, when tirapazamine was administered 30 min after radiation treatment under air-breathing conditions, cell killing was greater in SCCVII tumors compared to SiHa tumors. Carbogen breathing during the exposure to tirapazamine did not change the cell survival in SCCVII tumors, but it enhanced cell killing in the SiHa tumors. Interestingly, carbogen breathing during radiation treatment produced greater cell killing in the SiHa tumors than in the SCCVII tumors. The vascular architecture and type of hypoxia in the two tumors probably underlie the differences in the responses of the two tumors. These findings suggest that the effectiveness of tirapazamine and other hypoxic cytotoxins may be dependent on tumor type.

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The perfusion of human tumour xenografts was manipulated by administration of diltiazem and pentoxifylline, and the extent that observed changes in tumour perfusion altered tumour radiosensitivity was determined. 2 tumour systems having intrinsically different types of hypoxia were studied. The responses of SiHa tumours, which have essentially no transient hypoxia, were compared to the responses of WiDr tumours, which contain chronically and transiently hypoxic cells. We found that relatively modest increases in net tumour perfusion increased tumour cell radiosensitivity in WiDr tumours to a greater extent than in SiHa tumours. Moreover, redistribution of blood flow within WiDr tumours was observed on a micro-regional level that was largely independent of changes in net tumour perfusion. Through fluorescence-activated cell sorting coupled with an in vivo–in vitro cloning assay, increases in the radiosensitivity of WiDr tumour cells at intermediate levels of oxygenation were observed, consistent with the expectation that a redistribution of tumour blood flow had increased oxygen delivery to transiently hypoxic tumour cells. Our data therefore suggest that drug-induced changes in tumour micro-perfusion can alter the radiosensitivity of transiently hypoxic tumour cells, and that increasing the radiosensitivity of tumour cells at intermediate levels of oxygenation is therapeutically relevant. © 2001 Cancer Research Campaign http://www.bjcancer.com

Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea–hypopnea syndrome

To better understand how humans adapt to hypoxia, the levels of hemoglobin (Hb), serum erythropoietin (Epo), and vascular endothelial growth factor (VEGF) were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found. The induction in patients with severe sleep apnea was greater than that reported in other types of hypoxia. (Blood. 2001;98:1255-1257)

Gene expression of insulin-like growth factor-I, its receptor and binding proteins in retina under hypoxic conditions

Hypoxia is the main stimulus for neovascularization in the retina. Insulin-like growth factor-I (IGF-I) is thought to be one of the mediators of this process. Severe persistent hypoxia, as occurs in central retinal artery occlusion, is associated with less retinal neovascularization than relative hypoxia. To study the influence of different types of hypoxia on the IGF system, we used a model of neonatal rat retina that responds with neovascularization to a relative hypoxic stimulus produced by alternating oxygen concentrations in the respired air. We studied the influence of 24-hour hypoxia (10% oxygen), 48-hour hyperoxia (75% oxygen), and relative hypoxia (shifting from 48 hours in 75% oxygen to 24 hours in room air) on the gene expression of IGF-I, IGF-I receptor (IGF-IR), and IGF binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 in retina using a solution hybridization RNase protection assay. Hypoxia induced a significant increase in retinal IGF-IR (178%), IGFBP-2 (227%), and IGFBP-3 (317%) mRNA; however, retinal IGF-I mRNA was reduced, as well as serum growth hormone (GH). Relative hypoxia caused a similar but less pronounced trend in the gene expression of IGF-IR and the binding proteins, whereas retinal IGF-I mRNA was unchanged and serum GH was elevated. Both hypoxia and relative hypoxia may cause IGF system stimulation in the retina through upregulation of IGF-IR and IGFBPs. This stimulation may result in neovascularization. However, during hypoxia, low levels of tissue oxygenation and reduced local production of IGF-I may impede the neovascularization process.

Effects of systemic hypoxia on R-R interval and blood pressure variabilities in conscious rats.

The effects of systemic hypoxia with different levels of CO2 on R-R interval (RRI) and systolic blood pressure (SBP) variabilities were investigated in conscious rats. Wistar rats chronically instrumented for the measurement of blood pressure, electrocardiogram, and renal sympathetic nerve activity (RSNA) were exposed to hypocapnic (Hypo), isocapnic (Iso), and hypercapnic (Hyper) hypoxia. On another day, the rats were treated with atropine and exposed to the same type of hypoxia. Sinoaortic denervation (SAD)-treated rats were exposed to Iso and Hyper, and RRI and SBP variabilities before and during hypoxia were analyzed using the maximum-entropy method with high resolution. With regard to RRI variability, very low frequency (VLF), low frequency (LF), and high frequency (HF) powers all decreased during Hypo, increased during Hyper, and did not change during Iso in intact rats. Changes during Hypo were attenuated by atropine, and those during Hyper were abolished by either atropine or SAD. The ratio of LF power to HF power decreased independently of increases in RSNA during each type of hypoxia. On the other hand, there were no changes in VLF, LF, or HF power in SBP variability during each type of hypoxia in intact rats. In atropine-treated rats, LF power increased during Iso and Hyper and HF power increased during each type of hypoxia. There was no difference in respiratory frequency among the three kinds of hypoxia in both intact and atropine-treated rats. The results suggest that arterial PCO2 level rather than respiration frequency produces changes in powers of RRI variability through changes in parasympathetic nerve activity and that with regard to SBP variability, parasympathetic nerve activity masks changes in LF power that reflect an increase in RSNA and those in HF power that reflect a mechanical consequence of respiration.

Changes of electrocorticograms and oxygen tension (Po 2) of the cerebral cortex in the different types of hypoxia

Changes of electrocorticograms and oxygen tension (Po 2) of the cerebral cortex in the different types of hypoxia

Efficacy of agents counteracting hypoxia in fractionated radiation regimes

Background and purpose: Solid tumours contain hypoxic cells which are resistant to radiotherapy. This study compares the efficacy of several strategies to counteract diffusion-limited hypoxia, or intermittent hypoxia in a fractionated regimen of 1 to 6 × 2 Gy. Materials and methods: Nicotinamide (250 mg/kg), perflubron emulsion (Oxygent ™) (4 ml/kg), tirapazamine (SR4233) (0.10 mmol/kg) and carbogen breathing, administered alone or in combination, were investigated on two tumour cell lines: EMT6 (a rodent mammary carcinoma) and HRT18 (a human rectal adenocarcinoma) using a clonogenic assay. The radiosensitizing effect of the agents was assessed after 1 and 6 × 2 Gy for drugs used alone, and 1, 2, 4, 6 × 2 Gy for drugs used in combination. Results: At the end of the fractionated radiation regimen, the combination of nicotinamide + carbogen induced the greatest radiosensitization for EMT6 tumours, while greatest radiosensitization of HRT18 was obtained with nicotinamide + carbogen + tirapazamine. Conclusion: The efficacy of the strategies for overcoming hypoxia using a fractionated regimen depends on the tumour cell line. These differences could be linked to differences in the initial percentages of acute and chronic hypoxic cells, and to changes in the two types of hypoxia during treatment.

Venous Oxygen Saturation (SvO2) During Alveolar Hypoxia and Anemic Hypoxia. 115

Background: We studied SvO2 and markers of tissue hypoxia to assess the value of SvO2 during two types of hypoxia. Subjects: Two groups of ventilated neonatal piglets. Intervention: We induced alveolar hypoxia by giving FiO2: 0.1 in one group (ALV) and anemic hypoxia by exchanging blood with plasma in the other group (ANEM). SvO2 was measured by a fiberoptic catheter (Oximetrix, Abbott Lab). Aorta flow (Qt), arterial and venous bloodgases, hemoglobin and lactate were measured. O2 delivery (DO2), percent change O2 consumption (perc.ch VO2) and percent change lactate(perc.ch LAC) were calculated. Mann-Whitney U test was applied. Results: *: p = 0.002; Table

Effect of acute and chronic intermittent hypoxia on DNA topoisomerase II α expression and mitomycin C-Induced DNA damage and cytotoxicity in human colon cancer cells

Recently, we reported that alterations in topoisomerase II (topo II) activity appear to contribute to mitomycin C (MMC) resistance in HT-29R13 human colon cancer cells under aerobic conditions. In this study, the expression of topo II α and topo II βin parent HT-29 and MMC resistant variant HT-29R13 cells was investigated under aerobic, acute hypoxic (after 4 hr in 95% N 2, 5% CO 2 <0.01% O 2), and chronic intermittent hypoxic (after 4 hr hypoxia/day × 7 days) conditions. Acute hypoxia induced topo II α mRNA and protein, effects that were more pronounced in HT-29 cells. Chronic intermittent hypoxia caused a decrease in topo α mRNA and protein, changes that were again more pronounced in HT-29 cells. The observed changes in topo II α protein were associated with parallel changes in topo II activity under all conditions tested. Topo II β mRNA was expressed at a very low level in both cell lines under aerobic and hypoxic conditions. Compared with cells under aerobic conditions, HT-29 cells were more sensitive to MMC under acute hypoxia but more resistant under chronic intermittent hypoxia. In contrast, the sensitivity of HT-29R13 cells was unchanged under acute hypoxia, but the cells were more resistant under chronic intermittent hypoxia. Under all conditions tested, the degree of cytotoxicity corresponded to the frequency of MMC-induced DNA cross-links and topo II α protein levels and activity. Our results demonstrated that MMC cytotoxicity in hypoxic cells is highly dependent upon the type of hypoxia and the cell type. Hypoxia has significant effects on topo II α expression in HT-29 and HT-29R13 cells which correlate with MMC cytotoxicity.

Effect of adrenaline on the response of erythrocyte 2,3-diphosphoglycerate in rabbits in vivo

1. 1. A 6 hr time-course response of erythrocyte 2, 3-diphosphoglycerate was studied in rabbits following adrenaline administration. 2. 2. Eight female New Zealand white rabbits weighing about 3.6 Kg each were injected intra-peritoneally with a total of 0.97 mg/kg of adrenaline (0.56 mg/kg at time 0 min and 0.41 mg/kg at time 0.5 hr), and the venous level of red blood cell (RBC) 2,3-DPG was monitored at 0 hr, 1 hr, 3 hr, and 6 hr, respectively. As controls, the level of 2,3-DPG was also monitored in these rabbits weeks prior to the experiment. 3. 3. A significant ( p<0.05) rise in the mean level of 2.3-DPG (μmol-ml −1 RBC) was reached 3 hr after the initial injection of adrenaline, and the level returned to the preexposure level by the end of 6 hr. 4. 4. It is speculated that adrenaline may be one of the contributors that increases the level of 2,3-DPG during the resting period following exhaustive exercise because this catecholamine has been reported to increase following this type of hypoxia.

Effect of hypoxic and carbon monoxide-induced hypoxia on regional myocardial segment work and O2 consumption.

The purpose of this study was to investigate the potentially greater responses of regional myocardial work and O2 consumption to hypoxic hypoxia than to CO-induced hypoxia. Twenty open-chest anesthetized dogs were studied under control and four hypoxic conditions, hypoxic hypoxia induced with either 8% O2 (SaO2 = 56%) or 6% O2 (SaO2 = 40%) gas mixtures, or CO-induced hypoxia produced by a 1% CO gas mixture for either 7 min (SaO2 = 67%; SaCO = 30%) or 20 min (SaO2 = 40%; SaCO = 56%). Ultrasonic crystals and a force gauge were utilized to measure myocardial shortening and force. Regional myocardial segment work was calculated by integrating myocardial segment shortening multiplied by its corresponding force. Radioactive microspheres were used to measure regional coronary blood flow during each condition. Transmural biopsies were utilized to measure arterial and venous O2 saturation with a four-wavelength microspectrophotometric method. Regional O2 extraction and consumption were calculated. Regional coronary blood flow (77 +/- 38 ml/min per 100 g, control) increased with severe hypoxic hypoxia (293 +/- 206) and CO-induced hypoxia (150 +/- 128). Regional myocardial O2 extraction was decreased with both hypoxic and CO hypoxia. Regional myocardial O2 consumption was maintained even with severe hypoxic and CO hypoxia. Regional myocardial segment work/min increased from 343 +/- 205 g* mm/min with increasing levels of hypoxic hypoxia (564 +/- 677) and decreased with increasing levels of CO hypoxia (169 +/- 111). Regional segment work increased with increasing levels of hypoxic hypoxia and decreased with increasing CO hypoxia. The differential effects on segment work caused by the two types of hypoxia may be due to direct metabolic or autonomic differences.

Ventilatory and metabolic responses to cold and CO-induced hypoxia in awake rats

Experiments were carried out in awake rats to compare the effects of ambient and CO-induced hypoxia on thermoregulation and ventilatory control. Measurements of metabolic rate (V̇ O 2 ), ventilation (V̇), shivering (EMG) and colonic temperature (Tc) were made at fixed ambient temperature (Ta) of 25, 15 and 5°C. Animals were exposed to ambient hypoxia (F I O 2 of 21, 17, 14, 12 and 10%) or to CO hypoxia (F I CO of 0.03% in air). The results show that: (1) Both ambient and CO-induced hypoxia provoked decreases in V̇ O 2 and Tc which were more marked at low Ta values; non-shivering thermogenesis was depressed with both types of hypoxia, whereas shivering was depressed only with ambient hypoxia; (2) Ventilatory response to ambient hypoxia was blunted at low Ta values and CO-induced hypoxia did not affect ventilation. It is concluded that: (1) hypoxia affects markedly the control of Tc by altering thermogenesis: inhibition of non-shivering thermogenesis seems to result from a decrease in Ca O 2 whereas inhibition of shivering seems to result from a decrease in Pa O 2 ; (2) during hypoxia, ventilation is controlled by the opposite stimulation from chemoreceptors and inhibition from hypometabolism. However, as revealed by CO-induced hypoxia, another stimulatory factor may also interact with the control of breathing.

Influence of pH on calcium influx during hypoxia in rat cortical brain slices.

Acidity of brain intracellular and extracellular fluids appears to increase brain injury from stroke, but low extracellular pH decreases the activity of N-methyl-D-aspartate receptor ion channels and decreases calcium influx into isolated neurons. To further investigate the role of acid-base balance in hypoxic brain injury, we studied the influences of intracellular and extracellular pH on calcium influx in cortical brain slices during hypoxia. Intracellular calcium ([Ca2+]i) and pH (pHi) were measured fluorometrically with the dyes fura-2 and biscarboxyethyl carboxyfluorescein, respectively, during two types of hypoxia: (1) slice perfusate equilibrated with N2/CO2 at pH 6.6 or 6.2 ("gaseous hypoxia") or (2) perfusate equilibrated with 95% O2/5% CO2 plus 100 mumol/L NaCN at pH 7.3, 6.6, or 6.2 ("chemical hypoxia"). Changes in perfusate pH under aerobic conditions did not change [Ca2+]i. However, influx of calcium caused by gaseous or chemical hypoxia increased significantly with decreasing perfusate pH. During chemical hypoxia, the elevation in [Ca2+]i at perfusate pH 6.2 was twice that at perfusate pH 7.3. Change in [Ca2+]i was correlated with perfusate pH but not pHi. These results, which differ from previous studies showing acid inhibition of calcium influx in isolated neurons, suggest that low extracellular pH may exacerbate cellular injury during severe hypoxia or ischemia in the intact brain.

Stable enhancement of tissue-type plasminogen activator levels in blood: Interrupted chamber hypoxia mimics effects of alpine hypoxia

The influence of native mountain, artificial acute and interrupted prolonged barochamber hypoxia on the tissue-type plasminogen activator (t-PA) level in blood and tissues was studied in Wistar rats. All types of hypoxia induced an elevation of blood t-PA activity due to a stimulatory effect on the lung vascular endothelium. In contrast to acute barochamber hypoxia a middle-term adaptation to the hypoxic circumstances caused a stable enhancement of blood t-PA activity. The acute barochamber hypoxia by an unknown pathway stimulated only the release of t-PA, but the long-lasting hypoxia caused both the secretion and synthesis of t-PA de novo.