Effects of indomethacin on cardiac output distribution in normal and asphyxiated piglets

We determined the effect of breathing 9% CO2/10% O2/81% N2 (asphyxia) on cardiac output distribution (microspheres) in 4-5 day old unanesthetized, chronically instrumented piglets prior to and following intravenous indomethacin administration. Thirty minutes of asphyxia caused PaCO2 to increase from 35 +/- 2 mmHg to 66 +/- 2 mmHg, PaO2 to decrease from 73 +/- 4 mmHg to 41 +/- 1 mmHg, and pH to decrease from 7.52 +/- 0.05 to 7.21 +/- 0.07. Arterial pressure was increased slightly but cardiac output was not changed significantly. Asphyxia caused blood flow to the brain, diaphragm, liver, heart, and adrenal glands to increase while causing decreases in blood flow to the skin, small intestine, and colon. Blood flows to the stomach and kidneys tended to decrease, but the changes were not significant. Treatment with indomethacin during asphyxia did not alter arterial pressure or cardiac output but decreased cerebral blood flow to the preasphyxiated level and decreased adrenal blood flow about 20%. Indomethacin did not alter blood flow to any other systemic organ. At this time the piglet was allowed to breathe air for 2.5 hr undisturbed. Two and a half hours after indomethacin administration, blood flows to all organs returned to the preasphyxia control levels with the exception of cerebral blood flow which was reduced (93 +/- 13 to 65 +/- 7 ml/100 g X min). Three hours after indomethacin administration, the cerebral hyperemia caused by asphyxia was less (134 +/- 17 ml/100 g X min) than prior to indomethacin (221 +/- 15 ml/100 g X min). Indomethacin did not alter the asphyxia-induced changes to any other systemic organ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional cerebral blood flow response during and after acute asphyxia in newborn piglets

The hemodynamic response during and after acute asphyxia was studied in 14 newborn piglets. An apnea-like asphyxial insult was produced in paralyzed mechanically ventilated piglets by discontinuing ventilation until the piglets became bradycardic (heart rate less than 80 beats/min). Seven piglets had organ blood flow measured by microspheres at control, during asphyxia (PO2 = 16 +/- 11 Torr, pH = 7.31 +/- 0.07, PCO2 = 47 +/- 9 Torr), and during recovery from asphyxia. During acute asphyxia, rapid organ blood flow redistribution occurred, producing decreased renal and skeletal muscle blood flow, while coronary blood flow increased. Although total brain blood flow changed little during asphyxia, regional cerebral blood flow (rCBF) analysis revealed significant nonhomogeneous blood flow distribution within the brain during asphyxia, with decreases to the cerebral gray and white matter and the choroid plexus, whereas brain stem structures had increased flow. During recovery with reventilation, total brain blood flow increased 24% above control, with a more uniform distribution and increased flow to all brain regions. The time course of rCBF changes during acute asphyxia was then determined in seven additional piglets with CBF measurements made sequentially at 30-60 s, 60-120 s, and 120-180 s of asphyxia. The vasoconstriction seen in cortical structures, concurrent with the reduction in skeletal and kidney blood flow, known to be sympathetically mediated, suggest a selective reflex effect in this brain region. The more gradual and progressive vasodilation in brain stem regions during asphyxia is consistent with chemical control. These findings demonstrate significant regional heterogeneity in CBF regulation in newborn piglets.     

Developmental changes in endothelium-derived vasorelaxant factors in cerebral circulation

Endothelium-derived prostanoids are predominant vasorelaxant factors in the cerebral circulation of newborn pigs in vivo, whereas in older pigs nitric oxide (NO)-mediated responses also contribute to the regulation of cerebral vascular tone. We compared the expression and activities of NO synthase and cyclooxygenase in the cerebral microcirculation of newborn and adult pigs. In adult animals, expression and activity of endothelial NO synthase in cerebral microvessels and in cultured cerebral endothelial cells is two- to threefold higher than in newborn pigs; acetylcholine and bradykinin cause a greater increase in NO production in adult pigs. Expression and activity of cyclooxygenase in cerebral microvascular endothelial cells is similar in newborn and adult pigs; acetylcholine and bradykinin stimulated dilator prostanoid production to the same degree in both age groups. Endothelial prostanoid synthesis in cerebral microvessels and cultured endothelial cells was inhibited 30-70% by NS-398, reflecting a large contribution of COX-2 in both newborn and adult animals. These data indicate that in the cerebral circulation of pigs, NO synthase is age-dependently upregulated, whereas endothelial cyclooxygenase is not altered during postnatal development.     

Effect of a dopamine antagonist on ventilation during sustained hypoxia in mice

To test the hypothesis that dopamine accumulated in the carotid body limits hyperventilation during acclimatization to sustained hypoxia, we administered the dopamine antagonist droperidol to mice undergoing acclimatization to an inspired O2 fraction (FIo2) of 0.1. Twelve mice were exposed to hypoxia for 10 days and ventilation in 10% O2 and in 7% CO2 in air were measured daily by a plethysmographic method. Under both conditions ventilation increased during acclimatization to hypoxia: ventilation in 10% O2 increased from 39.4 +/- 3.8 (mean +/- SE) ml/min before exposure to sustained hypoxia to 72.2 +/- 4.2 ml/min after 3 days of continuous hypoxia, and ventilation in 7% CO2 in air at the same time increased from 113.2 +/- 5.4 ml/min to 140.0 +/- 5.6 ml/min. Twelve mice were exposed to FIo2 of 0.1 for 10 days and received droperidol (300 micrograms/kg intraperitoneally) before exposure to sustained hypoxia and on the 2nd, 4th, and 8th days of continuous hypoxia. Before exposure to sustained hypoxia, droperidol increased ventilation in 10% O2 from 40.1 +/- 2.5 ml/min to 72.5 +/- 5.2 ml/min, but after 2, 4, and 8 days of continuous hypoxia droperidol caused an acute fall in ventilation (ventilation in 10% O2 after droperidol on day 2: 49.1 +/- 3.1 ml/min, on day 4: 44.4 +/- 3.7 ml/min, and on day 8: 27.8 +/- 3.4 ml/min). Two days after the animals were returned to room air, ventilation in 10% O2 again increased in response to droperidol. We conclude that dopamine in the carotid body does not limit ventilatory responses to hypoxia during acclimatization to sustained hypoxia.     

Effect of 100% O2 on hypoxic eucapnic ventilation

We measured ventilation in nine young adults while they breathed pure O2 after breathing room air and after 5 and 25 min of hypoxia. With isocapnic hypoxia (arterial O2 saturation 80 +/- 2%) mean ventilation increased at 5 min and then declined, so that at 25 min values did not differ from those on room air. After 3 min of O2 breathing, ventilation was greater than that on room air or after 25 min of isocapnic hypoxia, whether the hyperoxia had been preceded by hypoxia or normoxia. During transitions to pure O2 breathing, ventilation was analyzed breath by breath with a moving average technique, searching for nadirs before and after increases in PO2. After both 5 and 25 min of hypoxia, O2 breathing was associated with transient depressions of ventilation, which were greater after 25 min than after 5 min. Significant depressions were not observed when hyperoxia followed room air breathing, and O2-induced nadirs after hypoxia were lower than those observed during room air breathing. O2 transiently depressed ventilation after hypoxia but not after room air breathing. These results suggest that the normal ventilatory response to isocapnic hypoxia has two components, an excitatory one from peripheral chemoreceptors, which is turned off by O2 breathing, and a slower inhibitory one, probably of central origin, which is affected less promptly by O2 breathing.     

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.     

Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans

The sympathetic response to hypoxia depends on the interaction between chemoreceptor stimulation (CRS) and the associated hyperventilation. We studied this interaction by measuring sympathetic nerve activity (SNA) to muscle in 13 normal subjects, while breathing room air, 14% O2, 10% O2, and 10% O2 with added CO2 to maintain isocapnia. Minute ventilation (VE) and blood pressure (BP) increased significantly more during isocapnic hypoxia (IHO) than hypocapnic hypoxia (HHO). In contrast, SNA increased more during HHO [40 +/- 10% (SE)] than during IHO (25 +/- 19%, P less than 0.05). To determine the reason for the lesser increase in SNA with IHO, 11 subjects underwent voluntary apnea during HHO and IHO. Apnea potentiated the SNA responses to IHO more than to HHO. SNA responses to IHO were 17 +/- 7% during breathing and 173 +/- 47% during apnea whereas SNA responses to HHO were 35 +/- 8% during breathing and 126 +/- 28% during apnea. During ventilation, the sympathoexcitation of IHO (compared with HHO) is suppressed, possibly for two reasons: 1) because of the inhibitory influence of activation of pulmonary afferents as a result of a greater increase in VE, and 2) because of the inhibitory influence of baroreceptor activation due to a greater rise in BP. Thus in humans, the ventilatory response to chemoreceptor stimulation predominates and restrains the sympathetic response. The SNA response to chemoreceptor stimulation represents the net effect of the excitatory influence of the chemoreflex and the inhibitory influence of pulmonary afferents and baroreceptor afferents.     

Leukotrienes increase levels of prostanoids in cerebrospinal fluid in piglets

We investigated effects of exogenous leukotrienes (C4, D4, or E4) on levels of prostanoids in cerebrospinal fluid in newborn pigs (1-5 days). A "closed" cranial window was placed over the parietal cortex. Pial arterial diameter was measured with a microscope and electronic micrometer system. Levels in cerebrospinal fluid (CSF) of 6-keto-Prostaglandin F1 alpha (6-keto-PGF1 alpha), Thromboxane B2 (TXB2), and Prostaglandin E2 (PGE2) were measured by radioimmunoassay. Topical application of leukotrienes C4, D4, or E4 (5,000 ng/ml) similarly constricted pial arteries by 15 +/- 2% (n = 14) (mean +/- SEM). In addition, leukotrienes increased levels of 6-keto-PGF1 alpha from 806 +/- 136 to 1,612 +/- 304 pg/ml (n = 13), TXB2 from 161 +/- 31 to 392 +/- 81 pg/ml (n = 10), and PGE2 from 2,271 +/- 342 to 4,636 +/- 740 pg/ml (n = 13). Each type of leukotriene had similar effects on prostanoid synthesis. In other experiments (n = 5), we found that 2.0 ng/ml PGE2 in CSF dilated pial arteries by 24 +/- 8% and that 1.0 ng/ml PGI2 dilated pial arteries by 15 +/- 6%. These results indicate that leukotrienes are able to increase levels of prostanoids in cerebral cortex.     

Effects of asphyxia at birth on postnatal glucose regulation in the rat

We have characterized the effect of a period of asphyxia at birth, followed by recovery, upon newborn rats. Asphyxiated pups were subjected to 3 to 5% (v/v) inspired oxygen during the first 20 min of life and then maintained in room air for 6 h. Control pups were maintained in room air throughout the 6-h period. Hypoxia produced severe asphyxia as reflected by a pH of 6.76 +/- 0.05, PaCO2 of 87 +/- 3 mm Hg and PaO2 of 15.4 +/- 4 mm Hg, and by a greatly increased blood lactate/pyruvate ratio. Plasma catecholamine concentrations in asphyxiated pups were elevated (epinephrine 13,866 +/- 250 pg/ml, norepinephrine 9611 +/- 1813 pg/ml) compared to control animals (epinephrine 973 +/- 234 pg/ml, norepinephrine 774 +/- 133 pg/ml) at 20 min. Asphyxia initially increased plasma glucose concentration, and then with recovery it fell below controls. Hepatic glycogen stores did not differ between asphyxiated and control pups. Plasma insulin concentrations remained elevated during asphyxia and the usual neonatal surge of plasma glucagon was significantly delayed. Neonatal asphyxia increases catecholamines, causes lactic acidemia, and alters insulin and glucagon levels. The interactions between these variables alters the normal pattern of glucose availability during the neonatal period.     

Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA.

Breathing 100% O2 at 1 atmosphere absolute (ATA) is known to be associated with a decrease in cerebral blood flow (CBF). It is also accompanied by a fall in arterial Pco2 leading to uncertainty as to whether the cerebral vasoconstriction is totally or only in part caused by arterial hypocapnia. We tested the hypothesis that the increase in arterial Po2 while O2 was breathed at 1.0 ATA decreases CBF independently of a concurrent fall in arterial Pco2. CBF was measured in seven healthy men aged 21-62 yr by using noninvasive continuous arterial spin-labeled-perfusion MRI. The tracer in this technique, magnetically labeled protons in blood, has a half-life of seconds, allowing repetitive measurements over short time frames without contamination. CBF and arterial blood gases were measured while breathing air, 100% O2, and 4 and 6% CO2 in air and O2 backgrounds. Arterial Po2 increased from 91.7 +/- 6.8 Torr in air to 576.7 +/- 18.9 Torr in O2. Arterial Pco2 fell from 43.3 +/- 1.8 Torr in air to 40.2 +/- 3.3 Torr in O2. CBF-arterial Pco2 response curves for the air and hyperoxic runs were nearly parallel and separated by a distance representing a 28.7-32.6% decrement in CBF. Regression analysis confirmed the independent cerebral vasoconstrictive effect of increased arterial Po2. The present results also demonstrate that the magnitude of this effect at 1.0 ATA is greater than previously measured.     

Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans

The effects of mild hypoxia on brain oxyhemoglobin, cytochrome a,a3 redox status, and cerebral blood volume were studied using near-infrared spectroscopy in eight healthy volunteers. Incremental hypoxia reaching 70% arterial O2 saturation was produced in normocapnia [end-tidal PCO2 (PETCO2) 36.9 +/- 2.6 to 34.9 +/- 3.4 Torr] or hypocapnia (PETCO2 32.8 +/- 0.6 to 23.7 +/- 0.6 Torr) by an 8-min rebreathing technique and regulation of inspired CO2. Normocapnic hypoxia was characterized by progressive reductions in arterial PO2 (PaO2, 89.1 +/- 3.5 to 34.1 +/- 0.1 Torr) with stable PETCO2, arterial PCO2 (PaCO2), and arterial pH and resulted in increases in heart rate (35%) systolic blood pressure (14%), and minute ventilation (5-fold). Hypocapnic hypoxia resulted in progressively decreasing PaO2 (100.2 +/- 3.6 to 28.9 +/- 0.1 Torr), with progressive reduction in PaCO2 (39.0 +/- 1.6 to 27.3 +/- 1.9 Torr), and an increase in arterial pH (7.41 +/- 0.02 to 7.53 +/- 0.03), heart rate (61%), and ventilation (3-fold). In the brain, hypoxia resulted in a steady decline of cerebral oxyhemoglobin content and a decrease in oxidized cytochrome a,a3. Significantly greater loss of oxidized cytochrome a,a3 occurred for a given decrease in oxyhemoglobin during hypocapnic hypoxia relative to normocapnic hypoxia. Total blood volume response during hypoxia also was significantly attenuated by hypocapnia, because the increase in volume was only half that of normocapnic subjects. We conclude that cytochrome a,a3 oxidation level in vivo decreases at mild levels of hypoxia. PaCO is an important determinant of brain oxygenation, because it modulates ventilatory, cardiovascular, and cerebral O2 delivery responses to hypoxia.     

Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-betaII, PKC-gamma, PKC-eta, PKC-mu, and PKC-lambda also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-epsilon and PKC-zeta were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 microM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-gamma and PKC-theta in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.     

Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O(2)) significantly reduced arterial oxygen partial pressure (from 99 +/- 3 to 65 +/- 2, 51 +/- 2, 41 +/- 1, and 39 +/- 2 mmHg, respectively) and significantly increased RSNA (by 8 +/- 3, 44 +/- 25, 62 +/- 21, and 76 +/- 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 +/- 1, 5 +/- 2, 11 +/- 3, and 14 +/- 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.     

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36+/-4% of hemisphere volume) than in SHR (19+/-5%) or WKY rats (5+/-2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2*- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model.     

O2 radicals mediate reperfusion lung injury in ischemic O2-ventilated canine pulmonary lobe

This study was undertaken to determine whether lung injury after a period of ischemia reperfusion is caused by O2 ventilation during ischemia and whether this injury is mediated by reactive O2 metabolites. Isolated canine left lower pulmonary lobes were subjected to room temperature ischemia for 6 h while being ventilated with either 100% O2, room air, or 100% N2. After the ischemic period, all lobes were perfused with autologous blood and ventilated with 100% O2 for an additional 4 h. In lobes ventilated with 100% O2 during the ischemic period, massive weight gain (228%) occurred 4 h after reperfusion. A marked increase in pulmonary shunt was noted. Lobes ventilated with room air behaved similarly. In contrast, lobes ventilated with 100% N2 gained significantly less weight (54%) and did not manifest any increase in pulmonary shunt. When lobes ventilated with 100% O2 or room air were pretreated with superoxide dismutase (SOD), the injury was significantly reduced. Pressure-volume deflation study of lobes, after ischemia only, demonstrated that ventilation with 100% O2 and with 100% N2 both equally decreased pulmonary compliance. We conclude that lung ischemia-reperfusion injury is related to O2 ventilation during ischemia and that injury can be prevented by administration of SOD or ventilation with 100% N2. This suggests that the injury is related to O2 metabolites produced during O2 ventilation in the absence of the circulation.     

Chemical control of tracheal vascular resistance in dogs

With anesthetized dogs we have measured upper tracheal vascular resistance on both sides of the trachea simultaneously by perfusing the cranial tracheal arteries and measuring inflow pressures at constant flows. The ratio of pressure to flow gave vascular resistance (Rtv). Lung airflow, blood pressure (BP), heart rate, and pressure in a cervical tracheal balloon (Ptr) were also measured. In paralyzed dogs, systemic hypoxia due to artificial ventilation with 10% O2-90% N2 increased Rtv by +8.1 +/- 1.0% (SE), Ptr by +76 +/- 22.8%, and BP by +18.9 +/- 24%. After bilateral cervical vagosympathectomy the increases in Rtv and BP were present (+8.8 +/- 0.9 and +22.3 +/- 0.3%, respectively). After carotid body denervation Rtv, Ptr, and BP increased (+6.4 +/- 1.3, +58.6 +/- 31.6, and +14.6 +/- 3.3%, respectively). After vagotomy Rtv and BP increased (+14.1 +/- 1.7 and +22.4 +/- 10.1%, respectively). Tracheal perfusion with hypoxic blood caused a small vasodilation (-2.2 +/- 1.1%). Systemic hypercapnia due to artificial ventilation with 8% CO2-92% air increased Rtv by +16.7 +/- 3.8%, Ptr by +67 +/- 2.0%, and BP by +12.9 +/- 9.9%. Tracheal perfusion with hypercapnic blood caused a small vasodilation (-2.5 +/- 1.2%). Stimulation of the carotid body chemoreceptors with KCN caused a small increase in Rtv (+1.2 +/- 0.5%) and increases in Ptr (+49.8 +/- 13.6%) and BP (+11.1 +/- 2.1%). Systemic hypoxia and hypercapnia caused tracheal vasoconstriction mainly by an action on the central nervous system.     

Posthypoxic ventilatory decline during NREM sleep: influence of sleep apnea.

We wished to determine the severity of posthypoxic ventilatory decline in patients with sleep apnea relative to normal subjects during sleep. We studied 11 men with sleep apnea/hypopnea syndrome and 11 normal men during non-rapid eye movement sleep. We measured EEG, electrooculogram, arterial O(2) saturation, and end-tidal P(CO2). To maintain upper airway patency in patients with sleep apnea, nasal continuous positive pressure was applied at a level sufficient to eliminate apneas and hypopneas. We compared the prehypoxic control (C) with posthypoxic recovery breaths. Nadir minute ventilation in normal subjects was 6.3 +/- 0.5 l/min (83.8 +/- 5.7% of room air control) vs. 6.7 +/- 0.9 l/min, 69.1 +/- 8.5% of room air control in obstructive sleep apnea (OSA) patients; nadir minute ventilation (% of control) was lower in patients with OSA relative to normal subjects (P < 0.05). Nadir tidal volume was 0.55 +/- 0.05 liter (80.0 +/- 6.6% of room air control) in OSA patients vs. 0.42 +/- 0.03 liter, 86.5 +/- 5.2% of room air control in normal subjects. In addition, prolongation of expiratory time (Te) occurred in the recovery period. There was a significant difference in Te prolongation between normal subjects (2.61 +/- 0.3 s, 120 +/- 11.2% of C) and OSA patients (5.6 +/- 1.5 s, 292 +/- 127.6% of C) (P < 0.006). In conclusion, 1) posthypoxic ventilatory decline occurred after termination of hypocapnic hypoxia in normal subjects and patients with sleep apnea and manifested as decreased tidal volume and prolongation of Te; and 2) posthypoxic ventilatory prolongation of Te was more pronounced in patients with sleep apnea relative to normal subjects.     

Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise

We examined the relationship between changes in cardiorespiratory and cerebrovascular function in 14 healthy volunteers with and without hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 80%] at rest and during 60-70% maximal oxygen uptake steady-state cycling exercise. During all procedures, ventilation, end-tidal gases, heart rate (HR), arterial blood pressure (BP; Finometer) cardiac output (Modelflow), muscle and cerebral oxygenation (near-infrared spectroscopy), and middle cerebral artery blood flow velocity (MCAV; transcranial Doppler ultrasound) were measured continuously. The effect of hypoxia on dynamic cerebral autoregulation was assessed with transfer function gain and phase shift in mean BP and MCAV. At rest, hypoxia resulted in increases in ventilation, progressive hypocapnia, and general sympathoexcitation (i.e., elevated HR and cardiac output); these responses were more marked during hypoxic exercise (P < 0.05 vs. rest) and were also reflected in elevation of the slopes of the linear regressions of ventilation, HR, and cardiac output with Sa(O(2)) (P < 0.05 vs. rest). MCAV was maintained during hypoxic exercise, despite marked hypocapnia (44.1 +/- 2.9 to 36.3 +/- 4.2 Torr; P < 0.05). Conversely, hypoxia both at rest and during exercise decreased cerebral oxygenation compared with muscle. The low-frequency phase between MCAV and mean BP was lowered during hypoxic exercise, indicating impairment in cerebral autoregulation. These data indicate that increases in cerebral neurogenic activity and/or sympathoexcitation during hypoxic exercise can potentially outbalance the hypocapnia-induced lowering of MCAV. Despite maintaining MCAV, such hypoxic exercise can potentially compromise cerebral autoregulation and oxygenation.     

The effect of hypoxia on performance during 30 s or 45 s of supramaximal exercise

The purpose of this study was to evaluate the effect of hypoxia (10.8 +/- 0.6% oxygen) on performance of 30 s and 45 s of supramaximal dynamic exercise. Twelve males were randomly allocated to perform either a 30 s or 45 s Wingate test (WT) on two occasions (hypoxia and room air) with a minimum of 1 week between tests. After a 5-min warm-up at 120 W subjects breathed the appropriate gas mixture from a wet spirometer during a 5-min rest period. Resting blood oxygen saturation was monitored with an ear oximeter and averaged 97.8 +/- 1.5% and 83.2 +/- 1.9% for the air (normoxic) and hypoxic conditions, respectively, immediately prior to the WT. Following all WT trials, subjects breathed room air for a 10-min passive recovery period. Muscle biopsies from the vastus lateralis were taken prior to and immediately following WT. Arterialized blood samples, for lactate and blood gases, were taken before and after both the warm-up and the performance of WT, and throughout the recovery period. Open-circuit spirometry was used to calculate the total oxygen consumption (VO2), carbon dioxide production and expired ventilation during WT. Hypoxia did not impair the performance of the 30-s or 45-s WT. VO2 was reduced during the 45-s hypoxic WT (1.71 +/- 0.21 l) compared with the normoxic trial (2.16 +/- 0.26 l), but there was no change during the 30-s test (1.22 +/- 0.11 vs 1.04 +/- 0.17 l for the normoxic and hypoxic conditions, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclooxygenase products stimulate carbon monoxide production by piglet cerebral microvessels

Products of arachidonic acid (AA) metabolism by cyclooxygenase (Cox) are important in regulation of neonatal cerebral circulation. The brain and cerebral microvessels also express heme oxygenase (HO) that metabolizes heme to carbon monoxide (CO), biliverdin, and iron. The purpose of this study in newborn pig cerebral microvessels was to address the hypothesis that Cox products affect HO activity and HO products affect Cox activity. AA (2.0-20 microM) increased prostaglandin E2 (PGE2) measured by radioimmunoassay (RIA) and also CO measured by gas chromatography/mass spectrometry (GC/MS). Further, 10(-4) M indomethacin, which inhibited Cox, reduced both AA and heme-induced CO production. Conversely, neither exogenous 2 x 10(-6) M heme, which markedly increased CO production, nor the inhibitor of HO, chromium mesoporphyrin, altered PGE2 synthesis. Because AA metabolism by Cox generates both prostanoids and superoxides, we determined the effects of the predominant prostanoid and superoxide on CO production. Although PGE2 caused a small increase in CO production, xanthine oxidase plus hypoxanthine, which produces superoxide, strongly stimulated the production of CO by cerebral microvessels. This increase was mildly attenuated by catalase. These data suggest that Cox-catalyzed AA metabolites, most likely superoxide and/or a subsequent reactive oxygen species, increase cerebrovascular CO production. This increase seems to be caused, at least in part, by the elevation of HO-2 catalytic activity. Conversely, Cox activity is not affected by HO-catalyzed heme metabolites. These data suggest that some cerebrovascular functions attributable to Cox activity could be mediated by CO.