Biomedical subjects
J K Barclay
Publications and source records attributed to J K Barclay.
Free radicals may contribute to oxidative skeletal muscle fatigue.
We used mouse soleus in vitro (n = 30) and canine gastrocnemius-plantaris preparations (n = 20) pump-perfused at the animal's blood pressure to establish if free radicals contribute to fatigue in oxidative skeletal muscle. The soleus from each leg contracted for 200 ms (70 Hz) once every minute for 60 min in Hepes buffer gassed with 100% oxygen at 27 degrees C. When contracting in Hepes alone, both muscles fatigued at 0.9 mN/mm2.min over the 60 min. The addition of purines to the bath increased the rate to 1.4 mN/mm2.min and the addition of xanthine oxidase to generate free radicals increased the rate again to 1.9 mN/mm2.min. Thus free radicals appeared to attenuate oxidative skeletal muscle function. Each canine muscle contracted isometrically at 4 Hz for 30 min and then rested for 45 min before contracting for a second 30 min at 4 Hz. In each experiment, we infused saline at 0.76 mL/min into resting muscle and at 1.91 mL/min during the first contraction period. During the remainder of the experiment, we infused, at the same rates, saline (n = 4), 10 microM dimethyl sulfoxide (DMSO) (n = 4) to identify the effect of scavenging hydroxyl radicals, 1 mM allopurinol to establish the effect of blocking xanthine oxidase (n = 4), or 200 microM desferoxamine to determine the effect of chelating iron (n = 4). With saline, the fatigue rate over the 30 min of contractions increased from 5.0 +/- 0.2 to 6.3 +/- 0.5 N/kg.min from the first to the second stimulation period. The fatigue rate was slower in the second period with each of the three experimental substances (DMSO, 5.9 +/- 0.8 to 3.2 +/- 0.3; allopurinol, 7.3 +/- 1.1 to 4.6 +/- 0.6; desferoxamine, 6.8 +/- 0.8 to 4.4 +/- 0.8 N/kg.min). The fatigue rate was the same as control when DMSO was infused only during the second contraction period. Therefore, free radicals appeared to contribute to fatigue in oxidative skeletal muscle.
Differences between VO2 maxima of twitch and tetanic contractions are related to blood flow.
The purpose of this investigation was to compare oxygen uptake (VO2) and fatigue characteristics of isotonic tetanic contractions with those observed during isotonic twitches in dog gastrocnemius-plantaris muscle. Tetanic contractions (1/s, 200-ms trains of 50 impulses/s) elicited a peak VO2 of 9.01 +/- 0.42 mumol.g-1.min-1, which declined 29% in 30 min. The peak was significantly lower during 4/s twitches (6.23 +/- 0.36 mumol.g-1.min-1), but the rate of decline was similar. Peak blood flow (Q) was 37% higher and decreased more slowly during tetanic than twitch contractions. VO2/Q and VO2/venous PO2 were similar in both groups at peak VO2 and later declined or remained constant over time. Power was significantly greater with tetanic contractions with the relative decline between 3 and 30 min similar in both groups (32 and 37%). In conclusion, tetanic contractions result in significantly higher VO2 and power than do twitch contractions. This was derived primarily from increased Q because the arteriovenous O2 difference was similar. A significant determinant of the difference in Q between twitch and tetanic contractions is mechanical hindrance of Q. There is relatively more time for unhindered flow in the tetanic contractions. In electrically stimulated muscles, maximal VO2 is related to Q and reflects mainly Q through the muscle rather than the VO2 capacity of the muscle.
A comparison of midazolam with and without nalbuphine for intravenous sedation.
The introduction of nalbuphine to intravenous sedation with midazolam added little to the quality of sedation for short operative procedures. There was a greater tendency for patients who received nalbuphine and midazolam to sleep in the afternoon after treatment compared with those who received only midazolam. Significantly more patients had nausea and vomiting in the midazolam/nalbuphine group than did patients in the midazolam-only group.
Effect of acidosis on skeletal muscle metabolism with and without propranolol.
Does the stimulatory effect of circulating catecholamines counteract the inhibitory effect of acidosis on skeletal muscle metabolism? To investigate this possibility, we studied gastrocnemii in dogs breathing either air (n = 10) or 4% carbon dioxide in air (n = 10) at rest and during contractions. In five dogs from each group, we infused propranolol into the arterial supply of the right and left muscles for 40 min. After 30 min of infusion, the left muscle was stimulated at 3 Hz for 10 min. During the 10th min of contractions, we removed and froze both muscles in liquid nitrogen. Oxygen uptake and blood flow to the left muscle prior to or during stimulation was not affected by acidosis either with or without propranolol. Glycogen concentration in resting muscle was unaffected by acidosis with or without propranolol. There was an acidosis related decrease of approximately 50% in the glycolytic intermediates (glucose 6-phosphate, fructose 1,6-diphosphate, alpha-glycerol phosphate, and dihydroxyacetone phosphate) in unstimulated muscles without beta-blockade. At rest, acidosis decreased muscle lactate by 50% with and 64% without propranolol, but lactate release was decreased only with acidosis without propranolol (1.4-0.1 mumols/kg.s). Acidosis without propranolol had no effect on the changes in glycogen concentration or the change in the concentration of glycolytic intermediates resulting from contractions. In beta-blocked muscle, the difference between stimulated and unstimulated concentrations of glycogen and glycolytic intermediates including lactate was 20-50% smaller with acidosis. Thus, with beta-blockade, the acidotic effects at rest disappeared and an inhibition of the metabolic adjustment to contractions appeared, indicating that circulating catecholamines do modify some metabolic effects of acidosis.
Effects of ischemic and hypoxic hypoxia on VO2 and lactic acid output during tetanic contractions.
We measured O2 uptake (VO2), CO2 output (VCO2), and net lactic acid output (L) during a 30-min period of repetitive 1/s isotonic tetanic contractions of the dog gastrocnemius-plantaris muscle group. The conditions were modest ischemic hypoxia (ischemia), hypoxia hypoxia (hypoxia), and free-flow normoxia (control). The major goal was to assess the effects of these perturbations on L during contractions. Ischemia and hypoxia were initiated just before the start of the contractions and at minute 7 of contractions in separate groups of experiments. Whenever applied, both ischemia and hypoxia reduced VO2 compared with the control values. When ischemia was initiated at the start of contractions, L was reduced transiently compared with the controls. When ischemia began at minute 7, L was increased modestly but transiently compared with the controls. When hypoxia was initiated at the start of contractions, L was increased during the entire period of contractions. The L pattern was the same as in the controls, rising to a maximal value at 3 min and declining steadily to a lower value at 30 min. When hypoxia began at minute 7, L declined initially at a slower rate than it did in the controls and was thereby elevated above the controls from 9 to 30 min. Ischemia was associated with a more rapid reduction in mechanical performance than hypoxia. The data suggest that the mechanisms of the decreased mechanical performance and VO2 are different for ischemia and hypoxia.
Antibiotics revisited.
The choice of an antibiotic for the management of an acute dental infection should be made from a relatively small range of agents. There is little evidence for prescribing the newer, more expensive, wide-spectrum, antibiotics. Failure to respond to therapy is usually due to inadequacy of dose, or failure to eliminate aggravating factors. The temptation to use antibiotics for the management of trivial infections should be resisted, and such problems managed by careful attention to first principles. The prophylactic use of antibiotics is less clear cut. Guidelines have been produced by expert committees that cover some situations, but such guidelines cannot be all-embracing. By weighing individual factors, the dentist should be able to reach a decision as to when antibiotic cover is indicated. This can only be done by maintaining contact with the literature in order to note changing recommendations, and drawing conclusions from conflicting opinions.
Hypothesis: local vascular regulation is a key to flow limited muscle function.
The ability of canine oxidative skeletal muscle in situ to maintain developed isometric force is flow limited during twitch contractions at greater than 3 Hz. This limitation implies a mismatching of blood flow and the metabolic rate. The blood flow past a muscle cell is determined by the number of capillaries per fibre, the vascular conductance, the capillaries perfused and vascular autoregulation. Of these, capillary number is regulated on a time scale of days while the other three require seconds to minutes. Each of the regulatory systems involves hypoxia, adenosine and the eicosanoids as contributing factors which would predict that regulatory systems working on the same time scale should change in parallel. This does not appear to be the case at high metabolic rates. The resulting mismatching of flow and metabolism accelerates the fatigue process. This peripheral vascular limitation can exist without a central cardiovascular limit being reached.
Oxidation/reduction state of cytochrome oxidase during repetitive contractions.
There is disagreement regarding whether inadequate O2 determines maximal O2 uptake (VO2max) and lactic acid output (L) during muscular activity. Direct assessment of mitochondrial cytochrome oxidase (cytochrome a-a3) oxidation/reduction (O/R) state should provide an unequivocal answer for this issue. A new near-infrared spectrophotometric method was used to measure the O/R state of cytochrome a-a3 of dog gastrocnemius-plantaris muscle in situ during repetitive isotonic twitch and tetanic contractions. Three contraction frequencies were used for each contraction type in alternating sequence to provide a wide range of VO2 up to VO2max. VO2 and L were measured after 3 and 9 min of a 10-min contraction period, and 15 min were allowed for recovery between contraction periods. VO2 increased with contraction frequency. L was variably increased with contraction frequency at 3 min and uptake usually occurred at 9 min, except at the highest tetanic frequency. The O/R span of cytochrome a-a3 was determined by respiring the animals with 100% N2 to determine the most reduced state. This was followed by respiration with 100% O2, which gave the most oxidized state transiently during recovery. Within this span in muscles at rest, cytochrome a-a3 was 50-80% oxidized. During contractions of both types at all frequencies, cytochrome a-a3 always became more oxidized by an additional 10-20%. These findings should put to rest any arguments that inadequate O2 is a determinant of VO2max or L under the conditions of these experiments: repetitive contractions with free flow in self-perfused muscles and normoxia.
Facial abscess: a case report.
This report describes a patient with a migratory abscess as a sequel to the surgical removal of a mandibular third molar tooth. Culture of pus drained from the abscess revealed no growth, probably because of previous management with antibiotics.
Effects of ischemia on VO2, tension, and vascular resistance in contracting canine skeletal muscle.
This study examined the changes in O2 consumption (VO2), vascular resistance, and tension development during skeletal muscle contractions at reduced flow. We tested the hypothesis that when VO2 is limited by O2 supply, the skeletal muscle vasculature is not maximally dilated because of the fall in contractile force that accompanies the decrease in O2 supply. During 30 min of ischemic contractions, tension fell by 45 +/- 4% and VO2 fell 54 +/- 1% from preischemic levels. The O2 cost per unit tension did not change compared with nonischemic muscles. After the initial flow reduction, flow fell an additional 16 +/- 3% over 30 min. Adenosine infusion after 30 min of ischemic contractions increased flow by 42 +/- 3% but increased VO2 by only 9.8 +/- 2.3% and had no effect on tension development. When perfusion pressure was returned to normal after 30 min of ischemic contractions, twitch tension did not begin to recover within 20 min but tetanic tension showed a small improvement. VO2, although increased, remained well below the preischemic level. These results suggest that because of the reduced tension during ischemic contractions, the O2 supply-to-consumption ratio is nearly normal, which could explain the presence of the vasodilator reserve. The defect in tension development is long lived, producing a "stunned" muscle in which excess O2 supply does not restore function or VO2 to normal.
Physiological determinants of Qmax in contracting canine skeletal muscle in situ.
Canine skeletal muscle preparations in situ contain varying mixtures of fast and slow fatigue resistant fibers. All vessels on the arterial side of the vascular bed in these preparations from the conduit arteries to the arterioles contribute to the vascular resistance. The vascular beds autoregulate at rest and during contractions, indicating that the effects of the surgery are minimal. Stimulation frequency and pattern, i.e., twitch or brief tetanic contractions, the force exerted, and the length at which the muscle contracts, combine to determine the metabolic rate, which in turn, establishes the blood flow at a given perfusion pressure. When blood flow is normalized for oxygen uptake, the ratio is similar for twitch and rhythmic brief tetanic contractions. The ratio stays constant over a wide range of frequencies even though the flow increases and is greater than the theoretical minimum set by the maximum arteriovenous oxygen concentration difference. The infusion of vasodilators such as adenosine results in higher flows than those obtained with 6 Hz stimulation alone, indicating the presence of a "pharmacological reserve". The peak blood flow measured with isometric twitch contractions at 6 Hz in constant pressure pump perfused muscles at the optimum length for tension development averages 19.7 +/- 1.1 ml.kg-1.s-1. The pharmacological maximum at 6 Hz averages 25.9 +/- 1.6 ml.kg-1.s-1 with an observed maximum of 33.2 ml.kg-1.s-1.
Root in the maxillary sinus.
The accidental displacement of a root into the maxillary sinus is a recognized complication of exodontia. Such roots should normally be removed early rather than late in order to minimize the likelihood of maxillary sinus complications. A root left within the maxillary sinus may, on occasion, pass spontaneously into the nose. Appropriate treatment and possible complications are discussed.
Carbonic anhydrase III inhibition in normocapnic and hypercapnic contracting mouse soleus.
The physiological role of carbonic anhydrase III in slow-twitch skeletal muscle was investigated using isolated mouse soleus (N = 30) contracting once every 1.7 min for 75 min in Krebs-Henseleit solution gassed with either 95% oxygen - 5% carbon dioxide (normocapnia) or 90% oxygen - 10% carbon dioxide (hypercapnia). Each contraction was 500 ms in duration at 50 Hz. When muscles contracted in normocapnic solution (pH 7.42), the developed tension decreased an average of 6.1 +/- 0.8% over 25 min. For the next 50 min, 15 muscles remained normocapnic, while the remainder contracted in hypercapnic solution (pH 7.20). Tension decreased significantly more with hypercapnia. For the last 25 min, both normocapnic and hypercapnic muscles were divided into three treatment groups (N = 5). One group continued in the same environment, while acetazolamide (final concentration of 10(-5) M) was added to the bath of the second and sodium cyanate (final concentration of 10(-5) M) was added to the bath of the third group. Acetazolamide had no effect on tension in either carbon dioxide environment. Sodium cyanate significantly decreased tension from the hypercapnic control but had no effect in normocapnia. Thus carbonic anhydrase III inhibition with sodium cyanate increased the effect of hypercapnia implying that carbonic anhydrase III assists in the regulation of free hydrogen ion concentration in slow-twitch skeletal muscle.
Hyperoxia, mitochondrial redox state, and lactate metabolism of in situ canine muscle.
The effect of hyperoxia on lactate production and release and the mitochondrial NAD+-to-NADH ratio was studied in the in situ canine gastrocnemius to determine whether elevated PO2 altered metabolic regulation. Dogs breathed either air (21% O2) [arterial O2 partial pressure (PaO2) 90 mmHg; n = 8] or hyperoxia (100% O2) (PaO2 546 mmHg; n = 8). The left muscle was stimulated for 10 min at 3 Hz and then both right and left muscles were quick frozen in N2. Hyperoxia did not affect O2 uptake, blood flow, and developed tension. Activity increased glucose 6-phosphate (G-6-P), D-fructose 6-phosphate (F-6-P), NH3, lactate, and F-6-P/F-1,6-P in both treatment groups. No significant differences in arterial or venous lactate, muscle lactate, glucose uptake, or glycogen depletion were noted in hyperoxia. Cytoplasmic NAD+/NADH was in a more oxidized state in hyperoxia at rest but not during activity. The increase in NH3 with stimulation was significantly larger in hyperoxia. Activity decreased alpha-ketoglutarate in hyperoxia but not in air. At stimulation, the estimated mitochondrial NAD+/NADH increased in both groups suggesting that hypoxia was not present. Thus hyperoxia did not affect mitochondrial redox state or lactate production and release in active muscle.
Metronidazole and dry socket: prophylactic use in mandibular third molar removal complicated by non-acute pericoronitis.
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Skeletal muscle lactate release and glycolytic intermediates during hypercapnia.
The effects of respiratory acidosis on glycolysis in the autoperfused canine gastrocnemius-plantaris were studied using anesthetized dogs that were ventilated either with air (n = 30) or with 4% CO2-21% O2-75% N2 (n = 30). The left muscle group was stimulated at 3 Hz for up to 20 min, after which the active and the contralateral resting muscles were removed and frozen in liquid N2. Blood flow, VO2, Vco2, and tension development were unaffected by CO2. Glycogen catabolism was not affected, but lactate release (La) was lower (P less than 0.05) during activity with CO2; and greater fructose 6-phosphate, fructose 6-phosphate/fructose 1,6-diphosphate, and alpha-glycerophosphate/dihydroxyacetone phosphate ratios resulted (P less than 0.05). With respiratory acidosis, muscle lactate tended to accumulate early in contractions, but a net lactate uptake occurred during the last 10 min of contractions. Thus, respiratory acidosis reduced lactate efflux and there was a net uptake late in the contraction period. Glycogen phosphorylase did not appear to be affected by the respiratory acidosis, but there was evidence of inhibition at the phosphofructokinase step as well as a tendency for lactate to accumulate within the muscle. La often occurred in a direction contrary to the muscle-venous lactate concentration difference with either air or CO2 and La also decreased far more rapidly over time than did the arterial-venous H+.
A delivery-independent blood flow effect on skeletal muscle fatigue.
The hypothesis that hyperperfusion decreases muscle fatigue by increasing O2 and substrate delivery to the muscle was tested. Canine gastrocnemius-plantaris in situ preparations were stimulated at 5 Hz for 4 min during a free-flow control period and for 20 min during a pump-perfused experimental period. O2 delivery during these two periods was matched either by decreasing blood flow in animals breathing 100% O2 (high O2/low flow) [experimental-to-control ratio (E/C) = 0.97 + 0.02] or by increasing the blood flow in animals breathing 14% O2 (low O2/high flow) (E/C = 1.01 + 0.01). Plasma flow estimated from hematocrit to approximate substrate delivery was matched in the two contraction periods either by maintaining blood flow at the steady-state level (constant flow) (E/C = 0.98 + 0.10) or by increasing flow in animals with a dextran for 6% of blood volume exchange (dilute/high flow) (E/C = 1.02 + 0.02). E/C for initial developed tension was 1.00 + 0.02. Over 20 min, developed tension decreased 15.0 + 1.1% with low O2/high flow and 16.0 + 1.8% with dilute/high flow. Tension decreased by 28.0 + 3.0 and 27.8 + 1.5% with high O2/low flow and constant flow, respectively. Thus hyperperfusion decreased fatigue by a mechanism independent of increased O2 and substrate delivery.