Attenuation of human hypoxic pulmonary vasoconstriction by acetazolamide and methazolamide.

Acetazolamide (AZ), a carbonic anhydrase inhibitor used for preventing altitude illness attenuates hypoxic pulmonary vasoconstriction (HPV) while improving oxygenation. Methazolamide (MZ), an analog of acetazolamide, is more lipophilic, has a longer half-life, and activates a major antioxidant transcription factor. However, its influence on the hypoxic pulmonary response in humans is unknown. The aim of this study was to determine whether a clinically relevant dosing of MZ improves oxygenation, attenuates HPV, and augments plasma antioxidant capacity in men exposed to hypoxia compared with an established dosing of AZ known to suppress HPV. In this double-blind, placebo-controlled crossover trial, 11 participants were randomized to treatments with MZ (100 mg 2× daily) and AZ (250 mg 3× daily) for 2 days before 60 min of hypoxia (FIO2 ≈0.12). Pulmonary artery systolic pressure (PASP), alveolar ventilation (V̇A), blood gases, and markers of redox status were measured. Pulmonary vascular sensitivity to hypoxia was determined by indexing PASP to alveolar PO2. AZ caused greater metabolic acidosis than MZ, but the augmented V̇A and improved oxygenation with hypoxia were similar. The rise in PASP with hypoxia was lower with MZ (9.0 ± 0.9 mmHg) and AZ (8.0 ± 0.7 mmHg) vs. placebo (14.1 ± 1.3 mmHg, P < 0.05). Pulmonary vascular sensitivity to hypoxia (ΔPASP/ΔPAO2) was reduced equally by both drugs. Only AZ improved the nonenzymatic plasma antioxidant capacity. Although AZ had only plasma antioxidant properties, MZ led to similar improvements in oxygenation and reduction in HPV at a dose causing less metabolic acidosis than AZ in humans.NEW & NOTEWORTHY Both acetazolamide and methazolamide are effective in the prevention of acute mountain sickness by inducing an increase in ventilation and oxygenation. Acetazolamide attenuates hypoxic pulmonary vasoconstriction; however, it was previously unknown whether methazolamide has the same effect in humans. This study shows that a dosing of methazolamide causing less metabolic acidosis improves oxygenation while attenuating hypoxic pulmonary vasoconstriction and pulmonary vascular sensitivity to hypoxia. Acetazolamide improved plasma antioxidant capacity better than methazolamide.

Influence of myocardial oxygen demand on the coronary vascular response to arterial blood gas changes in humans.

It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial Po2 and Pco2 or if coronary vascular responses are the result of concomitant increases in myocardial O2 consumption/demand ([Formula: see text]). We hypothesized that the coronary vascular response to Po2 and Pco2 would be attenuated in healthy men when [Formula: see text] was attenuated with ß1-adrenergic receptor blockade. Healthy men (age: 25 ± 1 yr, n = 11) received intravenous esmolol (ß1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized crossover study and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and after 5 min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate, and arterial blood pressure. LADV values at the end of each hypoxic condition were compared between esmolol and placebo. The rate-pressure product (RPP) and left ventricular mechanical energy (MELV) were calculated as indexes of [Formula: see text]. All gas manipulations augmented RPP, MELV, and LADV, but only RPP and MELV were attenuated (4-18%) after ß1-adrenergic receptor blockade ( P < 0.05). Despite attenuated RPP and MELV responses, ß1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response compared with placebo during poikilocapnic hypoxia (29.4 ± 2.2 vs. 27.3 ± 1.6 cm/s) and isocapnic hypoxia (29.5 ± 1.5 vs. 30.3 ± 2.2 cm/s). Hypercapnic hypoxia elicited a feedforward coronary dilation that was blocked by ß1-adrenergic receptor blockade. These results indicate a direct influence of arterial Po2 on coronary vascular regulation that is independent of [Formula: see text]. NEW & NOTEWORTHY In humans, arterial hypoxemia led to an increase in epicardial coronary artery blood velocity. ß1-Adrenergic receptor blockade did not diminish the hypoxemic coronary response despite reduced myocardial O2 demand. These data indicate hypoxemia can regulate coronary blood flow independent of myocardial O2 consumption. A plateau in the mean left anterior descending coronary artery blood velocity-rate-pressure product relationship suggested ß1-adrenergic receptor-mediated, feedforward epicardial coronary artery dilation. In addition, we observed a synergistic effect of Po2 and Pco2 during hypercapnic hypoxia.

Measuring the human ventilatory and cerebral blood flow response to CO2: a technical consideration for the end-tidal-to-arterial gas gradient.

Our aim was to quantify the end-tidal-to-arterial gas gradients for O2 (PET-PaO2) and CO2 (Pa-PETCO2) during a CO2 reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO-, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-PETCO2 would be greater in hypoxia compared with normoxia, 2) the Pa-PETCO2 would be similar, whereas the PET-PaO2 gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against PETCO2 compared with PaCO2, and 4) previously derived prediction algorithms will accurately target PaCO2. PETCO2 was controlled by dynamic end-tidal forcing in steady-state steps of -8, -4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇E), internal carotid artery blood flow (Q̇ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇E and relative changes in Q̇ICA, and MCAv against PETCO2, predicted PaCO2, and measured PaCO2. The Pa-PETCO2 was similar between hypoxia and normoxia and PFO+ and PFO-. The PET-PaO2 was greater in PFO+ by 2.1 mmHg during normoxia (P = 0.003). HCVR and CVR plotted against PETCO2 underestimated HCVR and CVR indexed against PaCO2 in normoxia and hypoxia. Our PaCO2 prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to PETCO2 compared with PaCO2.

Gas density alters expiratory time constants before and after experimental lung injury.

NEW FINDINGS: What is the central question of this study? Does the induction of a model of lung injury affect the expiratory time constant (τE) in terms of either total duration or morphology? Does ventilation with gases of different densities alter the duration or morphology of τE either before or after injury? What is the main finding and its importance? The use of sulfur hexafluoride in ventilating gas mixtures lengthens total expiratory time constants before and after lung injury compared with both nitrogen and helium mixtures. Sulfur hexafluoride mixtures also decrease the difference and variability of τE between fast- and slow-emptying compartments before and after injury when compared with nitrogen and helium mixtures. Acute lung injury is characterized by regional heterogeneity of lung resistance and elastance that may lead to regional heterogeneity of expiratory time constants (τE). We hypothesized that increasing airflow resistance by using inhaled sulfur hexafluoride (SF6) would lengthen time constants and decrease their heterogeneity in an experimental model of lung injury when compared with nitrogen or helium mixtures. To overcome the limitations of a single-compartment model, we employed a multisegment model of expiratory gas flow. An experimental model of lung injury was created using intratracheal injection of sodium polyacrylate in anaesthetized and mechanically ventilated female Yorkshire-cross pigs (n = 7). The animals were ventilated with 50% O2 and the remaining 50% as nitrogen (N2), helium (He) or sulfur hexafluoride (SF6). Values for τE decreased with injury and were more variable after injury than before (P < 0.001). Values for τE increased throughout expiration both before and after injury, and the rate of increase in τE was lessened by SF6 (P < 0.001 when compared with N2 both before and after injury). Altering the inhaled gas density did not affect indices of oxygenation, dead space or shunt. The use of SF6 in ventilating gas mixtures lengthens total expiratory time constants before and after lung injury compared with both N2 and He mixtures. Importantly, SF6 mixtures also decrease the difference and variability of τE between fast- and slow-emptying compartments before and after injury when compared with N2 and He mixtures.

End tidal-to-arterial CO2 and O2 gas gradients at low- and high-altitude during dynamic end-tidal forcing.

We sought to characterize and quantify the performance of a portable dynamic end-tidal forcing (DEF) system in controlling the partial pressure of arterial CO2 (Pa(CO2)) and O2 (Pa(O2)) at low (LA; 344 m) and high altitude (HA; 5,050 m) during an isooxic CO2 test and an isocapnic O2 test, which is commonly used to measure ventilatory and vascular reactivity in humans (n = 9). The isooxic CO2 tests involved step changes in the partial pressure of end-tidal CO2 (PET(CO2)) of -10, -5, 0, +5, and +10 mmHg from baseline. The isocapnic O2 test consisted of a 10-min hypoxic step (PET(O2) = 47 mmHg) from baseline at LA and a 5-min euoxic step (PET(O2) = 100 mmHg) from baseline at HA. At both altitudes, PET(O2) and PET(CO2) were controlled within narrow limits (<1 mmHg from target) during each protocol. During the isooxic CO2 test at LA, PET(CO2) consistently overestimated Pa(CO2) (P < 0.01) at both baseline (2.1 ± 0.5 mmHg) and hypercapnia (+5 mmHg: 2.1 ± 0.7 mmHg; +10 mmHg: 1.9 ± 0.5 mmHg). This P(a)-PET(CO2) gradient was approximately twofold greater at HA (P < 0.05). At baseline at both altitudes, PET(O2) overestimated Pa(O2) by a similar extent (LA: 6.9 ± 2.1 mmHg; HA: 4.5 ± 0.9 mmHg; both P < 0.001). This overestimation persisted during isocapnic hypoxia at LA (6.9 ± 0.6 mmHg) and during isocapnic euoxia at HA (3.8 ± 1.2 mmHg). Step-wise multiple regression analysis, on the basis of the collected data, revealed that it may be possible to predict an individual's arterial blood gases during DEF. Future research is needed to validate these prediction algorithms and determine the implications of end-tidal-to-arterial gradients in the assessment of ventilatory and/or vascular reactivity.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance.

We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the 'CBF reserve', and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg(-1)) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects' arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s(-1) (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s(-1) (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.

Pulmonary mechanics and gas exchange during exercise in Kenyan distance runners.

PURPOSE: The purpose of this study was to determine arterial blood gases, the mechanical limits for generating expiratory flow and the work performed by the respiratory muscles during treadmill exercise in Kenyan runners. METHODS: Kenyan runners (10 men and 4 women; mean ± SD age = 25.2 ± 1.3 yr) were instrumented with a radial artery catheter, an esophageal balloon-tipped catheter, and an esophageal temperature probe for the determination of blood gases, the work of breathing and core temperature, respectively. Testing occurred at 1545 m above sea level. RESULTS: There were significant decreases in the arterial partial pressure of O2 and oxyhemoglobin saturation and a widening of the alveolar-to-arterial difference in O2 from rest to peak exercise. The mechanical work of breathing increased with increasing minute ventilation and was commensurate with values expected for treadmill running in elite athletes. During heavy exercise, significant expiratory flow limitation was present in half of the subjects while the remaining subjects demonstrated impending flow limitation. CONCLUSIONS: Pulmonary system limitations were present in Kenyan runners in the form of exercise-induced arterial hypoxemia, expiratory flow limitation, and high levels of respiratory muscle work. It appears that Kenyan runners do not possess a pulmonary system that confers a physiological advantage.