Effects of acetazolamide and dexamethasone on cerebral hemodynamics in hypoxia

Previous attempts to detect global cerebral hemodynamic differences between those who develop headache, nausea, and fatigue following rapid exposure to hypoxia [acute mountain sickness (AMS)] and those who remain healthy have been inconclusive. In this study, we investigated the effects of two drugs known to reduce symptoms of AMS to determine if a common cerebral hemodynamic mechanism could explain the prophylactic effect within individuals. With the use of randomized, placebo-controlled, double-blind, crossover design, 20 healthy volunteers were given oral acetazolamide (250 mg), dexamethasone (4 mg), or placebo every 8 h for 24 h prior to and during a 10-h exposure to a simulated altitude of 4,875 m in a hypobaric chamber, which included 2 h of exercise at 50% of altitude-specific VO(2max). Cerebral hemodynamic parameters derived from ultrasound assessments of dynamic cerebral autoregulation and vasomotor reactivity were recorded 15 h prior to and after 9 h of hypoxia. AMS symptoms were scored using the Lake Louise Questionnaire (LLQ). It was found that both drugs prevented AMS in those who became ill on placebo (~70% decrease in LLQ), yet a common cerebral hemodynamic mechanism was not identified. Compared with placebo, acetazolamide reduced middle cerebral artery blood flow velocity (11%) and improved dynamic cerebral autoregulation after 9 h of hypoxia, but these effects appeared independent of AMS. Dexamethasone had no measureable cerebral hemodynamic effects in hypoxia. In conclusion, global cerebral hemodynamic changes resulting from hypoxia may not explain the development of AMS.     

Effects of temperature on respiration and acid-base balance in a monitor lizard

Summary Ventilation, gas exchange, blood gas tensions and arterial pH were measured simultaneously in monitor lizards,Varanus exanthematicus. In contrast to previously studied poikilotherms, the arterial pH is independent of body temperature within the normally encountered temperature range (Fig. 1). This exception to the relative alkalinity concept (Rahn, 1966) is correlated with the finding thatV. exanthematicus maintains a constant ratio of ventilation to oxygen uptake (and CO₂ production) at different temperatures (Fig. 3). The increase in arterial (Fig. 1) is related to an increase in physiological dead space; i.e., alveolar ventilation increases less with temperature than total ventilation (Fig. 4). This may result from the increased frequency of breathing which results in a reduced breath holding time (Fig. 2). Varanid lizards have a higher oxygen requirement than other reptiles. This is reflected in the control of ventilation, the specialized lung morphology, the high arterial saturation due to low intracardiac shunting, pH regulation and other mammal-like features ofVaranus.     

Effect of acetazolamide on gas exchange and acid-base control after maximal exercise.

To investigate the interactions between the systems that contribute to acid-base homeostasis after severe exercise, we studied the effects of carbonic anhydrase inhibition on exchange of strong ions and CO2 in six subjects after 30 s of maximal isokinetic cycling exercise. Each subject exercised on two randomly assigned occasions, a control (CON) condition and 30 min after intravenous injection of 1,000 mg acetazolamide (ACZ) to inhibit blood carbonic anhydrase activity. Leg muscle power output was similar in the two conditions; peak O2 uptake (VO2) after exercise was lower in ACZ (2,119 +/- 274 ml/min) than in CON (2,687 +/- 113, P less than 0.05); peak CO2 production (VCO2) was also lower (2,197 +/- 241 in ACZ vs. 3,237 +/- 87 in CON, P less than 0.05) and was accompanied by an increase in the recovery half-time from 1.7 min in CON to 2.3 min in ACZ. Whereas end-tidal PCO2 was lower in ACZ than in CON, arterial PCO2 (PaCO2) was higher, and a large negative end-tidal-to-arterial difference (less than or equal to 20 Torr) was present in ACZ on recovery. In ACZ, postexercise increases in arterial plasma [Na+] and [K+] were greater but [La-] was lower. Arteriovenous differences across the forearm showed a greater uptake of La- and Cl- in CON than in ACZ. Carbonic anhydrase inhibition with ACZ, in addition to impairing equilibration of the CO2 system to the acid-base challenge of exercise, was accompanied by changes in equilibration of strong inorganic ions. A lowered plasma [La-] was not accompanied by greater uptake of La- by inactive muscle.     

The effect of acid-base balance on fatigue of skeletal muscle

H+ ions are generated rapidly when muscles are maximally activated. This results in an intracellular proton load. Typical proton loads in active muscles reach a level of 20-25 mumol X g-1, resulting in a fall in intracellular pH of 0.3-0.5 units in mammalian muscle and 0.6-0.8 units in frog muscle. In isolated frog muscles stimulated to fatigue a proton load of this magnitude is developed, and at the same time maximum isometric force is suppressed by 70-80%. Proton loss is slowed when external pH is kept low. This is paralleled by a slow recovery of contractile tension and seems to support the idea that suppression results from intracellular acidosis. Nonfatigued muscles subjected to similar intracellular proton loads by high CO2 levels show a suppression of maximal tension by only about 30%. This indicates that only a part of the suppression during fatigue is normally due to the direct effect of intracellular acidosis. Further evidence for a component of fatigue that is not due to intracellular acidosis is provided by the fact that some muscle preparations (rat diaphragm) can be fatigued with very little lactate accumulation and very low proton loads. Even under these conditions, a low external pH (6.2) can slow recovery of tension development 10-fold compared with normal pH (7.4). We must conclude that there are at least two components to fatigue. One, due to a direct effect of intracellular acidosis, acting directly on the myofibrils, accounts for a part of the suppression of contractile force. A second, which in many cases may be the major component, is not dependent on intracellular acidosis. This component seems to be due to a change of state in one or more of the steps of the excitation-contraction coupling process. Reversal of this state is sensitive to external pH which suggests that this component is accessible from the outside of the cell.     

Physicochemical analysis of phasic menstrual cycle effects on acid-base balance

In accordance with Stewart's physicochemical approach, the three independent determinants of plasma hydrogen ion concentration ([H(+)]) were measured at rest and during exercise in the follicular (FP) and luteal phase (LP) of the human menstrual cycle. Healthy, physically active women with similar physical characteristics were tested during either the FP (n = 14) or LP (n = 14). Arterialized blood samples were obtained at rest and after 5 min of upright cycling at both 70 and 110% of the ventilatory threshold (T(Vent)). Measurements included plasma [H(+)], arterial carbon dioxide tension (Pa(CO(2))), total weak acid ([A(Tot)]) as reflected by total protein, and the strong-ion difference ([SID]). The transition from rest to exercise in both groups resulted in a significant increase in [H(+)] at 70% T(Vent) versus rest and at 110% T(Vent) versus both rest and 70% T(Vent). No significant between-group differences were observed for [H(+)] at rest or in response to exercise. At rest in the LP, [A(Tot)] and Pa(CO(2)) were significantly lower (acts to decrease [H(+)]) compared with the FP. This effect was offset by a reduction in [SID] (acts to increase [H(+)]). After the transition from rest to exercise, significantly lower [A(Tot)] during the LP was again observed. Although the [SID] and Pa(CO(2)) were not significantly different between groups, trends for changes in these two variables were similar to changes in the resting state. In conclusion, mechanisms regulating [H(+)] exhibit phase-related differences to ensure [H(+)] is relatively constant regardless of progesterone-mediated ventilatory changes during the LP.     

Cerebrospinal fluid acid-base balance during muscular exercise

Ventilation, metabolism, arterial blood gases, and blood and cerebrospinal fluid (CSF) acid-base status were measured in exercise studies on seven ponies during mild, moderate, and near-maximal treadmill exercise. CSF and arterial blood were sampled via indwelling catheters. Generally measurements were made during the 3rd, 6th, and 9th minute of steady-state exercise, with CSF sampled only during the 9th minute. Alveolar ventilation (VA) and metabolic rate (VO2) increased proportionately during exercise below the anaerobic threshold, but above this threshold, VA increased at a faster rate than VO2. The similarity of these response to those observed in man suggests the pony is a suitable animal model for study of exercise hyperpnea. No change in CSF acid-base balance occurred with light-to-moderate work; however, with near-maximal work a fall in CSF carbon dioxide partial pressure due to hyperventilation caused CSF to become alkaline (pH = 7.380) relative to rest (pH = 7.330). CSF lactate increased slightly with exercise but had no effect on CSF [HCO3-], which remained constant from rest to severe exercise. We conclude that it is unlikely the hyperpnea at any intensity of exercise results from an increased H+ stimulation at the medullary chemoreceptor.     

Effects of feeding on metabolism, gas transport, and acid-base balance in the bullfrog Rana catesbeiana

Massive feeding in ectothermic vertebrates causes changes in metabolism and acid-base and respiratory parameters. Most investigations have focused on only one aspect of these complex changes, and different species have been used, making comparison among studies difficult. The purpose of the present study was, therefore, to provide an integrative study of the multiple physiological changes taking place after feeding. Bullfrogs (Rana catesbeiana) partly submerged in water were fed meals (mice or rats) amounting to approximately (1)/(10) of their body weight. Oxygen consumption increased and peaked at a value three times the predigestive level 72-96 h after feeding. Arterial PO(2) decreased slightly during digestion, whereas hemoglobin-bound oxygen saturation was unaffected. Yet, arterial blood oxygen content was pronouncedly elevated because of a 60% increase in hematocrit, which appeared mediated via release of red blood cells from the spleen. Gastric acid secretion was associated with a 60% increase in plasma HCO3(-) concentration ([HCO3(-)]) 48 h after feeding. Arterial pH only increased from 7.86 to 7.94, because the metabolic alkalosis was countered by an increase in PCO(2) from 10.8 to 13.7 mm Hg. Feeding also induced a small intracellular alkalosis in the sartorius muscle. Arterial pH and HCO3(-) returned to control values 96-120 h after feeding. There was no sign of anaerobic energy production during digestion as plasma and tissue lactate levels remained low and intracellular ATP concentration stayed high. However, phosphocreatine was reduced in the sartorius muscle and ventricle 48 h after feeding.     

Effects of NaHCO3 loading on acid-base balance, lactate concentration, and performance in racing greyhounds

This investigation examined the effects ofNaHCO₃ loading on lactateconcentration ([La]), acid-base balance, and performance for a 603.5-m sprint task. Ten greyhounds completed aNaHCO₃ (300 mg/kg body weight) andcontrol trial in a crossover design. Results are expressed as means ± SE. Presprint differences (P < 0.05) were found for NaHCO₃ vs.control, respectively, for blood pH (7.47 ± 0.01 vs. 7.42 ± 0.01), HCO₃ (28.4 ± 0.4 vs. 23.5 ± 0.3 meq/l), and base excess (5.0 ± 0.3 vs. 0.2 ± 0.3 meq/l). Peak blood [La] increased(P < 0.05) inNaHCO₃ vs. control (20.4 ± 1.6 vs. 16.9 ± 1.3 mM, respectively). Relative to control,NaHCO₃ produced a greater(P < 0.05) reduction in blood baseexcess (18.5 ± 1.4 vs. 14.1 ± 0.8 meq/l) andHCO₃ (17.4 ± 1.2 vs.12.8 ± 0.7 meq/l) from presprint to postexercise. Postexercise peak muscle H⁺concentration ([H⁺])was higher (P < 0.05) inNaHCO₃ vs. control (158.8 ± 8.8 vs. 137.0 ± 5.3 nM, respectively). Muscle[H⁺] recoveryhalf-time (7.2 ± 1.6 vs. 11.3 ± 1.6 min) and time to predosevalues (22.2 ± 2.4 vs. 32.9 ± 4.0 min) were reduced(P < 0.05) inNaHCO₃ vs. control, respectively.No differences were found in blood[H⁺] or blood[La] recovery curves or performance times.NaHCO₃ increased postexerciseblood [La] but did not reduce the muscle or blood acid-basedisturbance associated with a 603.5-m sprint or significantly affectperformance.

     

Effect of acetazolamide on cerebral blood flow and capillary patency.

This study investigated the effects 2 h after administration of acetazolamide on cerebral blood flow and the pattern of cerebral capillary perfusion. Arterial blood pressure, heart rate, arterial blood gases, and pH were recorded in two groups of rats along with either regional cerebral blood flow or the percentage of capillary volume per cubic millimeter and number per square millimeter perfused as determined in cortical, thalamic, pontine, and medullary regions of the brain. Blood pressure, heart rate, and arterial PCO2 were not significantly different between the rats receiving acetazolamide (100 mg/kg) and the controls. Arterial blood pH was significantly lower in the acetazolamide rats. Blood flow increased significantly in the cortical (+ 102%), thalamic (+ 89%), and pontine (+ 88%) regions receiving acetazolamide. In control rats, approximately 60% of the capillaries were perfused in all of the examined regions. The percentage of capillaries per square millimeter perfused was significantly greater in the cortical (+ 52%), thalamic (+ 49%), and pontine (+ 47%) regions of acetazolamide rats compared with controls. In the medulla the increases in blood flow and percentage of capillaries perfused were not significant. Thus in the regions that acetazolamide increased cerebral blood flow, it also increased the percentage of capillaries perfused.