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L C Ou

Publications and source records attributed to L C Ou.

At least 37 records · Page 2Linked to original sources
PubMed1993

Possible role of pulmonary blood volume in chronic hypoxic pulmonary hypertension.

Chronic hypoxia increases the total blood volume (TBV) and pulmonary arterial blood pressure (Ppa) and induces pulmonary vascular remodeling. The present study was undertaken to assess how the pulmonary blood volume (PBV) changes during hypoxia and the possible role of PBV in chronic hypoxic pulmonary hypertension. A novel method has been developed to measure the TBV, PBV, and Ppa in conscious rats. The method consists of chronic implantation of a loose ligature around the ascending aorta and pulmonary artery, so that when the ligature is drawn tightly, it traps the blood in the pulmonary vessels and left heart and simultaneously kills the rat. The pulmonary veins are then ligated to separate the left ventricular blood volume from the PBV. This surgical approach, together with chronic catheterization of the pulmonary artery and the use of 51Cr-labeled red blood cells, allows measurement of TBV, PBV, and Ppa. This method has been used to analyze the relationships between TBV and PBV and between Ppa or right ventricular hypertrophy and PBV in two rat strains with markedly different TBV and Ppa responses to chronic hypoxia. PBV per given lung weight did not increase and even decreased during hypoxia despite marked increases in TBV. There was a close correlation between Ppa or right ventricular hypertrophy and PBV in the two strains of chronically hypoxic animals, suggesting that a greater PBV plays a significant role in the development of severe chronic hypoxic pulmonary hypertension in the altitude-susceptible Hilltop rats.

Animals↗
PubMed1992

Ventilatory and hematopoietic responses to chronic hypoxia in two rat strains.

Hilltop (H) and Madison (M) strains of Sprague-Dawley rats exhibit strikingly different susceptibilities to the effects of chronic altitude exposure. The H rats develop greater polycythemia, hypoxemia, and pulmonary hypertension. We studied ventilation, pulmonary gas exchange, tissue oxygenation, and hematologic adaptations in the two rat strains during a 50-day exposure to a simulated altitude (HA) of 5,500 m (18,000 ft). There were no strain differences among the variables we studied under sea level (SL) conditions. Within the first 14 days of hypoxic exposure, the only significant strain differences were that erythropoietin (EPO) rose much higher and erythroid activity was greater in the H rats, even though arterial Po2 and PCo2 (Pao2 and PaCo2, respectively), renal venous PO2 (Prvo2), and ventilation (VE) were equivalent in the two strains during this time. By day 14 at HA, the H rats had significantly higher erythroid activity, hematocrit (Hct), and EPO levels, significantly lower PaO2 and PrvO2, but equivalent VE and PaCO2. These changes persisted for the remainder of the exposure, except that the Hct continued to rise and the increase was greater in H rats. Despite the greater O2-carrying capacity of H rats in the later stages of hypoxic exposure, PaO2 and PrvO2 were significantly lower in H rats. There were no strain differences at either SL or HA in ventilatory responses to hypercapnia or hypoxia, in blood O2 affinity or 2,3-diphosphoglycerate, in extrarenal production of EPO, or in EPO clearance. We conclude that early in the hypoxic exposure the H rats produce more EPO at apparently equivalent levels of hypoxia, and this is the first step in the pathogenesis of the maladaptation to HA manifest by H rats. We find no consistent evidence that differences in VE contribute to the variable susceptibility to hypoxia in the two rat strains.

Altitude Sickness↗
PubMed1991

Acute hypoxia-induced diuresis in rats.

Acute hypoxia elicits diuresis, natriuresis, and hypotension in many mammalian species, but the cause of this effect remains unclear. The present study, using chronically instrumented rats, was undertaken to assess a possible role of atrial natriuretic factor (ANF) in these hypoxic responses. Acute hypoxia (10.5% O2) increased urine output and sodium and potassium excretion. Systemic arterial blood pressure fell during acute hypoxia. Levels of ANF significantly increased with acute hypoxia. The plasma levels of ANF during acute hypoxia were similar to those found following bolus doses of exogenous ANF which are known to cause diuresis, natriuresis and a fall in blood pressure. Increased ANF levels may play a role in mediating physiologic responses to hypoxia in the rat.

Animals↗
PubMed1989

Does atrial natriuretic factor protect against right ventricular overload? I. Hemodynamic study.

We studied the effects of synthetic atrial natriuretic factor (ANF, 28-amino acid peptide) on base-line perfusion pressures and pressor responses to hypoxia and angiotensin II (ANG II) in isolated rat lungs and on the following hemodynamic and renal parameters in awake, chronically instrumented rats: cardiac output (CO), systemic (Rsa) and pulmonary (Rpa) vascular resistances, ANG II- and hypoxia (10.5% O2)-induced changes in Rsa and Rpa, and urine output. Intra-arterial ANF injections lowered base-line perfusion pressures and blunted hypoxia- and ANG II-induced pressor responses in the isolated lungs. Bolus intravenous injection of ANF (10 micrograms/kg) into intact rats decreased CO and arterial blood pressures of both systemic and pulmonary circulations and increased Rsa. ANG II (0.4 micrograms/kg) increased both Rsa and Rpa, and hypoxia increased Rpa alone in the intact rats. ANF (10 micrograms/kg) inhibited both ANG II- and hypoxia-induced increases in Rpa but did not significantly affect the ANG II-induced increase in Rsa. The antagonistic effect of ANF on pulmonary vasoconstriction was reversible and dose-dependent. The threshold doses of ANF required to inhibit pulmonary vasoconstriction were in the same range as those required to elicit diuresis and natriuresis. The data demonstrate that ANF has a preferential relaxant effect on pulmonary vessels constricted by hypoxia or ANG II. Both the renal and the pulmonary vascular effects of ANF may represent fundamental physiological actions of ANF. These actions may serve as a negative feedback control system that protects the right ventricle from excessive mechanical loads.

Angiotensin II↗
PubMed1989

Does atrial natriuretic factor protect against right ventricular overload? II. Tissue binding.

Previous studies have led us to hypothesize that the physiological significance of the diuretic and pulmonary vaso-relaxant effects of atrial natriuretic factor (ANF) is to protect the right heart. This study was designed to evaluate the relative importance of various peripheral tissues as sites of ANF action by tracing the temporal pattern of distribution of 125I-ANF and quantitating the specific binding sites. An in vivo approach, utilizing trace amount of 125I-ANF was adopted to simulate physiological conditions. 125I-ANF injected either intravenously or intra-arterially was quickly bound to peripheral tissues with less than 5% remaining in the circulation after 1 min. The relative binding capacity was greatest in the lung, followed by the kidney, right ventricle, adrenal gland, and left ventricle. The magnitude of specific ANF binding sites per gram of tissue weight followed a similar order. The data demonstrate that ANF released under all circumstances is quickly bound to the target organs, particularly the lung and the kidney, and suggest that these two organs could be the most important target organs of ANF. This evidence provides further support for the proposed hypothesis that a major evolutionary role of ANF is the protection of the right ventricle from mechanical loads.

Adrenal Glands↗
PubMed1988

Lung angiotensin converting enzyme activity in rats with differing susceptibilities to chronic hypoxia.

The decrease in lung angiotensin converting enzyme (ACE) activity occurring in rats during chronic hypoxia might be related to the pulmonary haemodynamic response or to the hypoxia. A study in rats was carried out to investigate this question. Rats from the Hilltop (H) strain are known to develop more severe pulmonary hypertension as a result of chronic hypoxia than rats from the Madison (M) strain despite having virtually identical arterial and mixed venous oxygen tensions. Rats from H and M strains were exposed to hypoxia (0.5 atm) for 3-21 days and lung and serum ACE activities were determined. After three days' hypobaria lung ACE activity was significantly lower and serum ACE significantly higher in H than in M rats. Linear regressions for lung ACE activity and right ventricular:body weight ratios showed significant inverse correlations and were similar in the two strains. The results suggest that pulmonary hypertension and not hypoxia determines the reduction in lung ACE activity, possibly by releasing ACE into the blood stream.

Animals↗
PubMed1988

Kainic acid on the rostral ventrolateral medulla inhibits phrenic output and CO2 sensitivity.

We used the neurotoxin, kainic acid, which is known to stimulate neuronal cell bodies as opposed to axons of passage by binding to specific amino acid receptors to determine whether cells with such receptors have access to the ventrolateral medullary surface and are involved in central ventilatory chemosensitivity. Pledgets with 4.7 mM kainic acid were placed bilaterally on the rostral, intermediate, or caudal ventilatory chemosensitive areas for 1-2 min in chloralose-urethan-anesthetized, paralyzed, vagotomized, glomectomized, and servo-ventilated cats. Application of kainic acid on the caudal or intermediate areas produced no consistent significant effects on eucapnic phrenic output or on the slope or maximum value of the phrenic nerve response to increased end-tidal PCO2. Rostral area kainic acid produced immediate augmentation and then diminution of blood pressure and phrenic output. Apnea developed in six of nine cats by 40 min. In all five cats in which it could be tested, the slope of the CO2 response was clearly decreased. Of [3H]kainic acid applied to the rostral area, 88.4% was shown to be within 2 mm of the ventral surface. Comparison of surface application sites of this and other studies suggests that an area overlapping the border of the original rostral and intermediate areas allows access to neurons involved in the chemoreception process, which may also provide tonic facilitatory input to cardiorespiratory systems.

Animals↗
PubMed1988

Pirenzepine prevents diethyl pyrocarbonate inhibition of central CO2 sensitivity.

Application by pledget of the M1-antimuscarinic receptor agent pirenzepine (40 mM) to the rostral chemosensitive areas of the ventrolateral medulla in anesthetized, paralyzed, vagotomized, glomectomized, and servoventilated cats inhibited the slope of the integrated phrenic response to CO2 by 32.5% (P less than 0.03) and the maximum value by 21.1% (P less than 0.01). Similar application of the imidazole-histidine blocking agent diethyl pyrocarbonate (DEPC) decreased the slope by 40.3% (P less than 0.01) and the maximum value by 29.3% (P less than 0.05). Both responses confirm previous results. DEPC treatment decreased the effectiveness of subsequent pirenzepine application such that although slope and maximum were further decreased, the values were not significantly different from those after DEPC. Pirenzepine treatment prevented any subsequent DEPC inhibitory effect. The results raise the possibility that the inhibitory effects of DEPC on CO2 chemosensitivity are via muscarinic receptors and that muscarinic receptor involvement in CO2 chemosensitivity requires the presence of imidazole-histidine. Analysis by scintillation counting of successive 100-micron sections of medulla after rostral area application of [3H]pirenzepine indicated that the pirenzepine and DEPC effects are most probably within 2.0 mm of the ventral surface as measured from the midline, well away from the dorsal and ventral respiratory group neurons.

Animals↗
PubMed1987

Reticulocytosis, increased mean red cell volume, and greater blood viscosity in altitude susceptible compared to altitude resistant rats.

We have identified two strains (H and M) of Sprague-Dawley rat with markedly different susceptibilities and cardiopulmonary responses to chronic hypobaria. To further characterize factors responsible for these differing cardiopulmonary responses to chronic hypobaria, the present study examined differences in hematologic responses between the strains and assessed the contribution of differences in blood viscosity to differences in pulmonary vascular resistance. Following a 4-5 week exposure to simulated high altitude (0.5 atm), hemoglobin, hematocrit, mean red cell volume, and reticulocyte count were all increased in the susceptible H compared to the resistant M rats, whereas red blood cell counts were similar. Sea level controls manifested no differences. Blood viscosity, measured in a capillary viscometer, was 53% greater in chronically hypoxic H than in M rats, and plasma viscosities were similar. Blood from high altitude H rats increased pulmonary vascular resistance more than blood from high altitude M rats when perfused into lungs isolated from high altitude rats of either strain. In conclusion, high altitude H rats have an increased population of immature red cells, leading to a greater mean red cell volume and hematocrit than in high altitude M rats. These hematologic differences contribute to the the increased blood viscosity and greater pulmonary vascular resistance of H compared to M rats after 4 weeks' high altitude exposure.

Altitude↗
PubMed1987

Time course of cardiopulmonary responses to high altitude in susceptible and resistant rat strains.

We have identified two strains (H and M) of Sprague-Dawley rat with distinctly different susceptibilities and cardiopulmonary responses to hypoxia. In this study, we studied the development of cardiopulmonary and hematological responses to hypoxia and the post-hypoxic regression of these responses in the two strains over time. Under sea level conditions, there were no differences between the two strains. On exposure to hypobaric hypoxia (0.5 atm), right ventricular peak systolic pressure (RVPP) and right ventricular hypertrophy (RVH) increased more rapidly in the susceptible (H) than in the resistant (M) strain. In contrast, post-hypoxic reversal of these changes occurred at comparable rates. Hematocrits rose at similar rates in the two strains until after two weeks, when that of the H strain slightly exceeded that of the M strain. With the progression of RVH, left ventricular plus septal to body weight ratio (LV + S) g/100 g bw decreased in M rats but increased in the H rats. As a result, a conspicuous overall cardiac hypertrophy developed in the H rats but only a minimal cardiac hypertrophy occurred in the M strain. The data show that susceptibility to hypoxia in H rats is associated with more rapid development of RV systolic hypertension and biventricular hypertrophy than in M rats. The mechanism for the accelerated cardiopulmonary responses in the H rats most likely involves greater hypoxic pulmonary vasoconstriction or pulmonary vascular remodeling. Differences in hematocrit between the strains do not contribute to the early cardiopulmonary responses.

Altitude↗
PubMed1987

Pulmonary artery structural changes in two colonies of rats with different sensitivity to chronic hypoxia.

Chronic hypoxia causes more severe pulmonary hypertension in the Hilltop colony of Sprague-Dawley rats than in the Madison colony and also greater polycythemia and vasoconstriction. This study examines the structural features of the pulmonary artery bed, another contributing factor to hypoxic hypertension. After 14 days of hypobaric hypoxia, in Hilltop rats, more of the intraacinar arteries became muscular, and the medial thickness of intraacinar and preacinar arteries was greater. In Hilltop control rats, muscle was found in more intraacinar arteries, but, paradoxically, acute hypoxic vasoconstriction was less. Thus, while in chronic hypoxia increased muscle correlates with pulmonary hypertension, in control rats the reserve seems to be true. The increased muscle in control Hilltop rats could, however, predispose to the greater muscularization seen after chronic hypoxia.

Animals↗
PubMed1986

Acute and chronic pulmonary pressor responses to hypoxia: the role of blunting in acclimatization.

We studied two strains of Sprague-Dawley rats: the Madison (M) that acclimatizes successfully to high altitude; and the Hilltop (H), that manifests signs of chronic mountain sickness at high altitude and has a high mortality rate. Awake, chronically instrumented animals were tested at sea level, at intervals during 30 days at a simulated altitude of 5500 m, and during 10 to 15 days of recovery at sea level. Mean pulmonary artery pressure (PAP) rose at high altitude to reach 60 mm Hg in H and 40 mm Hg in M, but the acute pressor response to hypoxia at sea level was much more pronounced in M than H. Depression of PAP by normoxic exposures in H rats at high altitude was slightly early in the period of stay but was enhanced with further prolongation of high altitude residence. The M rats, in contrast, had a blunted response (normoxia had very little depressant effect on PAP) after the first 24 h at high altitude, and it remained so for the duration of the stay. On return to sea level the response of H rats remained unchanged for 7 days, but the blunted response of the M rats at high altitude reversed at sea level to become exaggerated. We conclude: that responses of PAP to acute hypoxia do not forecast what the chronic response will be; that the appearance of an unidentified mechanism during chronic hypoxia in the M strain attenuates the vasoreactivity of the pulmonary vessels to hypoxia; and that the absence of such a blunting mechanism in H leads to the higher PAP in this strain and its morbid consequences. The hypothesis is put forward that the existence of such a blunting mechanism is an important factor in the adaptability of species to high altitude.

Adaptation, Physiological↗
PubMed1986

Hepatic heme and drug metabolism in rats with chronic mountain sickness.

Rats chronically exposed to hypobaric conditions develop pulmonary hypertension, right heart failure, hemoglobinemia, and in preliminary studies were recently found to have increased hepatic cytochrome P-450 content and activity of heme oxygenase, the rate-limiting enzyme for heme breakdown. To further delineate effects of chronic hypoxic, hypobaric exposure, on hepatic physiology and biochemistry, we have studied heme and drug metabolism in male Sprague-Dawley rats exposed to hypoxic conditions for 4-5 wk. Hypoxia, produced by exposure of rats to room air under hypobaric conditions (approximately 380 Torr), caused marked polycythemia [hematocrit (Hct) 70% vs. control Hct 43%], plasma hemoglobinemia, depletion of plasma haptoglobin, and decreased hemopexin concentrations. It also led to significant (20-30%) increases in concentrations of total hepatic heme and microsomal cytochrome P-450 and increased activities of heme oxygenase. In contrast, activity of 5-aminolevulinate synthase, the rate-limiting enzyme of hepatic heme synthesis, was significantly decreased in hypoxic rats and was not as inducible as in control normoxic rats. Hypoxia did not alter the rest of the heme synthetic pathway, as shown by a normal rate of conversion of 5-aminolevulinate to heme. Hypoxic exposure had no effect on the concentration of hepatic cytochrome-b5 but decreased activity of NADPH-cytochrome c reductase. Rates of metabolism of aminopyrine, benzphetamine, ethoxyresorufin, and warfarin were similar in hepatic microsomes obtained from hypoxic and normoxic rats. Thus the oxygen-requiring processes of hepatic heme and drug metabolism were well maintained despite chronic profound hypoxia sufficient to cause cardiopulmonary complications.

5-Aminolevulinate Synthetase↗
PubMed1985

Responses of blood volume and red cell mass in two strains of rats acclimatized to high altitude.

Two strains of rats, one that adapts successfully to high altitude (HA) (Madison = M) and the other that adapts poorly and suffers a high mortality rate at high altitude (Hilltop = H) were studied during 40 days of exposure to a simulated altitude of 18 000 ft (5450 m; PB = 175). The time rate of change of blood volume (TBV), red cell volume (RBCV), plasma volume (PV) and hematocrit (Hct), and the interrelationships of these variables, particularly emphasizing TBV, PV and Hct as functions of RBCV, were compared in the M and H strains. Sea level control values in the two strains were not different, but by the 5th day at HA RBCV and TBV had expanded to a greater extent in H than M - a difference that was maintained throughout the 40 days - but PV decreased similarly in the two strains. By 30 days the inter-strain differences of RBCV, TBV, and Hct became more pronounced but still no difference of PV was noted. The most significant feature was the greater polycythemic response of H, which at the extreme range was not associated with any further decrease of PV and therefore resulted in rapid expansion of TBV. The probable effects of these responses on cardiovascular function and oxygen transport are discussed, comparing the differences of H and M strains, which became maladaptive in H. The similarity of the responses in H to those of man with chronic mountain sickness is noted.

Adaptation, Physiological↗
PubMed1984

Ventilatory responses and blood gases in susceptible and resistant rats to high altitude.

On exposure to a stimulated altitude of 5500 m (18 000 ft), the Hilltop (H) strain of Sprague-Dawley rats develops signs of chronic mountain sickness (CMS) (severe polycythemia, severe pulmonary hypertension and right ventricular hypertrophy) associated with a high mortality rate. In contrast, the Madison (M) strain of Sprague-Dawley rats remains healthy with less severe cardiopulmonary and hematological responses. We tested the hypothesis that hypoventilation in the H rats relative to the M rats, leading to greater alveolar hypoxia or hypoxemia, could account for the different hematological and cardiopulmonary responses between the two strains. Ventilatory responses and blood gases were compared under normoxia and acute and chronic hypoxia in fully awake and unrestrained animals of the two strains. There were no differences in VE, Pao2, PaCO2, pHa, P-vO2, PvCO2 and pH-v under either acute or chronic hypoxia between the two strains of rats. It is concluded that relative hypoventilation does not contribute to altitude susceptibility in H rats.

Acid-Base Equilibrium↗
PubMed1984

The role of pulmonary vascular responses to chronic hypoxia in the development of chronic mountain sickness in rats.

A strain of Sprague-Dawley rat obtained from Hilltop Labs, Scottsdale, PA (H rats), develops more severe pulmonary hypertension, right ventricular hypertrophy, and polycythemia than a strain obtained from Madison, WI (M rats), following exposure to simulated high altitude. We sought to determine whether differences in pulmonary vascular responses to chronic hypoxia could explain the differing high altitude susceptibilities of the two strains. Vasoconstrictor responses to hypoxia and angiotensin II were tested in blood perfused lungs isolated from rats of both groups exposed to stimulated high altitude (4 to 5 weeks, 0.5 atm), or from sea level controls. Pressure-flow curves, serving as an index of 'passive' vascular resistance, were also determined in the isolated lungs. Vasoconstrictor responses to hypoxia were blunted in high altitude rats of both the H and M strains compared to sea level controls, and the H sea level rats had blunted vasoconstrictor responses to hypoxia compared to the M sea level rats. Vasoconstrictor responses to angiotensin II were similar among the groups and were unaffected by chronic high altitude exposure. Pressure-flow curves were greater in both high altitude groups than in the sea level groups, and those of the H high altitude rats were slightly greater than those of the M high altitude rats. Thus, differences in vasoconstrictor responses to hypoxia do not explain the greater pulmonary hypertension of H high altitude rats. However, greater 'passive' vascular resistance, probably due to more extensive structural remodeling of pulmonary vessels, does appear to contribute to the greater pulmonary hypertension of the H rats.

Altitude Sickness↗