Ventilatory control in peripheral chemoreceptor-denervated ponies during chronic hypoxemia.

The present study was designed to provide further insight into the role of the carotid and aortic chemoreceptors in ventilatory (VE) acclimatization during sojourn at altitude. Measurements were made: 1) on 10 ponies near sea level (SL, 740 Torr) under normal conditions, 2) on 6 of these at SL following chemoreceptor denervation (CD), and 3) subsequently on all 10 during 4 days of hypobaric hypoxia (PaO2 = 40-47 Torr). CD resulteo in hypoventilation at SL (deltaPaCO2 = d8 Torr, P less than 0.05), and it prevented hyperventilation normally observed with injection of NaCN and acute exposure to hypoxia (less than 1 h). In contrast, hyperventilation was evident in normal ponies during acute hypoxia (deltaPaCO2 = -6.7 Torr). Ventilation increased in both groups between the 2nd and 8th h of hypoxia (deltaPaCO2 from 1 h = -4 Torr, P less than 0.05). This change, a common characteristic of acclimatization, persisted throughout 4 days of hypoxia in the normal ponies. However, in the CD ponies this change was evident consistently only through the 12th h and after the 44 h hyperventilation was no longer evident. We conclude that the peripheral chemoreceptors are essential in ponies for normal VE acclimatization to this degree of hypoxemia. Two additional findings in CD ponies suggest the presence of a CNS inhibitory influence on the VE control center during chronic hypoxemia. First, acute hyperoxygenation on the 4th day of hypoxemia induced hyperventilation (deltaPaCO2 = -5 Torr, P less than 0.05). Second, again on the 4th day and during hyperoxygenation, VE responsiveness to CO2 and doxapram HCl was greater than at sea level.     

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

Ventilatory response of intact cats to carbon monoxide hypoxia

Adult intact conscious or anesthetized cats have been exposed to either hypoxia or low concentrations of CO in air. In addition, the ventilatory response to CO2 was studied in air, hypoxic hypoxia, and CO hypoxia. The results show that 1) in conscious cats, low concentrations of CO (0.15%) induce a slight decrease in ventilation and higher concentrations of CO (0.20%) induce first a small decrease in ventilation and then a characteristic tachypnea similar to the hypoxic tachypnea described in carotid-denervated cats; 2) in anesthetized cats, CO hypoxia induces only mild changes in ventilation; and 3) the ventilatory response to CO2 is increased in CO hypoxia in both conscious and anesthetized animals but differs from the increase observed during hypoxia. It is concluded that the initial decrease in ventilation may be caused by some brain stem depression of the respiratory centers with CO hypoxia, whereas the tachypnea originates probably at some suprapontine level. Conversely, the possible central acidosis may account for the potentiation of the ventilatory response to CO2 observed in either conscious or anesthetized animals.     

Ventilatory muscle recruitment in exercise with O2 in obstructed patients with mild hypoxemia

Respiratory muscle dysfunction limits exercise endurance in severe chronic airflow obstruction (CAO). To investigate whether inspiring O2 alters ventilatory muscle recruitment and improves exercise endurance, we recorded pleural (Ppl) and gastric (Pga) pressures while breathing air or 30% O2 during leg cycling in six patients with severe CAO, mild hypoxemia, and minimal arterial O2 desaturation with exercise. At rest, mean (+/- SD) transdiaphragmatic pressure (Pdi) was lower inspiring 30% O2 compared with air (23 +/- 4 vs. 26 +/- 7 cmH2O, P less than 0.05), but the pattern of Ppl and Pga contraction was identical while breathing either gas mixture. Maximal transdiaphragmatic pressure was similar breathing air or 30% O2 (84 +/- 30 vs. 77 +/- 30 cmH2O). During exercise, Pdi increased similarly while breathing air or 30% O2, but the latter was associated with a significant increase in peak inspiratory Pga and decreases in peak inspiratory Ppl and expiratory Pga. In five out of six patients, exercise endurance increased with O2 (671 +/- 365 vs. 362 +/- 227 s, P less than 0.05). We conclude that exercise with O2 alters ventilatory muscle recruitment and increases exercise endurance. During exercise inspiring O2, the diaphragm performs more ventilatory work which may prevent overloading the accessory muscles of respiration.     

Muscle metabolism during heavy-intensity exercise after acute acetazolamide administration.

Carbonic anhydrase (CA) inhibition is associated with a lower plasma lactate concentration ([La(-)](pl)), but the mechanism for this association is not known. The effect of CA inhibition on muscle high-energy phosphates [ATP and phosphocreatine (PCr)], lactate ([La(-)](m)), and glycogen was examined in seven men [28 +/- 3 (SE) yr] during cycling exercise under control (Con) and acute CA inhibition with acetazolamide (Acz; 10 mg/kg body wt iv). Subjects performed 6-min step transitions in work rate from 0 W to a work rate corresponding to approximately 50% of the difference between the O(2) uptake at the ventilatory threshold and peak O(2) uptake. Muscle biopsies were taken from the vastus lateralis at rest, at 30 min postinfusion, at end exercise (EE), and at 5 and 30 min postexercise. Arterialized venous blood was sampled from a dorsal hand vein and analyzed for [La(-)](pl). ATP was unchanged from rest values; no difference between Con and Acz was observed. The fall in PCr from rest [72 +/- 3 and 73 +/- 3.6 (SE) mmol/kg dry wt for Con and Acz, respectively] to EE (51 +/- 4 and 46 +/- 5 mmol/kg dry wt for Con and Acz, respectively) was similar in Con and Acz. At EE, glycogen (mmol glucosyl units/kg dry wt) decreased to similar values in Con and Acz (307 +/- 16 and 300 +/- 19, respectively). At EE, no difference was observed in [La(-)](m) between conditions (46 +/- 6 and 43 +/- 5 mmol/kg dry wt for Con and Acz, respectively). EE [La(-)](pl) was higher during Con than during Acz (11.4 +/- 1.0 vs. 8.2 +/- 0.6 mmol/l). The similar [La(-)](m) but lower [La(-)](pl) suggests that the uptake of La(-) by other tissues is enhanced after CA inhibition.     

Timolol plus acetazolamide: effect on formation of cerebrospinal fluid in cats and rats

Administration iv of 50 mg X kg-1 acetazolamide (A) and 3 mg X kg-1 timolol (T) causes the formation of cerebrospinal fluid (f-CSF) to be reduced to 43.7% of the control rate compared with a reduction to 82.5% of control by T alone and to 52.6% of control by A alone. The effect of combined drugs is the same when A is combined with T initially, when A is added to T after studying T alone, or when T is added to A after studying A alone. In contrast, in rats f-CSF is not influenced by T, either alone or when in combination with A. The rate in rats is reduced to 55% of control by treatments with A or A and T. Decrease in formation of cerebrospinal fluid by A occurs through inhibition of carbonic anhydrase, but the means whereby T (a known blocker of beta-adrenergic receptors) causes a reduction in f-CSF is not established; it is known that it does not inhibit carbonic anhydrase. Control of f-CSF by the sympathetic nervous system is discussed.     

Age-dependent metabolic effects of repeated hypoxemia in piglets

The aim of this study was to determine whether repeated exposure to hypoxemia would modify the response to hypoxemia during maturation. We exposed piglets to three 1-h cycles of hypoxemia (PaO2 = 30 to 35 mmHg; 1 mmHg = 133.3 Pa) at 1 week (n = 9), 2-3 weeks (n = 10), and 4-5 weeks of age (n = 10). O2 consumption (V(O2)) and CO2 production (V(CO2)) were measured, and alveolar ventilation (V(A)) was derived from V(CO2) and PaCO2. Levels of lactic acid (lactate) and serum catecholamines were also measured. With hypoxemia, time had a significant effect on V(O2) and body temperature in an age-dependent fashion: that is, whereas the 1 week group and the 4-5 week group showed both variables decreasing over time, the 2-3 week group showed no drop in V(O2) and a small increase in body temperature over time. Lactate levels increased with hypoxemia in all animals during the first exposure. However, with repeated exposures to hypoxemia, only the 2-3 week group continued to increase its lactate levels. Furthermore, the changes in lactate levels paralleled the changes in epinephrine levels with hypoxemia. We found, too, that although V(A) increased significantly with hypoxemia in all animals, this change was not modified by age or repeated exposures. No significant effects of age or repeated exposures were found in the cardiovascular response to hypoxemia. We concluded that, from a metabolic viewpoint, after repeated exposures to hypoxemia the 2-3 week animals responded differently.     

Action of acetazolamide on the chick embryo during late development.

Acetazolamide was injected into chick embryos on the 14th or 15th day of incubation. Doses ranging between 5 and 10 mg per egg produced a retardation in the growth of long bones. The affected bones contained a normal proportion of mineral as determined by ashing and presented a normal histological picture. On the basis of these findings, it is suggested that the alterations were not due to a specific direct effect of the drug on bones. The incorporation of 131-I by the thyroid glands of acetazolamide-injected embryos was analyzed radioautographically and quantitated on the same 6 mu-paraffin sections, with a thin window Geiger counter. The incorporation appeared notably reduced 3 h after the injection of acetazolamide and the reduction persisted for a least 24 h.the electron microscopical observation of thyroid follicular cells from similarly treated embryos showed that the cytological characteristics indicating an active protein synthesis were unmodified with respect to those found in control embryos. These results may indicate that acetazolamide inhibits the iodination of the throid hormone without interfering with the synthesis of the globulin. It is suggested that the growth retardation observed in the embryos treated with acetazolamide may be secondary to the action of the drug on the thyroid gland, although this action appears to be a transitory one.     

Selective metabolic effects of salbutamol in anesthetized cats.

Salbutamol was found to produce a selective stimulation of beta adrenergic receptors mediating metabolic responses in anesthesized cats. Salbutamol was infused intravenously at a rate of 1 μg/Kg/min; this agent produced a significant decrease in diastolic blood pressure and concomitantly increased blood glucose and lactate while decreasing plasma potassium. Salbutamol did not elevate plasma free fatty acids. In contrast to salbutamol, comparable infusions of isoproterenol produced all cardiovascular and metabolic effects non-selectively. The cardiovascular and metabolic effects of salbutamol were blocked by oxprenolol, a beta adrenergic receptor antagonist. The apparent selectivity of action of salbutamol suggests that metabolic beta adrenergic receptors are heterogeneous and can be differentiated into at least two separate types.     

Ventilatory effects of hypercapnic end-tidal PCO2 clamps during aerobic exercise of varying intensity

Nine subjects performed a sequence of sustained and randomised changes between 40 W and 100 W on a cycle ergometer while the end-tidal PO2 was kept close to 17.3 kPa (130 mm Hg) by means of a dynamic forcing technique (reference experiment). In a second series inspiratory CO2 was additionally manipulated so as to hold end-tidal PCO2 (PETCO2) near 6.5 kPa (49 mm Hg; 'CO2-clamp' experiment). By this forcing PETCO2 oscillations were attenuated and more evenly distributed over the frequency range. Ventilation (VT) responded to this manoeuvre with an upward trend that could not be ascribed to a slow CO2-response component, changes in metabolic rate or a dissociation of end-tidal and arterial PCO2. VT differences between reference and CO2-clamp experiments were abolished within a 3-min period following the termination of the external CO2 control. The present results suggest that the CO2-H+ stimulus plays a major role in adjusting ventilation when exercise intensity is decreased. The underlying CO2 effect appears to be neither additive nor bi-directionally symmetrical.