Effects of crocetin on pulmonary gas exchange in foxhounds during hypoxic exercise.

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.     

Effect of hyperventilation on oxygenation of the brain cortex of newborn piglets

A new phosphorescence imaging method (Rumsey et al. Science Wash. DC 241: 1649-1651, 1988) has been used to continuously monitor the PO2 in the blood of the cerebral cortex of newborn pigs. A window was prepared in the skull and the brain superfused with artificial cerebrospinal fluid. The phosphorescent probe for PO2, Pd-meso-tetra(4-carboxyphenyl)porphine, was injected directly into the systemic blood. The phosphorescence of the probe was imaged, and the lifetimes were measured using flash illumination and a gated video camera. The PO2 in the blood of the veins and capillary beds of the cortex was calculated from the lifetimes. Systemic blood pressure was continuously monitored while the systemic arterial PCO2, PO2, and blood pH were measured periodically. The PO2 in the blood was quantitated for 60- to 200 microns2 regions within the image (from a total field of approximately 3 mm diam). The PO2 in the microvasculature was not uniform across the viewing field but increased or decreased in each region independently of the other regions. Thus at any point in time the PO2 in a region could be substantially above or below the average value. During hyperventilation, which lowered arterial PCO2 and increased pH of the blood, the average PO2 decreased in proportion to the decrease in arterial PCO2. For example, hyperventilation, which decreased arterial PCO2 from its normal value of 40 Torr to 10 Torr, caused a rapid (within 5 min) decrease in PO2 in the blood of capillaries and veins to approximately one-third of normal.     

Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation

Pressure-flow relationships in the ventilated lung have not been previously determined in undelivered fetal sheep. Therefore we studied 11 late-gestation chronically prepared fetal sheep during positive-pressure ventilation with different gas mixtures to determine the roles of mechanical distension and blood gas tensions on pressure-flow relationships in the lung. Ventilation with 3% O2-7% CO2 produced a substantial fall in pulmonary vascular resistance even though arterial blood gases were not changed. Increases in pulmonary arterial PO2 during ventilation were associated with falls in pulmonary vascular resistance beyond that measured during mechanical distension. Decreases in pulmonary arterial PCO2 and associated increases in pH were also associated with falls in pulmonary vascular resistance. Pulmonary blood flow ceased at a pulmonary arterial pressure that exceeded left atrial pressure, indicating that left atrial pressure does not represent the true downstream component of driving pressure through the pulmonary vascular bed. The slope of the driving pressure-flow relationship in the normal mature fetal lamb was therefore different from the ratio of pulmonary arterial pressure to pulmonary arterial flow. We conclude that mechanical ventilation, increased PO2 and decreased PCO2, and/or increased pH has an important influence on the fall in pulmonary vascular resistance elicited by positive pressure in utero ventilation of the fetal lamb and that the downstream driving pressure for pulmonary blood flow exceeds left atrial pressure.     

Transcutaneous pO2 of volunteers during hyperbaric oxygenation

Continuous transcutaneous pO2 measurements (tcPO2 measurements) were performed in healthy volunteers who were breathing air and oxygen under hyperbaric conditions (max. 4 ata). The results show a close correlation of PO2 values measured by the noninvasive method, in blood from discret arterial punctures, chamber PO2, respectively, the PO2 of the inspiratory gas mixture which was checked up to maximal values of 2,200 mm Hg. The PO2 in the arterial blood samples was measured immediately after the puncture insight the hyperbaric chamber using a specially designed through electrode.     

Influence of oxygen partial pressures on protein synthesis in feeding crabs

Many water-breathing animals have a strategy that consists of maintaining low blood PO2 values in a large range of water oxygenation level (4-40 kPa). This study examines the postprandial changes in O2 consumption, arterial blood PO2, and tissue protein synthesis in the shore crab Carcinus maenas in normoxic, O2-depleted, and O2-enriched waters to study the effects of this strategy on the O2 consumption and peptide bond formation after feeding. In normoxic water (21 kPa), the arterial PO2 was 1.1 kPa before feeding and 1.2 kPa 24 h later. In water with a PO2 of 3 kPa (arterial PO2 0.6 kPa), postprandial stimulation of protein synthesis and O2 consumption were blocked. The blockade was partial at a water PO2 of 4 kPa (arterial PO2 0.8 kPa). An increase in environmental PO2 (60 kPa, arterial PO2 10 kPa) resulted in an increase in protein synthesis compared with normoxic rates. It is concluded that the arterial PO2 spontaneously set in normoxic Carcinus limits the rates of protein synthesis. The rationale for such a strategy is discussed.     

Erythropoietin responses to progressive blood loss over 10 days in the ovine fetus

Long-term loss of fetal blood can occur with fetomaternal hemorrhage, vasoprevia, or placental previa. Our objective was to determine the effects of progressive fetal blood loss over 10 days on fetal plasma erythropoietin (EPO) concentration and its relationship to arterial PO(2), hematocrit, and the volume of blood loss. Late-gestation fetal sheep (n = 8) were hemorrhaged daily at a rate of 1 ml/min over 10 days. The extent of hemorrhage differed in each fetus and ranged from 30 to 80 ml/day, with the cumulative volume removed ranging from 78 to 236 ml/kg estimated fetal weight. Four fetuses served as time controls. EPO concentration measurements were by radioimmunoassay. Statistical analyses included regression, correlation, and analysis of variance. We found that EPO and arterial PO(2) were unchanged until the cumulative hemorrhage volume exceeded 20-40 ml/kg. Once this threshold was exceeded, plasma EPO concentration increased progressively throughout the study and averaged 14.3 +/- 3.2 times basal values on day 10. EPO concentration, arterial PO(2), and hematocrit changes were related curvilinearly to cumulative hemorrhage volume (P < 0.01), whereas the relationship between plasma EPO and arterial PO(2) was log linear (P < 0.001). We conclude that 1) fetal plasma EPO concentration and arterial PO(2) are insensitive to a slow, mild-to-moderate blood loss over several days; 2) unlike the rapid return of EPO to normal within 48 h after acute hemorrhage, fetal EPO concentration undergoes a progressive increase with moderate-to-severe blood loss over several days; 3) the long-term hemorrhage-induced changes in EPO are best correlated with arterial PO(2); and 4) the fetal EPO response to hemorrhage does not appear to be limited by the fetus's ability to produce EPO.     

Arterial blood--spinal fluid oxygen gradient diminishes during alkalaemia in hyperoxic man

We investigated the effect of intravenous sodium bicarbonate (2 mmol x kg-1) on the arterial blood-spinal fluid PO2 gradient in twelve anaesthetized hyperoxaemic human subjects who were in preparation for surgical procedures The steady-state samples of arterial blood and lumbar fluid were withdrawn for the assessment of the acid-base status and electrolyte content in both fluid compartments before and after NaHCO3 injection. We found that NaHCO3 increased the arterial pH and PCO2, and decreased the blood-spinal fluid PO2 gradient significantly. The latter was a result of an increase in spinal fluid PO2 and a decrease in PaO2. The diminished PO2 gradient can be accounted for by the specific effect of carbamate and bicarbonate, distinct from that of pH, lowering the affinity of haemoglobin for oxygen. This might favor the maintenance of an adequate oxygen supply in the brain tissue under unfavorable conditions.     

Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats

This study investigated the pharmacokinetic properties of crocin following oral administration in rats. After a single oral dose, crocin was undetected while crocetin, a metabolite of crocin, was found in plasma at low concentrations. Simultaneously, crocin was largely present in feces and intestinal contents within 24h. After repeated oral doses for 6 days, crocin remained undetected in plasma and plasma crocetin concentrations were comparable to the corresponding data obtained after the single oral dose. Furthermore, the absorption characteristics of crocin were evaluated in situ using an intestinal recirculation perfusion method. During recirculation, crocin was undetected and low concentrations of crocetin were detected in plasma. The concentrations of crocin in the perfusate were reduced through different intestinal segments, and the quantities of drug lost were greater throughout the colon. These results indicate that (1) orally administered crocin is not absorbed either after a single dose or repeated doses, (2) crocin is excreted largely through the intestinal tract following oral administration, (3) plasma crocetin concentrations do not tend to accumulate with repeated oral doses of crocin, and (4) the intestinal tract serves as an important site for crocin hydrolysis.     

Time course of muscular blood metabolites during forearm rhythmic exercise in hypoxia

O2 concentration, PO2, PCO2, pH, osmolarity, lactate (LA), and hemoglobin (Hb) concentrations in deep forearm venous blood were repeatedly measured during submaximal exercise of forearm muscles. Concentrations of arterial blood gases were determined at rest and during exercise. Experiments were conducted under normoxia and hypobaric hypoxia (PB = 465 Torr). In arterial blood, data obtained during exercise were the same as those obtained during rest under either normoxia or hypoxia. In venous muscular blood, PO2 and O2 concentration were lower at rest and during exercise in hypoxia. The muscular arteriovenous O2 difference during exercise in hypoxia was increased by no more than 10% compared with normoxia, which implied that muscular blood flow during exercise also increased by the same percentage, if we assume that exercise O2 consumption was not affected by hypoxia. Despite increased [LA], the magnitude of changes in PCO2 and pH in hypoxia were smaller than in normoxia during exercise and recovery; this finding is probably due to the increased blood buffer value induced by the greater amount of reduced Hb in hypoxia. Hence all the changes occurring in hypoxia showed that local metabolism was less affected than we expected from the decrease in arterial PO2. The rise in [Hb] that occurred during exercise was lower in hypoxia. Possible underlying mechanisms of the [Hb] rise during exercise are discussed.     

Fetal sympathetic activity, transcutaneous PO2, and skin blood flow during repeated asphyxia in sheep

To improve detection of fetal distress, we examined whether increased fetal sympathetic activity during repeated episodes of asphyxia decreases skin blood flow, which can be monitored by recording transcutaneous PO2. Sympathetic activity was assessed by relating catecholamine concentrations in the fetal plasma to blood gas, acid-base, and heart rate variables which are commonly used to determine fetal distress. Fifteen experiments were conducted on 8 anaesthetised fetal sheep in utero between 125 and 145 days of gestation (term is at 147 days). They were subjected to 11 consecutive episodes of asphyxia of 30 (n = 3), 60 (n = 9), or 90 (n = 3) s over 33 min, achieved by arrest of uterine blood flow. Blood samples were drawn at 0, 33, and 60 min to determine arterial blood gases, acid base-balance, and concentrations of lactate, glucose, norepinephrine, and epinephrine. Fetal transcutaneous PO2, relative local skin blood flow, heart rate, arterial blood pressure, and arterial O2 saturation were recorded continuously. Fetal plasma concentrations of norepinephrine and epinephrine increased logarithmically as the duration of repeated asphyxia, anaerobic metabolism, and glucose concentrations increased, and as the mean O2 saturation, transcutaneous PO2, and local skin blood flow decreased. We conclude that during repeated episodes of asphyxia in fetal sheep near term, a significant increase in sympathetic activity can be detected indirectly by transcutaneous PO2 monitoring, because sympathetic activation reduces skin blood flow.     

Ventilatory effects and interactions with change in PaO2 in awake goats.

We utilized selective carotid body (CB) perfusion while changing inspired O2 fraction in arterial isocapnia to characterize the non-CB chemoreceptor ventilatory response to changes in arterial PO2 (PaO2) in awake goats and to define the effect of varying levels of CB PO2 on this response. Systemic hyperoxia (PaO2 greater than 400 Torr) significantly increased inspired ventilation (VI) and tidal volume (VT) in goats during CB normoxia, and systemic hypoxia (PaO2 = 29 Torr) significantly increased VI and respiratory frequency in these goats. CB hypoxia (CB PO2 = 34 Torr) in systemic normoxia significantly increased VI, VT, and VT/TI; the ventilatory effects of CB hypoxia were not significantly altered by varying systemic PaO2. We conclude that ventilation is stimulated by systemic hypoxia and hyperoxia in CB normoxia and that this ventilatory response to changes in systemic O2 affects the CB O2 response in an additive manner.     

Crocetin treatment inhibits proliferation of colon cancer cells through down-regulation of genes involved in the inflammation

Background

The current study was designed to investigate the effect of crocetin on the proliferation inhibition of colon cancer cells and the underlying mechanism.

Limitation of maximal O2 uptake and performance by acute hypoxia in dog muscle in situ

The factors that determine maximal O2 uptake (VO2max) and muscle performance during severe, acute hypoxemia were studied in isolated, in situ dog gastrocnemius muscle. Our hypothesis that VO2max is limited by O2 diffusion in muscle predicts that decreases in VO2max, caused by hypoxemia, will be accompanied by proportional decreases in muscle effluent venous PO2 (PvO2). By altering the fraction of inspired O2, four levels of arterial PO2 (PaO2) [21 +/- 2, 28 +/- 1, 44 +/- 1, and 80 +/- 2 (SE) Torr] were induced in each of eight dogs. Muscle arterial and venous circulation was isolated and arterial pressure held constant by pump perfusion. Each muscle worked maximally (3 min at 5-6 Hz, isometric twitches) at each PaO2. Arterial and venous samples were taken to measure lactate, [H+], PO2, PCO2, and muscle VO2. Muscle biopsies were taken to measure [H+] (homogenate method) and lactate. VO2max decreased with PaO2 and was linearly (R = 0.99) related to both PVO2 and O2 delivery. As PaO2 fell, fatigue increased while muscle lactate and [H+] increased. Lactate release from the muscle did not change with PaO2. This suggests a barrier to lactate efflux from muscle and a possible cause of the greater fatigue seen in hypoxemia. The gas exchange data are consistent with the hypothesis that VO2max is limited by peripheral tissue diffusion of O2.     

Changes in arterial oxygen tension and physiological status in resting, unrestrained Arctic charr Salvelinus alpinus (L.) exposed to mild hypoxia and hyperoxia

In arctic charr Salvelinus alpinus, arterial blood partial pressures of oxygen (PaO2) and carbon dioxide increased with increasing water oxygen tension (PwO2), while the water to arterial PO2 difference (PwO2-PaO2) did not change in relation to PwO2.     

Diffusion limitation in normal humans during exercise at sea level and simulated altitude

The relative roles of ventilation-perfusion (VA/Q) inequality, alveolar-capillary diffusion resistance, postpulmonary shunt, and gas phase diffusion limitation in determining arterial PO2 (PaO2) were assessed in nine normal unacclimatized men at rest and during bicycle exercise at sea level and three simulated altitudes (5,000, 10,000, and 15,000 ft; barometric pressures = 632, 523, and 429 Torr). We measured mixed expired and arterial inert and respiratory gases, minute ventilation, and cardiac output. Using the multiple inert gas elimination technique, PaO2 and the arterial O2 concentration expected from VA/Q inequality alone were compared with actual values, lower measured PaO2 indicating alveolar-capillary diffusion disequilibrium for O2. At sea level, alveolar-arterial PO2 differences were approximately 10 Torr at rest, increasing to approximately 20 Torr at a metabolic consumption of O2 (VO2) of 3 l/min. There was no evidence for diffusion disequilibrium, similar results being obtained at 5,000 ft. At 10 and 15,000 ft, resting alveolar-arterial PO2 difference was less than at sea level with no diffusion disequilibrium. During exercise, alveolar-arterial PO2 difference increased considerably more than expected from VA/Q mismatch alone. For example, at VO2 of 2.5 l/min at 10,000 ft, total alveolar-arterial PO2 difference was 30 Torr and that due to VA/Q mismatch alone was 15 Torr. At 15,000 ft and VO2 of 1.5 l/min, these values were 25 and 10 Torr, respectively. Expected and actual PaO2 agreed during 100% O2 breathing at 15,000 ft, excluding postpulmonary shunt as a cause of the larger alveolar-arterial O2 difference than accountable by inert gas exchange.(ABSTRACT TRUNCATED AT 250 WORDS)     

Operation Everest II: man at extreme altitude

Rapid ascent to high altitude may cause serious problems for climbers, skiers, and aviators. In contrast, gradual ascent enables humans to function where the unacclimatized cannot. To examine changes in the O2 transport system that produce acclimatization, eight men were taken in a decompression chamber (without other stresses experienced on high mountains) to a simulated altitude of 8,840 m (29,028 ft, ambient PO2 = 43 Torr) in 40 days. Maximal O2 uptake fell to 1.2 l/min, and arterial PO2 and PCO2 were 30 and 11 Torr, respectively, with arterial pH of 7.56. Many sophisticated studies were done: Swan-Ganz catheterization and inert gas diffusion studies at three altitudes showed that normal cardiac function persisted, pulmonary vascular resistance increased and at extreme altitude was not lowered by O2, and pulmonary ventilation-perfusion mismatch increased, though variably. This appears to be an important factor limiting performance at extreme altitude. This paper presents the background, general approach, and a summary of major observations reported in detail in other papers.     

Peripheral chemoreceptors in respiratory oscillations

The hypothesis that instability of cardiorespiratory control may depend on the response and sensitivity of carotid body chemoreceptors to arterial blood gases was studied in anesthetized cats under three different experimental conditions. 1) Following administration of the peripheral dopamine receptor blocker [domperidone (0.6-0.8 mg X kg-1, iv)], carotid chemoreceptor activity and its sensitivity to CO2 during hypoxia increased, leading to cardiorespiratory oscillations at low arterial PO2 in four of eight cats. Inhalation of 100% O2 promptly decreased chemoreceptor activity and eliminated the oscillations. Inhalation of CO2 stimulated the chemoreceptor activity and ventilation but did not eliminate the oscillations. Bilateral section of carotid sinus nerves abolished the cardiorespiratory oscillations. The implication is that the dopaminergic system in the carotid body keeps chemoreceptor responses to blood gas stimuli suppressed and hence cardiorespiratory oscillations damped. 2) Hypotension and circulatory delay induced by the partial occlusion of venous return led to cardiorespiratory oscillations at low but not at high arterial PO2. 3) A few cats developed cardiorespiratory oscillations without any particular experimental intervention. These oscillations were independent of arterial PO2 and chemoreceptor activity. Thus it is reasonable to conclude that the peripheral chemoreflex can play a critical role in developing cardiorespiratory oscillations in certain instances.     

Mechanism of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.     

Effect of acute hypoxia on microcirculatory and tissue oxygen levels in rat cremaster muscle.

Repeated exposure to brief periods of hypoxia leads to pathophysiological changes in experimental animals similar to those seen in sleep apnea. To determine the effects of such exposure on oxygen levels in vivo, we used an optical method to measure PO2 in microcirculatory vessels and tissue of the rat cremaster muscle during a 1-min step reduction of inspired oxygen fraction from 0.21 to 0.07. Under control conditions, PO2 was 98.1 +/- 1.9 Torr in arterial blood, 52.2 +/- 2.8 Torr in 29.0 +/- 2.7-microm arterioles, 26.8 +/- 1.7 Torr in the tissue interstitium near venous capillaries, and 35.1 +/- 2.6 Torr in 29.7 +/- 1.9-microm venules. The initial fall in PO2 during hypoxia was significantly greater in arterial blood, being 93% complete in the first 10 s, whereas it was 68% complete in arterioles, 47% at the tissue sites, and 38% in venules. In the 10- to 30-s period, the fall in normalized tissue and venular PO2 was significantly greater than in arterial PO2. At the end of hypoxic exposure, PO2 at all measurement sites had fallen very nearly in proportion to that in the inspired gas, but tissue oxygen levels did not reach critical PO2. Significant differences in oxyhemoglobin desaturation rate were also observed between arterial and microcirculatory vessels during hypoxia. In conclusion, the fall in microcirculatory and tissue oxygen levels in resting skeletal muscle is significantly slower than in arterial blood during a step reduction to an inspired oxygen fraction of 0.07, and tissue PO2 does not reach anaerobic levels.     

Lobar contribution to VA/Q inequality during constant-flow ventilation

Previous studies have shown that normal arterial PCO2 can be maintained during apnea in anesthetized dogs by delivering a continuous stream of inspired ventilation through cannulas aimed down the main stem bronchi, although this constant-flow ventilation (CFV) was also associated with a significant increase in ventilation-perfusion (VA/Q) inequality, compared with conventional mechanical ventilation (IPPV). Conceivably, this VA/Q inequality might result from differences in VA/Q ratios among lobes caused by nonuniform distribution of ventilation, even though individual lobes are relatively homogeneous. Alternatively, the VA/Q inequality may occur at a lobar level if those factors causing the VA/Q mismatch also existed within lobes. We compared the efficiency of gas exchange simultaneously in whole lung and left lower lobe by use of the multiple inert gas elimination technique in nine anesthetized open-chest dogs. Measurements of whole lung and left lower lobe gas exchange allowed comparison of the degree of VA/Q inequality within vs. among lobes. During IPPV with positive end-expiratory pressure, arterial PO2 and PCO2 (183 +/- 41 and 34.3 +/- 3.1 Torr, respectively) were similar to lobar venous PO2 and PCO2 (172 +/- 64 and 35.7 +/- 4.1 Torr, respectively; inspired O2 fraction = 0.44 +/- 0.02). Switching to CFV (3 l.kg-1.min-1) decreased arterial PO2 (112 +/- 26 Torr, P less than 0.001) and lobar venous PO2 (120 +/- 27 Torr, P less than 0.01) but did not change the shunt measured with inert gases (P greater than 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)