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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.

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 Multiple blood samples were withdrawn and urine was collected to assay diltiazem and metabolites [N-desmethyl diltiazem (MA), deacetyl diltiazem (DAD) and N-desmethyl deacetyl diltiazem (M2)].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.

The effect of propofol and thiopentone on cerebral (CBF), myocardial (MBF), muscular, and arterial hepatic blood flow was assessed with radiolabelled microspheres in 12 chronically instrumented dogs, six given propofol and six thiopentone. Tissue blood flows were measured in the awake animal, after 30 min of normoxic anaesthesia (room air), and after 30 min of hypoxic anaesthesia using a mixture of 10% O2 and 3% CO2 in nitrogen. The decrease in CBF from awake to normoxic anaesthesia was similar with propofol and thiopentone (propofol: 77 +/- 8 to 38 +/- 3 ml min-1 100 g-1, P < 0.01; thiopentone: 66 +/- 3 to 33 +/- 2 ml min-1 100 g-1, P < 0.01). During hypoxia, CBF rose moderately in the two groups (respectively +19% and +28%, P < 0.05). The MBF increased in propofol and thiopentone groups after 30 min of anaesthesia with air (propofol: 97 +/- 23 to 137 +/- 15 ml min-1 100 g-1; thiopentone: 82 +/- 7 to 141 +/- 10 ml min-1 100 g-1) and increased still more during hypoxia. The increase in MBF was related to an increase in heart rate and blood pressure. The quadriceps blood flow decreased during anaesthesia in normoxia and in hypoxia. The diaphragmatic blood flow increased with thiopentone under hypoxia. The hepatic arterial blood flow was unchanged. It is concluded that the effects of propofol on regional blood flows are very similar to those of thiopentone.

The effect of acute and chronic hypoxia on the disposition of lidocaine and its metabolites, and on regional blood flow has been examined in conscious beagles (n = 5). Each dog received an infusion of lidocaine for 5 h under three experimental conditions: (1) breathing air; (2) following acute exposure to a FIO2 of 8% and a FICO2 of 3.5% to generate a PaO2 of 45 mmHg without hypocapnia; and (3) after 6 days of hypoxemia. Multiple blood samples were drawn to assess the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). Three hours after the end of the infusion of lidocaine, the dogs received radioactive microspheres to estimate hepatic, renal and brain blood flow. Neither acute nor chronic moderate hypoxia affected the kinetics of lidocaine, the parent compound. However, both experimental conditions increased plasma concentrations of MEGX and GX and increased the ratio of the area under their plasma concentration curves to the dose of lidocaine received. Acute moderate hypoxia increased brain blood flow, although it did not affect liver or renal perfusion. Chronic moderate hypoxia did not significantly change the blood flow to any of the organs studied. It was concluded that acute and chronic moderate hypoxia decreases the rate of elimination of both active metabolites of lidocaine without modifying the perfusion to the organs responsible for their elimination.

Cimetidine blunts the increase in cerebral blood flow (CBF) normally observed during hypoxia. It is important, therefore, to know whether other H2-blockers also affect the cerebral circulation adaptation to hypoxia. Cerebral blood flow was measured in 24 awake dogs after an intravenous injection of either saline (control) or one of three H2-blockers: 1 mg/kg ranitidine, 0.4 mg/kg famotidine, or 1 mg/kg roxatidine. These doses are equipotent blockers of H2-gastric receptors. Each dog was studied during normoxia and after 2 and 4 h of normocapnic hypoxia (FIO2, 0.10; FICO2, 0.035). During each set of experimental conditions, a bolus of either saline or one of the anti-H2 drugs was administered, and, 15 min later, radiolabeled microspheres (ruthenium 103, scandium 46, and cerium 141) were injected into the left atrium for measurement of regional CBF. After death by an overdose of thiopental, each dog's brain was excised and fixed in 10% formaldehyde; it was then weighed and dissected by region, with the radioactivity measured in each region using a gamma counter. During hypoxia, PaO2 ranged from 45 to 50 mm Hg, and pH, PaCO2, and hematocrit were within the normal limits. In the control group CBF increased 34% above normoxic baseline levels after 2 h and 31% after 4 h of hypoxia. Ranitidine (1 mg/kg) did not prevent the increase in CBF during hypoxia, but famotidine and roxatidine prevented it. When the dose of ranitidine was doubled (2 mg/kg), it too abolished the increase of CBF induced by hypoxia. In conclusion, H2-receptor blockers could interfere with the adaptation of CBF during hypoxia.

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 explanation for the increased frequency of troubles with digoxin therapy in patients with chronic pulmonary diseases is debated. The reported effects of hypoxia in vivo on myocardial levels of digoxin are contradictory, and there have been few studies on the effects of hypercapnia. In the past, it has been shown in rat myocardial tissue at rest in vitro that hypoxia decreased and hypercapnic acidosis increased the digoxin uptake. We performed a new study in vitro in an isolated beating rat heart perfused at constant flow (37 degrees C) and stimulated at a constant frequency (6 Hz). The performances were recorded with an intraventricular balloon equipped with a tip-manometer catheter. The action of digoxin was studied by recording systolic pressure (PS) and diastolic pressure (PD), the left ventricular developed pressure (LVDP = PS - PD), the (dP/dt)max, and the ratio (dP/dt)max/PS. First, the heart was perfused for 30 min with a modified Tyrode's solution perfusate aerated with carbogen (pH = 7.40; PCO2 = 37 mmHg; PO2 = 530 mmHg) (1 mmHg = 133.32 Pa). Various parameters of contractions were recorded (initial control values). Then the heart was perfused for 15 min with Tyrode's solution aerated either with a hypoxic gas mixture (pH = 7.41; PCO2 = 36 mmHg; PO2 = 122 mmHg), a hypercapnic gas mixture (pH = 7.08; PCO2 75 mmHg; PO2 = 485 mmHg), or a hypoxic-hypercapnic gas mixture (pH = 7.09; PCO2 = 73 mmHg; PO2 = 124 mmHg). Control hearts were continuously perfused with Tyrode's solution aerated with carbogen.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

The object of this study was to assess the effect of moderate acute hypoxemia on plasma concentrations of atrial natriuretic factor (ANF), arginine vasopressin (AVP), plasma renin activity (PRA) and urinary excretion of prostaglandin E2 (UPGE2V). Eight volunteers were exposed for 2 hours to a gas mixture containing 10% O2, 4.5% CO2 and 85.5% N2. Hypoxia increased diastolic blood pressure and free water clearance. Hypoxia did not change the AVP, PRA or UPG2V, although increased ANF from 17.7 +/- 3.4 pg/mL to 27.2 +/- 1.7 pg/mL (p less than 0.005) at 120 minutes. ANF changes were closely associated with the rise in blood pressure.

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.

A recent study has shown in the conscious dog that hypoxia associated with respiratory acidosis could increase the in vivo distribution of digoxin in the myocardium. The aim of the present study was to evaluate in vitro the effects of hypoxia and (or) hypercapnic acidosis on the digoxin uptake. For this purpose, rat myocardium was incubated for 180 min with radiolabelled [3H]digoxin. The uptake of digoxin which was expressed in nanograms of digoxin bound per 100 mg of myocardium was decreased by hypoxia and increased by hypercapnic acidosis. The association of hypoxia and hypercapnic acidosis had no effect on the digoxin uptake, suggesting that in vitro hypoxia acts in an opposite way to hypercapnia.

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]