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The mechanism causing cerebral vasodilatation during hypoxia remains unclear. A role for histamine is suspected because H2 receptor-blocking drugs blunt the hypoxia-induced increase in cerebral blood flow (CBF). Moreover, in vitro blockade of H1 receptors by chlorpheniramine decreases the vasodilatation of cerebral arteries that is induced by histamine. The present study tested the hypothesis that an H1 receptor blocker (d-chlorpheniramine) would have a similar effect in vivo during hypoxia. Isocapnic hypoxia (inspired oxygen fraction, FIO2 = 0·10; inspired carbon dioxide fraction, FICO2 = 0·035) was induced in 16 conscious dogs randomly divided into two groups: eight dogs received saline intravenously (controls) at time 0 (normoxia) and after 2 h and 4 h hypoxia, and the other eight dogs received d-chlorpheniramine intravenously (0·5 mg kg-1) to block the H1 receptors. Regional CBF was measured by the radioactive microspheres technique 15 min after each injection of d-chlorpheniramine or saline. In the control group, CBF increased during hypoxia in all regions of the brain. In the d-chlorpheniramine group, total CBF increased similarly after 2 h of hypoxia. After 4 h of hypoxia, the increase was limited, especially in the pons, cerebral peduncles, hippocampus, hypothalamus, thalamus, and occipital lobes (six out of 12 studied regions). It is concluded that the H1 blocker d-chlorpheniramine did not strongly inhibit the increase in CBF during hypoxia. After cumulative doses, however, as in the fourth hour of hypoxia, the increase in total CBF was limited. [ABSTRACT FROM AUTHOR]

The mechanism causing cerebral vasodilatation during hypoxia remains unclear. A role for histamine is suspected because H2 receptor-blocking drugs blunt the hypoxia-induced increase in cerebral blood flow (CBF). Moreover, in vitro blockade of H1 receptors by chlorpheniramine decreases the vasodilatation of cerebral arteries that is induced by histamine. The present study tested the hypothesis that an H1 receptor blocker (d-chlorpheniramine) would have a similar effect in vivo during hypoxia. Isocapnic hypoxia (inspired oxygen fraction, FIO2 = 0.10; inspired carbon dioxide fraction, FICO2 = 0.035) was induced in 16 conscious dogs randomly divided into two groups: eight dogs received saline intravenously (controls) at time 0 (normoxia) and after 2 h and 4 h hypoxia, and the other eight dogs received d-chlorpheniramine intravenously (0.5 mg kg-1) to block the H1 receptors. Regional CBF was measured by the radioactive microspheres technique 15 min after each injection of d-chlorpheniramine or saline. In the control group, CBF increased during hypoxia in all regions of the brain. In the d-chlorpheniramine group, total CBF increased similarly after 2 h of hypoxia. After 4 h of hypoxia, the increase was limited, especially in the pons, cerebral peduncles, hippocampus, hypothalamus, thalamus, and occipital lobes (six out of 12 studied regions). It is concluded that the H1 blocker d-chlorpheniramine did not strongly inhibit the increase in CBF during hypoxia. After cumulative doses, however, as in the fourth hour of hypoxia, the increase in total CBF was limited.

The increase in cerebral blood flow (CBF) elicited by moderate hypoxia in anesthetized animals is little attenuated by nitric oxide (NO) synthase inhibitors. However, in previous studies, the effects of NO synthase inhibitors may have been altered by anesthetics. Consequently, we studied the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on cerebral and myocardial blood flows during hypoxia in the awake dog. Regional CBF and myocardial blood flows (MBF) were measured under normoxia and hypoxia in 16 beagle dogs after an intravenous (IV) injection of either saline (control, n = 8) or L-NAME 20 mg/kg (n = 8). One week after thoracotomy for catheter insertion, awake dogs were studied during three periods: normoxia and after 2 and 4 h of normocapanic hypoxia in an environmental chamber (FIO2 = 0.10, FICO2 = 0.035, balance N2). At each stage, a bolus injection of L-NAME or saline was followed 15 min later by left atrial injection of radiolabeled microspheres (141Ce, 103Ru, 46Sc) for regional CBF and MBF. After the dogs were killed, the brain and the heart were fixed in 10% formaldehyde, dissected by region and weighed, and radioactivity was measured in a gamma counter. During hypoxia, Pao2 was approximately 45 mm Hg with normal Paco2. In the control group, CBF increased by 45% after 2 h and 48% after 4 h of hypoxia; MBF increased by 69% and 60%, respectively. L-NAME prevented the CBF increase during hypoxia and the MBF increase after 2 h of hypoxia; after 4 h of hypoxia the measurement of MBF was confounded by cardiac dysfunction. These results suggest that NO plays a role in cerebral vasodilation during hypoxia in the awake animal.

Urinary cotinine was assessed by a radioimmune assay (RIA) in a random subsample of 63 (out of 285) children aged 5 to 6 from 10 kindergartens in Nancy (N-E France). The result was adjusted for urine concentration by expressing cotinine per mg creatinine. The correlation between two successive determinations was excellent (r = 0.989) and the difference between the two mean values was minimal and non-significant (121.4 +/- 25.9 vs 121.0 +/- 25.0). Expressed in percentage of their mean, the difference between two determinations was on average 8.2%. The urinary cotinine determinations allowed a satisfactory separation of children exposed vs unexposed to parental tobacco smoke.

The aim of this study was to assess whether moderate hypoxia affects the disposition of diltiazem. Six male beagle dogs received diltiazem (0.6 mg/kg) on three occasions: (1) while breathing air, i.e. during normoxia; (2) 1 h after initiating exposure to a FiO2 of 0.08, a FiCO2 of 0.035 and a FiN2 of 0.885, i.e. during acute hypoxia and normocapnia, and (3) during chronic hypoxia, i.e. after 120 h of exposure to a FiO2 of 0.08. Multiple blood samples were withdrawn and urine was collected to assay diltiazem and metabolites [N-desmethyl diltiazem (MA), deacetyl diltiazem (DAD) and N-desmethyl deacetyl diltiazem (M2)]. Breathing air, mean arterial partial pressure of oxygen was 83.2 +/- 3.2; during acute hypoxia 42.2 +/- 0.7; and during chronic hypoxia, 41.9 +/- 0.6 mm Hg. Acute hypoxia did not alter diltiazem disposition. Compared to dogs with normoxia, chronic hypoxia reduced diltiazem metabolic clearance, from 64 +/- 3 to 51 +/- 5 ml/min/kg (p < 0.05), as well as its volume of distribution, from 11.4 +/- 1.2 to 9.1 +/- 0.3 liters/kg (p < 0.05). Chronic hypoxia decreased the fraction of diltiazem metabolic clearance, normalized by the glomerular filtration rate, generating the M2 metabolite, although this experimental condition did not affect the formation of MA or DAD. It is concluded that chronic moderate hypoxia reduced diltiazem systemic clearance because it decreased selected pathways of biotransformation.

It is known that cimetidine inhibits the hypoxia-induced increase in cerebral blood flow (CFB) in dogs, but the mechanism of this inhibition is not fully understood. Since the accepted mechanisms explaining the increase in CBF during hypercapnia are very different from those active during hypoxia, acute hypercapnia was induced in 12 conscious dogs in order to study the cimetidine effect in this condition. Six dogs were given i.v. saline (control group) and the other six, i.v. cimetidine (4 mg kg-1). After 15 min, CBF and various muscular blood flow measurements were performed, using the microspheres technique under two conditions: (1) breathing air and (2) after 2 h inhalation of a gas mixture with FiCO2 0.10, FiO2 0.21 in nitrogen. The CBF increase was similar in both series with or without cimetidine. The changes in muscular blood flow were unaffected by the H2-blocker. We conclude that cimetidine has no effect on the CBF and on muscular blood flow during acute hypercapnia.

Chronic hypoxia is known to be associated with a thickening of the media of pulmonary arteries. The goal of the present study was to assess if cilazapril, a novel long-acting angiotensin converting enzyme (ACE) inhibitor, could prevent this thickening. For this purpose, three groups of rats were studied. One group was kept in normal room air. Two other groups were exposed to chronic hypoxia (inspired fraction of oxygen equal to 8% during 4 weeks). One group of hypoxic rats was treated with placebo and the other group received cilazapril (as food admixture of approximately 3 mg/kg/day). After 4 weeks, rats were anesthetized and pulmonary artery pressure and hematocrit measured. Then, the lungs were perfused and fixed and morphometry of the pulmonary arteries was performed. Hypoxia induced an increase in pulmonary artery pressure and hematocrit associated with a dramatic increase in the thickness of the media of the pulmonary arteries. Cilazapril completely prevented the thickening of the media of the pulmonary arteries but did not significantly decrease the pulmonary artery pressure or right ventricular weight.

The aim of the present study was to investigate the influence of hypoxemia combined with respiratory acidosis on the kinetics of digoxin in conscious dogs. One group of three beagles was exposed to air and 7 days later to 10% O2, 10% CO2, and 80% N2. In a second group of three dogs, the order of exposure to the two atmospheric conditions was reversed. The dogs received 25 micrograms/kg digoxin and blood and urine samples were collected over the next 29 h. At the conclusion of the second treatment, the dogs were sacrificed to determine digoxin concentrations in the left ventricle, liver, renal cortex, and skeletal muscle. Digoxin total body clearance increased from 6.2 +/- 0.9 in control to 9.0 +/- 1.0 mL X min-1 X kg-1 in hypoxemic and hypercapnic dogs (p less than 0.05). The digoxin apparent volume of distribution at steady state (Vss) was increased in the dogs with hypoxemia and hypercapnia (11.63 +/- 1.11 vs. 8.62 +/- 0.41 L/kg in the controls, p less than 0.05). As a consequence the digoxin plasma half-life remained unchanged (18.6 +/- 1.5 h in hypoxemic and hypercapnic dogs versus 20.1 +/- 2.8 h in the controls). In dogs with hypoxemia and hypercapnia, the ratio of tissue to plasma digoxin concentrations tended to increase in the liver, in the renal cortex, and in the left ventricle and remained unchanged in the left hind leg muscle. In vitro studies showed that the digoxin total binding to erythrocyte membranes was slightly increased in the dogs with hypoxemia and hypercapnia, resulting from an increase in the apparent intrinsic association constant for digoxin (p less than 0.003). It is concluded that hypoxemia combined with respiratory acidosis changes digoxin disposition in the conscious dog and is the cause of a digoxin redistribution into the tissues.

After a three day-period of hypercapnia, carbonic anhydrase blockade by acetazolamide inhibits the development of arterial blood alcalosis during the return in normal environment, and thus eliminates the transient increase in lactacidemia due to glycolysis stimulation.

Ten mongrel dogs (mean weight: 27 kg) awake and with an implanted femoral catheter have been maintained for three days in a controlled chamber (10% CO2 and 21% O2). Arterial blood samples, taken before admission and after one, two, four, six, 24, 48 and 72 hours of exposure, allowed to study blood gases and acid-base equilibrium. Glycemia, phosphatemia, erythrocyte concentration of glucose-6-phosphate (G-6-P), fructose-6-phosphate (F-6-P), fructose-1,6-diphosphate (F-1,6-DP), 2,3-diphosphoglycerate (2,3-DPG), pyruvate, lactate and ATP were also titrated by various enzymatic methods. In addition, nine reference subjects were studied in air (without CO2). During the hypercapnia, [H+] rapidly increases to 70 nmol/1, then progressively decreases after 24 hours, while [HCO3-] slowly rises. The glycemia stays high during the whole exposure. There is also an increase in inorganic phosphate, G-6-P and F-6-P, but during the first 24 hours only. F-1,6-DP, pyruvate and lactate remain lowered during the whole exposure. The 2,3-DPG diminishes after the sixth hour. These phenomena, related to the acidosis and probably to the phosphofructokinase inhibition don't arise in the reference subjects. However the latter present after a two and four hour-stay in the chamber a small decrease in pyruvicemia and lactacidemia.

The goals of this study were to document the effect of hypoxemia on the distribution of digoxin in conscious dogs. For this purpose, 6 beagles were exposed to air and 6 others to an atmosphere containing 10% O2, to generate a PaO2 equal to 46.3 +/- 0.3 mmHg (mean +/- SEM). The animals received 25 micrograms/kg of digoxin containing 2.17 micrograms/kg of 3H-digoxin, and then blood and urine samples were collected over the next 48 h, at which time they were killed to determine digoxin concentrations in several tissues. Five additional beagles were used to assess the influence of hypoxemia on the blood perfusion to these tissues using radioactive microspheres. The results, expressed as digoxin equivalents, indicated that hypoxemia increased the digoxin apparent volume of distribution (2.85 +/- 0.10 versus 2.01 +/- 0.11 L/kg; p less than 0.001) and the time required to achieve this distribution (9.7 +/- 1.4 versus 2.6 +/- 0.3 h; p less than 0.01). As digoxin clearance was not influenced by hypoxemia, the half-life was increased from 25.2 +/- 1.5 to 33.4 +/- 1.3 h (p less than 0.01). With hypoxemia, digoxin concentrations increased significantly in the brain and diaphragmatic muscle, but only marginally in other organs, including the heart, the latter despite a significant increase in blood flow. It is concluded that hypoxia does change digoxin disposition but does not increase digoxin heart concentrations. Therefore, factors other than changes in digoxin plasma kinetics and heart distribution may be responsible for the decrease in digitalis tolerance during hypoxemia.

In 14 beagle dogs, paraquat was infused in fractional doses to produce pulmonary fibrosis while avoiding fatal liver and kidney lesions. Activity of the three enzymes of the pentose pathway: glucose-6-phosphate dehydrogenase (G-6-PDH), glutathione reductase (GR) and glutathione peroxidase (GSH Px), which supply reduced equivalents against oxidant agents, were measured in the mediastinal lobe of the lung. After a single low dose (2-3 mg/kg body weight), GR and GSH Px activities were reduced. After repeated paraquat doses, pentose pathway enzyme activities were higher than after a single low dose; however, they did not significantly exceed the normal values as determined in control dogs. The activities of G-6-PDH, GR and GSH Px correlated with the total paraquat dose and with the extent of pulmonary fibrosis measured with an electronic image analyzer. The activity of pulmonary lactate dehydrogenase, which was also reduced after a single low dose of paraquat, did not show the same correlations.

It has been reported in experimental models that acute hypoxia reduced the activity of the hepatic cytochrome P-450. The objective of the present study was to investigate in conscious dogs whether acute and chronic hypoxia will influence the disposition of theophylline. To this purpose 6 beagle dogs received 8 mg/kg i.v. of theophylline while breathing air, after acute hypoxia (PaO2 of 48.5 +/- 0.3 mmHg) and after 96 hours of hypoxia. Theophylline and metabolites, 3-methylxanthine and 1,3-dimethyluric acid, were assayed by HPLC. Theophylline volume of distribution, while breathing air, was 0.51 +/- 0.03 L/kg and was not affected by hypoxia. Theophylline metabolic and renal clearances were 1.53 +/- 0.24 and 0.18 +/- 0.04 mL/min/kg and remained constant when the dogs were hypoxic. The urinary recovery of theophylline and metabolites was not affected by acute or chronic hypoxia. It is concluded, that in the dog hypoxia does not affect the disposition of theophylline.

Cimetidine is an H2 receptor-blocking drug frequently given to ICU patients for the prevention of stress ulcers. However, histamine causes potent cerebral vasodilation through the H2 receptors. This study tested the hypothesis that cimetidine, by blocking the H2 receptors, could blunt the increase of cerebral blood flow induced by hypoxia. We induced isocapnic hypoxia in 12 conscious dogs that were randomly divided into two groups. Six dogs received no treatment (control group), and the other six received iv cimetidine (4 mg/kg) to block the H2 receptors. Cerebral blood flow (CBF) was measured with the radioactive microsphere technique before, and 2 and 4 h after hypoxia was induced. In the control group, CBF significantly increased with hypoxia in all the regions of the brain. Cimetidine blunted this increase in all the regions of the brain except the pons and bulb. As a result of the reduced flow, cimetidine significantly decreased the oxygen supply to the brain compared to the control group. We conclude that cimetidine blunts the increase in CBF during hypoxia and might reduce oxygen supply to the brain in hypoxic patients.

This study aimed to assess the effect of hypoxemia on theophylline disposition. Ten patients with a mean (+/- SEM) of 58 +/- 3 years with COLD (PaO2 55 +/- 1 mm Hg, PaCO2 46 +/- 2 mm Hg, and pH of 7.39 +/- 0.01) were hospitalized to have oxygen therapy. Before starting O2, they received intravenously, 4 mg/kg of theophylline over a 20-minute period; blood samples and urine were collected for six hours. The results suggested that hypoxia does not influence the disposition of theophylline or its metabolites.

1. The aim of the present study was to assess the effects of hypercapnia or hypoxia on plasma concentrations of atrial natriuretic factor (ANF) in conscious unrestrained dogs. 2. For this purpose, chronically instrumented dogs were exposed in a random order to either room air, or to an atmosphere containing 21% O2/10% CO2/69% N2 to produce hypercapnia, or 10% O2/3% CO2/87% N2 to produce hypoxia without respiratory alkalosis. 3. Plasma concentrations of ANF did not change significantly during hypoxia. 4. In contrast, during hypercapnia, plasma concentrations of ANF increased by more than 100% and returned to baseline at the end of hypercapnia. 5. Hypercapnia, but not hypoxia, induced an increase in left atrial and central venous pressures. 6. We conclude that hypercapnia increases plasma ANF concentration, and that this increase may be secondary to an increase of the left and right atrial pressures. These phenomena may explain the increase in diuresis and natriuresis which has been described during hypercapnia.

New methods of respiratory support are needed to reduce the high mortality rate of acute respiratory failure. To simplify the procedures of extracorporeal CO2 elimination under apneic oxygenation, one approach is to replace the membrane lung by a hemodialyzer and to administer an alkali, since hemodialysis requires a lower blood flow rate than blood-gas exchange. This study compared the effectiveness of trishydroxymethyl aminomethane (THAM) and NaOH in this procedure. Twelve male Anglo-Poitevin dogs (25 to 33 kg) were anesthetized, curarized and mechanically hypoventilated (VE = 41% of the control value). After not less than 15 min, a venovenous shunt was used for dialysis with blood flow of 7-10 ml. min.-1kg-1 for at least 8 hours. The dialysate contained no acetate, bicarbonate or lactate, but was alkalinized to a pH of 8-9 by the addition of NaOH. A solution of THAM (0.5 N) was infused into the right heart at the rate of 0.30 ml.min.-1kg-1 in six animals, and NaOH (0.15 N) was infused in the other six at the rate of 0.80 ml.min-1kg-1. The injected volumes were compensated for by an equivalent amount of ultrafiltration. Elimination of CO2 (mean TCO2 = 2.3 ml.min.-1kg-1) was the same with both methods and the difference for the electrolytes and acid-base equilibrium was only very small. However, hemolysis was six times greater with NaOH than with THAM. Despite ultrafiltration, a similar marked weight gain was observed from the second hour of the experiment in the NaOH series, but only after 7 hours with THAM. It thus appears that hemodialysis combined with alkalinisation is still too complex a procedure to be safely applied in acute or chronic pulmonary failure.

Rats were exposed for 7 days to an oxygen concentration of 85% and then submitted to an aerosol of papain, immediately, 3, 7 or 15 days after this exposure. The number of animals dying increased as the time between the administration of papain and the end of the exposure to oxygen increased. The quantification of emphysema was made by measurement of the mean linear intercept (LM). The LM does not differ between animals pretreated with oxygen and which have received papain, immediately or after 3 days, and the controls in air not having received papain. On the contrary, the animals pretreated with oxygen and having received papain 7 or 15 days later show a significantly higher LM than do the controls in air having received papain. The protection of the lung against the elastolytic effect of papain by a preliminary stay in 85% O2 is short-term; its mechanism is discussed.

An experimental model of pulmonary interstitial fibrosis was attempted in beagle dogs by intravenous administration of weak doses of paraquat. After various trials, the final protocol involved the intravenous injection of 2 mg/kg repeated every eight days for three weeks, and then every 15 days. On the 70th day, areas of localized interstitial fibrosis were observed (less than 10% of the surface of the tissue sections) in an otherwise healthy parenchyma. There was no marked hepatic or renal lesion. The evolution of the inflammatory and toxic processes was followed by the changes: 1) in the animal's weight (drop in weight after the injection of paraquat), 2) in blood gases (essentially drop in PaO2 and in SaO2), 3) in ventilation and respiratory exchanges (increase of VE and ventilatory frequency, decrease of Duco2), and 4) in static pulmonary compliance (distinct fall after injection). All these modifications showed a close relationship to the pattern of the paraquat injections. They receded 15 days after the last injection and reappeared after a new injection. The pulmonary hemodynamic study carried out only at the beginning of the experiment and before the animal was killed showed only a few anomalies (reduction of the average pressure of the right atrium).