Normoxic Ventilation Research Articles

Cytosolic and membrane-bound cerebral nitric oxide synthase activity during hypoxia in cortical tissue of newborn piglets

To determine the role of nitric oxide production during hypoxia, the presence of two forms of neuronal nitric oxide synthase, cytosolic (cNOS) and membrane-bound (memNOS), in cortical tissue of newborn piglets and the effects of hypoxia on the activity of these enzymes were studied. Experiments were performed in 12 anesthetized and ventilated Yorkshire piglets, 2–4 days of age. Hypoxia was induced by decreasing the Fi0 2 to 0.07. The control group was ventilated maintaining normoxia. After 1 h of normoxic or hypoxic ventilation brain tissue was removed and frozen immediately in liquid nitrogen. Tissue hypoxia was confirmed by analysis of adenosine triphosphate (ATP) and phosphocreatine (PCr): ATP was reduced to 52% and PCr to 28% of control values. cNOS activity was 35.3 ± 13.7 pmol/mg protein per min in the control group and 28.3 ± 7.0 in the hypoxia group; memNOS activity was 10.5 ± 4.5 and 12.0 ± 3.9 pmol/mg protein per min in the control and hypoxia groups, respectively. Differences in cNOS and memNOS activity between control and hypoxic animals were not significant. The results indicate that both cNOS and memNOS are present in cortical tissue of newborn piglets and that the activity is unaffected by 1 h of tissue hypoxia. We suggest that production of nitric oxide and its derivative peroxynitrite during hypoxia may therefore be a potential mechanism for hypoxia-induced brain cell membrane lipid peroxidation.

The role of carotid body CO2 during ventilatory acclimatization to hypoxia in the goat.

During a prolonged exposure to hypoxia, ventilation ( V̇E ) increases in a time-dependent manner. Ventilatory acclimatization to hypoxia (VAH) is associated with an increase in carotid body (CB) hypoxic sensitivity (Engwall & Bisgard, 1990; Ryan et al, 1993). The increased hypoxic sensitivity has been demonstrated under both systemic isocapnic or poikilocapnic conditions (Engwall & Bisgard, 1990). However, carotid body (CB) hypocapnia has a fairly strong inhibitory influence on normoxic ventilation in the awake goat (Daristotle et al, 1990) and dog (Smith et al, 1995). The objective of this study was to determine whether the increase in CB hypoxic sensitivity is dependent on the level of CB CO2 pressure (PcbCO2) during the hypoxic exposure.KeywordsCarotid BodyVentilatory ResponseHypoxic ExposurePerfusion CircuitArterial ChemoreceptionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Comparison of the effects of sub-hypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia

To compare the effects of sub-anaesthetic concentrations of propofol and halothane on the respiratory control system, we have studied the acute ventilatory response to isocapnic hypoxia (AHVR) in 12 adults with and without three different concentrations of propofol and halothane. Target doses for propofol were 0, 0.05, 0.1 and 0.2 of the effective plasma concentration (EC50 = 8.1 micrograms ml-1). Target doses for halothane were 0, 0.05, 0.1 and 0.2 minimum alveolar concentration (MAC = 0.77%). The doses achieved experimentally were 0.01, 0.06, 0.13 and 0.26 of the EC50 for propofol and 0, 0.05, 0.11 and 0.20 MAC for halothane. During the experiment subjects breathed via a mouthpiece from an end-tidal forcing system. End-tidal PO2 (PE'O2) was held at 13.3 kPa for 5 min, and then at 6.7 kPa for 5 min. End-tidal PCO2 (PE'CO2) was held constant at 0.13-0.27 kPa greater than the subject's natural level throughout. The mean values for AHVR with propofol were: 12.8 (SEM 2.4) litre min-1 (0.01 EC50), 10.0 (1.9) litre min-1 (0.06 EC50), 9.8 (2.3) litre min-1 (0.13 EC50) and 4.9 (1.2) litre min-1 (0.26 EC50). The values for AHVR with halothane were: 11.9 (2.4) litre min-1 (0 MAC), 7.8 (1.6) litre min-1 (0.05 MAC), 5.9 (1.2) litre min-1 (0.11 MAC) and 3.2 (1.6) litre min-1 (0.2 MAC). The decline in AHVR with increasing dose for both drugs was statistically significant (ANOVA, P < 0.001); there was no significant difference between the two drugs with respect to this decline. Normoxic ventilation with propofol declined from 13.2 (1.6) litre min-1 (0.01 EC50) to 8.3 (0.9 litre min-1 (0.26 EC50), and with halothane declined from 13.5 (2.0) litre min-1 (0 MAC) to 11.8 (1.6) litre min-1 (0.2 MAC). This was significant for both drugs (ANOVA, P < 0.001).

Does Sleep Enhance the Effect of Subanesthetic Isoflurane on Hypoxic Ventilation?

After surgery, patients may receive little audiovisual stimulation and may sleep. Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR.

Does Sleep Enhance the Effect of Subanesthetic Isoflurane on Hypoxic Ventilation?

After surgery, patients may receive little audiovisual stimulation and may sleep.Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR. (Anesth Analg 1995;81:751-6)

Dithionite Increases Radical Formation and Decreases Vasoconstriction in the Lung

Dithionite is a powerful reducing agent used to deoxygenate hemoglobin and create anaerobic conditions in vitro. Recently, dithionite has been used as a convenient means of creating "hypoxia" in experiments studying the O2 sensor in the pulmonary circulation and carotid body. We evaluated the hypothesis that hypoxia created by hypoxic ventilation and that created by dithionite have different effects on the pulmonary circulation. In vitro, dithionite (10(-5) to 10(-3) mol/L), added to oxygenated Krebs' solution, rapidly created superoxide anion in a dose-dependent manner. Dithionite consumed O2 in parallel with the generation of superoxide radical, with both processes peaking within seconds. Anoxia was sustained only if resupply of O2 was prevented. In isolated rat lungs (whether perfused with autologous blood or Krebs' solution), hypoxic ventilation alone lowered perfusate PO2 from approximately 140 to 40 mm Hg and decreased lung levels of activated oxygen species (AOS), measured by luminol-enhanced chemiluminescence, before the onset of hypoxic pulmonary vasoconstriction. Constrictor responses to angiotensin II and KCl were not impaired by intermittent hypoxic challenges, and lung weight did not increase. In contrast, dithionite impaired constrictor responses of the Krebs' solution-perfused lungs to all vasoconstrictors tested and increased lung weight. When given as a bolus (5 x 10(-3) mol/L) into the pulmonary artery during normoxic ventilation, dithionite caused no vasoconstriction and only briefly lowered PO2 (because of constant resupply of O2 from the alveoli). When superimposed on hypoxic ventilation, dithionite further lowered PO2 from approximately 40 to approximately 0 mm Hg and caused additional constriction. Unlike hypoxic ventilation, dithionite increased AOS production. Antioxidant enzymes diminished dithionite-induced radical production and diminished the loss of vascular reactivity and lung edema. In conclusion, unlike hypoxic ventilation, dithionite causes edema and loss of vascular reactivity in the lung by generating superoxide anion and hydrogen peroxide. Hypoxia elicited by dithionite is not equivalent to authentic hypoxia because of the obligatory associated generation of AOS. Dithionite usage should not be substituted for authentic hypoxia in studies of O2 sensing.

Role of metabolic acidosis on cardiac mechanical performance during severe acute hypoxia and reoxygenation is small and transient

The aim was to determine whether the metabolic acidosis that develops during severe acute myocardial hypoxia improves or impairs the recovery of cardiac mechanical function during reoxygenation. Isolated rat hearts performed external work against a model of the rat systemic vascular impedance. Four groups of 10 hearts were used for mechanical studies. In these experiments, the hearts were subjected to normoxic ventilation for 15 min, hypoxic ventilation for 20 min, and reoxygenation for 60 min. The perfusate pH was either allowed to drift downward due to metabolic acidosis, or it was corrected to 7.4 as hypoxia or reoxygenation began. Mechanical performance was assessed by measuring heart rate and model "aortic" pressure and flow and by computing left ventricular mean, pulsatile, and total hydraulic power output and stroke work. A further four groups of 10 hearts were used for biochemical studies. In these experiments, myocardial high energy phosphates and calcium content were measured at the end of the period of hypoxia. When no attempt was made to regulate the perfusate pH, it drifted downward from 7.40(SEM 0.01) to 7.33(0.01) during hypoxia and then to 7.25(0.02) during reoxygenation. All mechanical variables measured and computed were severely depressed by hypoxia, whether the pH was regulated or not. Left ventricular total hydraulic hydraulic power output decreased to less than 10% of the control value in all experiment groups and recovered to 86.7-91.2% of the control value after 60 min of reoxygenation. Mechanical recovery was most rapid when the correction of acidosis was delayed until reoxygenation was begun. After 5 min of reoxygenation, it had recovered to 65.5% of the control value compared with a 37.0% recovery when the pH was allowed to drift and 34.9% when the pH was corrected to 7.4 during hypoxia. However, the differences in power output became non-significant after 10 min of reoxygenation. Myocardial creatine phosphate and adenosine triphosphate concentrations were decreased by hypoxia whether the pH was corrected (63.0% and 26.9% relative to the control), or not (68.9% and 35.0% relative to the control) (not statistically significant), but total cell calcium was not affected. In the isolated rat heart, correction of the moderate metabolic acidosis that developed during severe acute myocardial hypoxia improved the rate of mechanical recovery, but the effect was small and not sustained.

Exhaled nitric oxide in isolated pig lungs.

Endothelium-derived nitric oxide (NO) is an important regulator of vascular resistance. Low concentrations of NO have been recorded in the exhaled breath of spontaneously breathing animals and humans. To determine whether NO synthesis in the lung contributes to the NO measured in the breath, we measured the concentration of NO in the exhaled air of isolated perfused and ventilated porcine lungs by using a chemiluminescence method. With NO-free normoxic ventilation (21% O2-5% CO2-74% N2) of eight porcine lungs perfused with a Krebs-dextran and albumin perfusate, baseline exhaled NO was 5.8 +/- 1.8 parts per billion (ppb) and pulmonary vascular resistance (PVR) was 8.9 +/- 1.8 mmHg.l-1.min. Hypoxic ventilation (5% O2-5% CO2-90% N2) caused a fall in NO to 3.6 +/- 1.8 ppb and a rise in PVR to 13.6 +/- 3.6 mmHg.l-1.min. Vasoconstriction with the thromboxane analogue U-46619 (10(-9) M) raised PVR to 31.7 +/- 6.8 mmHg.l-1.min but did not decrease NO levels from baseline. Subsequent addition of acetylcholine (10(-6)M) lowered PVR to 22.1 +/- 4.5 mmHg.l-1.min and increased exhaled NO to 7.0 +/- 2.0 ppb. Addition of a NO synthase inhibitor, NG-nitro-L-arginine methyl ester (10(-5) M), to four lungs caused a rise in PVR to 43.0 +/- 7.0 mmHg.l-1.min and a decrease in NO to 1.5 +/- 1.0 ppb. Addition of autologous blood to the perfusate of four lungs caused no change in PVR from baseline but decreased exhaled NO to 2.7 +/- 0.5 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory Responses during Incremental Exercise in Men under Hyperoxic Conditions.

The aim of the present study was to explore the role of the carotid chemoreceptors in the regulation of breathing during incremental ramp exercise. We measured minute ventilation (VE), oxygen uptake (VO2), carbon dioxide output (VCO2), end-tidal PO2 and PCO2 (PETO2 and PETCO2), and heart rate (HR) during incremental exercise in healthy young men breathing air and 50% O2. During incremental exercise (15 W/min, from 0 to 300 W) VCO2 in hyperoxia did not differ from the normoxic response, but VE in hyperoxia increased more linearly with an increasing load in comparison to the curvilinear rise of normoxic VE. The isocapnic buffering of PETCO2 observed in normoxia at the transition from moderate to heavy work did not appear in hyperoxia until a very heavy work load had been attained. This agrees with the observation that normoxic VE/VCO2 that was consistently falling with load and became flat near the isocapnic point and then turned upward with a further increase in work load, while VE/VCO2 in hyperoxia decreased continuously during heavy exercise. These results would suggest the delayed onset of anaerobic metabolism and the depression of VE under hyperoxic conditions. However, we found that VE and HR increased from a specific work rate with a steeper slope during incremental exercise under both normoxic and hyperoxic conditions. There was a significant correlation between the work rates at which the inflection points of the VE and HR slopes were observed. These findings suggest that factors unrelated to peripheral chemoreceptor activity and affecting both the ventilatory and circulatory systems may be responsible for hyperpnea during heavy exercise.

Ventilatory and metabolic effects of repeated hypoxia in conscious newborn rabbits

To estimate posthypoxia depressing effects on newborns, ventilatory and metabolic effects of repeated hypoxia were studied in 1- to 3-day-old (group 1) and 2-wk-old (group 2) conscious rabbits. In group 1 (n = 18), ventilation was measured by means of a flow plethysmograph. The barometric method was used in group 2 (n = 21). In an additional 19 pups of group 1 and 17 rabbits of group 2, oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured with an open-flow method. In control animals minute ventilation (VE), respiratory rate, tidal volume, VO2, and VCO2 were recorded at 10-min intervals for approximately 100 min in room air. All variables did not change with time. Separate sets of newborns were exposed five times for 10 min to 10% O2 in N2. Each exposure was followed by 10 min of recovery in room air. VE measured during recoveries after hypoxia always returned to normal in group 1. In group 2, the normoxic VE during the last recovery was greater than the first value in hypoxia-treated rabbits (P < 0.05) and greater than the last value in control rabbits (P < 0.02). Although the VE response to hypoxia was not affected by repetitive exposures in group 2, at minute 5 of the fifth exposure the VE response was greater than that during the first trial in group 1 (P < 0.02). Repetitive exposures had no effects on metabolic response to hypoxia in all pups. Results of this study indicate that hypoxia-related central inhibition, if developed during the exposures, is reversed by 10 min of breathing room air in newborns.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen or low concentrations of nitric oxide reverse pulmonary vasoconstriction induced by nitric oxide synthesis inhibition in rabbits.

The objective of this study was to investigate the role of nitric oxide and oxygen in the regulation of pulmonary vascular resistance, especially by means of substitution with nitric oxide after inhibition of endogenous nitric oxide formation. In artificially ventilated open-chest rabbits pulmonary vascular resistance at normoxic ventilation (FIO2 = 21%) was 56 +/- 6 cmH2O ml-1 min-1 1000-1 (mRUL). N omega-nitro-L-arginine methyl ester (L-NAME, 30 mg kg-1), an inhibitor of NO synthase, increased pulmonary vascular resistance to 122 +/- 17 mRUL at normoxic ventilation. In response to L-NAME there was also an increase in mean arterial blood pressure. Exogenous nitric oxide (0.014-9 p.p.m. in the inhaled air) dose-dependently and reversibly counteracted the effect of L-NAME on pulmonary vascular resistance at normoxic ventilation, without affecting systemic blood pressure. In addition, the L-NAME-induced vasoconstriction was critically dependent on oxygen. Thus, during hypoxic ventilation (FIO2 = 10%) the pulmonary vascular resistance was increased approximately four-fold by the presence of L-NAME (30 mg kg-1), and increments in FIO2 (21-100%) dose-dependently and reversibly counteracted the effect of L-NAME on pulmonary vascular resistance. Taken together these findings demonstrate that inhalation of low doses of NO may act as a replacement when endogenous NO synthesis is inhibited, and that pulmonary vasoconstriction induced by NO synthesis inhibition is likely to be the result of interference with oxygen-dependent regulatory mechanisms. Endogenous NO co-operates with oxygen to evoke a vasodilator component of the pulmonary hypoxic pressor response, balancing a hitherto unknown constrictor mechanism.

EFFECT OF A SUB-ANAESTHETIC CONCENTRATION OF HALOTHANE ON THE VENTILATORY RESPONSE TO SUSTAINED HYPOXIA IN HEALTHY HUMANS

We selected nine normal subjects (8M, 1F; aged 25-43 yr) with brisk hypoxic ventilatory responses, and studied their ventilatory response to sustained isocapnic hypoxia (SaO2 82 (SEM 0.1) % for 25 min) in the presence and absence of 0.1% inspired halothane. Halothane had no significant effect on baseline ventilation or gas exchange. In the absence of halothane, ventilation increased initially from mean 7.57 (0.35) litre min-1 to 14.54 (0.91) litre min-1, and decreased subsequently to 10.74 (0.32) litre min-1 during hypoxia (both P < 0.05). In the presence of 0.1% inspired halothane, ventilation increased initially from 7.19 (0.47) litre min-1 to 12.08 (0.99) litre min-1 (P < 0.05), then decreased to 10.12 (0.28) litre min-1 during sustained hypoxia (ns compared with baseline normoxic ventilation). Halothane reduced significantly the initial increase in ventilation (P < 0.05), but did not enhance the subsequent decrease. These results confirm that a sub-anaesthetic concentration of halothane depresses the initial hypoxic ventilatory response; the response during prolonged periods of hypoxia is, however, less than the initial response and is reduced in the presence or absence of a sub-anaesthetic concentration of halothane.

NG-monomethyl-L-arginine does not restore loss of hypoxic pulmonary vasoconstriction induced by TNF-alpha

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. NG-monomethyl-L-arginine (L-NMMA) inhibits nitric oxide (NO) production and prevents some systemic manifestations of TNF-alpha. We tested using an isolated perfused canine lobe whether NO also mediates the pulmonary vascular effects of TNF-alpha. Total resistance (RT) was measured during control and hypoxic ventilation over a 90-min period in six control lobes, five lobes treated with TNF-alpha (250 micrograms), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 micrograms). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O.ml-1 x min during normoxic and hypoxic ventilation, respectively. RT decreased (P < 0.05) from a baseline of 0.0593 +/- 0.0133 to 0.0449 +/- 0.0176 cmH2O.ml-1 x min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O.ml-1 x min). L-NMMA pretreatment did not prevent the TNF-alpha-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O.ml-1 x min) to hypoxic (0.0545 +/- 0.0078 cmH2O.ml-1.min) ventilation (P > 0.10) in the L-NMMA + TNF-alpha group after TNF-alpha administration. We conclude that NO is not the mediator responsible for the acute pulmonary vascular effects of TNF-alpha.

Increased normoxic ventilation induced by repetitive hypoxia in conscious dogs.

To determine if a long-lasting increase in normoxic ventilatory drive is induced in conscious animals by repetitive hypoxia, we examined the normoxic [arterial O2 saturation (SaO2) > 93%] ventilatory response following successive episodes of 2-min eucapnic hypoxic challenges (SaO2 = 80%) in awake tracheotomized dogs. End-tidal CO2 was maintained at the resting level during and after repetitive hypoxia. The experimental protocol was performed twice in each of five dogs on separate days. To determine if changes in normoxic ventilation occurred between episodes of repetitive hypoxia, data were compared from six periods (epochs) for all experiments. The mean minute ventilation (VI) during three normoxic periods between episodes of intermittent hypoxia was 135, 154, and 169% of control (P < 0.05). VI during a 30-min recovery period was still higher at 183 and 172% of control (P < 0.05). Normoxic VI between hypoxic and recovery periods was significantly higher than the corresponding values in sham experiments. Our results indicate that a long-lasting increase in normoxic ventilation can be evoked in an awake unanesthetized dog by a short exposure to repetitive hypoxia.

Effects of Halothane on Hypoxic Pulmonary Vasoconstriction in Canine Atelectasis

We studied the interactions of atelectasis and halothane on hypoxic pulmonary vasoconstriction using an isolated canine lobe. We divided pulmonary vascular resistance into arterial, venous, and middle segmental resistances by a vascular occlusion technique. We found that middle segmental resistance significantly increased (P less than 0.05) from 0.016 +/- 0.007 cm H2O.mL-1.min-1 during normoxic ventilation to 0.06 +/- 0.007 cm H2O.mL-1.min-1 during hypoxic ventilation. We then produced sublobar atelectasis by introducing 4.5-mm steel ball bearings into the lobar bronchus, which resulted in a significant increase (P less than 0.05) of middle segmental resistance to 0.046 +/- 0.014 cm H2O.mL-1.min-1 during normoxic ventilation and a further significant increase (P less than 0.05) to 0.084 +/- 0.02 cm H2O.mL-1.min-1 during hypoxic ventilation. Ventilation with 2.0% halothane but not 0.5% halothane prevented the increases in middle segmental resistance observed with either atelectasis or hypoxic ventilation. Values of arterial and venous segmental resistances were not similarly affected. We conclude that sublobar atelectasis increases pulmonary vascular resistance by stimulating hypoxic pulmonary vasoconstriction. Both halothane and hypoxia primarily act upon the middle vascular segment, but their effects are in opposite directions and, in the former instance, are concentration-dependent.

Cardiovascular Effects of SKF 104078 in Lambs

We studied the effects of SKF 104078 in anesthetized, newborn lambs and compared it to nonspecific alpha-receptor blockade by tolazoline. SKF 104078 infusion decreased pulmonary and systemic arterial pressures in newborn lambs when infused during normoxic ventilation. When infused during hypoxia, SKF 104078 decreased cardiac output and systemic blood pressure without affecting pulmonary pressure. Due to the predominance of systemic effects, the usefulness of SKF 104078 in states of hypoxic pulmonary vasoconstriction is limited.

Endogenous nitric oxide as a probable modulator of pulmonary circulation and hypoxic pressor response in vivo

The objective of this study was to investigate the role of endogenous nitric oxide, formed from L-arginine, in the regulation of pulmonary circulation in vivo, with special reference to the hypoxic pressor response. In artificially ventilated open-chest rabbits, pulmonary vascular resistance at normoxic ventilation (FIO2 = 21%) was 78 +/- 16 cmH2O ml-1 min 1000-1 (mRUL). Hypoxic ventilation (FIO2 = 10%) increased pulmonary vascular resistance to 117 +/- 17 mRUL. N omega-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase, increased pulmonary vascular resistance at normoxic ventilation to 192 +/- 28 mRUL and during hypoxic ventilation to 462 +/- 80 mRUL. During N omega-nitro-L-arginine methylester infusion there was also an increase in mean arterial blood pressure as well as a decrease in cardiac output that was even more pronounced during hypoxic ventilation. L-arginine reversed the effect of N omega-nitro-L-arginine methylester on pulmonary vascular resistance at normoxic ventilation to 140 +/- 26 mRUL and at hypoxic ventilation to 239 +/- 42 mRUL. In spontaneously breathing closed-chest rabbits, N omega-nitro-L-arginine methylester evoked a marked decrease in arterial PO2 and increases in respiration frequency and central venous pressure, while blood pH, PCO2 and base excess remained unchanged. Taken together these findings indicate that endogenous nitric oxide, formed from L-arginine, might be a regulator of ventilation-perfusion matching at normoxic ventilation, and that nitric oxide acts as an endogenous modulator of the hypoxic pressor response.

Stiffened erythrocytes augment the pulmonary hemodynamic response to hypoxia

Isolated rat lungs were perfused with suspensions containing normal and stiffened erythrocytes (RBCs) during normoxic and hypoxic ventilation to assess the effect of reduced RBC deformability on the hypoxic pressor response. RBC suspensions were prepared with cells previously incubated in isotonic phosphate-buffered saline with or without 0.0125% glutaraldehyde. The washed RBCs were resuspended in isotonic bicarbonate-buffered saline (with 4% albumin) to hematocrits of approximately 35%. The lungs were perfused with control and experimental cell suspensions in succession while pulmonary arterial pressure was measured during normoxic (21% O2) and hypoxic (3% O2) ventilation. On the attainment of a peak hypoxic pressor response, flow rate was changed so that pressure-flow curves could be constructed for each suspension. RBC deformability was quantified by a filtration technique using 4.7-microns-pore filters. Glutaraldehyde treatment produced a 10% decrease in RBC deformability (P less than 0.05). Over the range of flow rates, Ppa was increased by 15-17% (P less than 0.05) and 26-31% (P less than 0.05) during normoxic and hypoxic ventilation, respectively, when stiffened cells were suspended in the perfusate. The magnitude of the hypoxic pressor response was 50-54% greater with stiffened cells over the three flow rates. In a separate set of experiments, normoxic and hypoxic arterial blood samples from conscious unrestrained rats were used to investigate the effects of acute hypoxia on RBC deformability. Deformability was measured with the same filtration technique. There was no difference in the deformability of hypoxic compared with normoxic RBCs. We conclude that the presence of stiffened RBCs enhances the hemodynamic response to hypoxia but acute hypoxia does not affect RBC deformability.

Regulation of capillary blood flow and oxygen supply in skeletal muscle in dogs during hypoxaemia.

1. Multiwire surface electrodes were used to measure local hydrogen clearance curves and tissue PO2 in vivo. Evaluation of the initial slopes of the hydrogen clearance curves enabled the measurement of capillary blood flow and its distribution. 2. Capillary blood flow and tissue PO2 frequency distribution histograms were measured in the m. sartorius of anaesthetized, relaxed mongrel dogs under conditions of normoxic (Fi, O2 = 0.3) and hypoxic (Fi, O2 = 0.15 and 0.1) artificial ventilation. 3. Stepwise hypoxaemia (hypoxic hypoxia) induced an increasing discrepancy between capillary blood flow and arterial blood flow. The former decreased by 6% whereas the latter increased by 86%. 4. PO2 histograms provided no evidence of cellular anoxia even at Fi,O2 = 0.1. Capillary blood flow histograms suggested a redistribution of the local pattern of flow. 5. A 34.7% reduction of O2 consumption was observed as the result of severe hypoxaemia. 6. The concept of heterogeneity of capillary blood flow as a functional O2 reserve is presented, together with evidence for oxygen-dependent regulation of capillary blood flow and oxygen consumption.

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured "on-line" using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.