The change in pulmonary function which follows cardiopulmonary bypass (CPBP), as practised with modern techniques, was evaluated in 10 patients undergoing coronary vein-graft operations. Measurements were made during the week before operation and on 5 occasions postoperatively. The study was preceded by an attempt to establish normal values for pulmonary blood-gas exchange, in the supine position. It proved impracticable to predict the normal range of alveoLar-to-arteriaL oxygen tension difference (AAsPq^) and venous admixture (Qva/Qt), when supine, according to age. The relationship of closing volume (CV) to expiratory reserve volume (ERV) was important in determining these and was not closely related to age. In the CPBP study, mean Qva/Qt breathing air, increased from 9.59% to a maximum of 13.71%, 22 hr postoperatively. Mean Qva/Qt, breathing oxygen, increased from 7.02% to a maximum of 15.71%, 48 hr postoperatively. Most of the deterioration in gas exchange appeared to be due to increase in regions of lung with no ventilation or with critically low ventilation/perfusion ratio (V/Q). These changes were no greater than those reported to follow upper abdominal operations without CPBP though this comparison is difficult to make because of technical and other differences. None of the preoperative tests afforded a reliable forecast of the postoperative venous admixture. Arterio-venous oxygen content difference (AavCt^) had risen significantly by 22 hr and was still raised at 48 hr. This probably indicates an abnormal cardiac output in this period. Ten days postoperatively Qva/Qt and AsvCq^ had returned to the preoperative level. Despite an attempt to select subjects whose lung function was normal before operation, there was variation not only in their preoperative clinical state but also in their postoperative clinical course. These variations may have accounted for some of the differences in physiological behaviour. Conclusions drawn from the mean values above should, therefore, be applied with caution in other circumstances. The group is, however, likely to be representative of the fittest patients having cardiac operations with CPBP at Green Lane Hospital.

No description available.

Less than one hundred years ago Paul Bert discovered that oxygen at raised pressures was injurious to a wide range of organisms and, in a number of experiments conducted over several years, he investigated this and other problems which form the basis for what has subsequently become high-pressure physiology. It seems however that the large amount of research which has been done in an attempt to understand the nature of oxygen poisoning has touted to confuse the original simple view of oxygen as a universal poison. A very large number of reactions which depend upon enzymes are adversely affected by raised pressures of oxygen, sufficient indeed to make it likely that the 'cause' of oxygen poisoning will not be found, in the sense that no single critical reaction will be identified as giving rise to any one of the various toxic manifestations. Instead the emphasis must be upon studying the way in which cellular metabolism is modified and finally disrupted by raised pressures of oxygen; and in particular by trying to identity the rate-limiting step within the complex of reactions.</p> The present work has been upon one aspect of oxygen toxicity, namely the development of convulsions in mice which have been exposed to raised pressures of oxygen. These experiments have been based upon two hypotheses; the first of these was that the dose-response relationship was related to the dynamics of the underlying biochemical processes and particularly, that the rate at which toxic signs developed would be determined by whichever reaction was rate-limiting. Attempts to correlate biochemical and physiological information have not so far been possible since there hare been no estimates available of the rate at which toxicity develops. The first task was therefore to define as accurately as possible the dose-response relationship between the ambient oxygen pressure and the time taken for convulsions to appear, and then, by dividing each exposure into two parts, to attempt to measure the rate at which toxicity develops. The second hypothesis was that the time to convulsions was not uniquely determined by the partial pressure of oxygen inspired and hence that the convulsion time would be modified by the presence of other respirable gases. Since it was thought that the nature of such modifications would give further information about the process which leads to convulsions, the interactions between oxygen and other gases, name, Carbon Dioxide, Nitrous Oxide, Nitrogen and Helium therefore form the second part of this work. The first notable feature of oxygen convulsions in mice was that at least two types of convulsion were distinguishable. The first type, referred to as minor convulsions, tended to occur early, was of short duration and was minor in intensity, while the second tended to occur later, was more prolonged and more violent and was called a major convulsion. A few animals showed chronic rolling movements after relatively long exposures. The second point of importance was that, for any particular oxygen pressure, convulsions in mice were found to be distributed in a skew manner. This could however be converted to a normal distribution by a logarithmic transformation, which also had the desirable feature that the standard deviation of the transformed results was independent of the mean, unlike the untransformed data. Consideration of the dose-response curve led to an approximate relationship in which the product of the ambient oxygen pressure and the mean logarithmic convulsion time for that pressure was found to be constant. A similar relationship was also found to describe the occurrence of minor convulsions and the relationship between minor and major convulsions expressed as the ratio between the slopes of the respective dose-response lines. When an initial exposure, short of convulsions, was immediately followed by a second exposure leading to convulsions, such divided exposures were found to be additive; that is, the parts were capable of being described by the same mathematical relationship as the whole. These divided exposures also led to the definition of a provoked threshold which for mice was at the pressure of about 3 atm. of oxygen. Exposure to pressures above this threshold shortened subsequent exposures, while exposures below the threshold had not detectable effect upon subsequent exposures. Other experiments using divided exposures, in which the time of the first exposure was varied, were interpreted as showing that the process leading to convulsions was, as a first approximation, exponential in form and that its rate was proportional to the ambient oxygen pressure. Estimates for the half-time of this process at 3 atm. and 4 atm. were 35 mins. and 22 mins. respectively. The first interaction to be investigated was that between oxygen and carbon dioxide and the results obtained were found to be in agreement with the findings of Marshall and Lambertsen (1961), since carbon dioxide at low levels hastened the onset of convulsions, although at high levels no significant effect could be demonstrated. This would seem to be consistent with the view that high carbon dioxide levels protect against convulsions and would point to a cross-over point at about 7 atm. of oxygen for carbon dioxide levels of 0.03-0.07 atm. Similar results were obtained for nitrogen, these tow gases, carbon dioxide and nitrogen both changed the slope and the intercept of the dose-response line as is shown diagrammatically in Figure 17. While the mechanism of action is not known it is speculated that both may lead to changes in intracellular pH. at lower concentrations, while at higher concentrations the anaesthetic properties of these gases may preponderate. The evidence obtained from the interaction with nitrous oxide seemed to show that more than one type of interaction was possible, since this gas altered the slope of the dose-response line. 0.54 atm. of N₂O gave a marked protection against convulsions, but did not appreciably alter the intercept. Helium was found to produce a marked acceleration in the onset of oxygen convulsions, bat no evidence was found for any convulsant action of helium itself, since supra-liminal oxygen pressures were necessary in order to show the effects of helium. The magnitude of the effect, judged by the change in slope of the dose-response time, was proportional to the helium partial pressure; hence the possibility has been considered that this effect was due not to any physiological action of helium, but rather to the effects of pressure 'per se'. The significance of the threshold, i.e. the minimum effective pressure to produce convulsions and the minimum response time, has been discussed. Two possible mechanisms to account for the threshold were considered. The first of these depends upon the fact that the tissue oxygen consumption tends to keep the tissue oxygen tension within normal limits until the total quantity of oxygen supplied exceeds the quantity being consumed. The second possibility which was considered was that of a competing recovery process which removed some product of the convulsion-producing reaction at a rate different from that at which it was produced. While on balance the first explanation was thought more likely, recovery undoubtedly does occur, and both may therefore be involved. Regarding the minimum response time, this was thought to be a simple consequence of the rate of the process to convulsions reaching a value; although the reason for this is not obvious, it was suggested that it might be due to the progressive inactivation of enzymes by oxygen at pressure. Consideration of the possible sites of action of oxygen in producing convulsions may perhaps be premature, since it is uncertain whether the convulsions represent a generalised reaction of brain tissue or whether there are particularly sensitive areas on the basal ganglia from which the convulsions originate. It was thought however that there was sufficient evidence to show that oxygen acts by disturbing cellular oxidations to make the choice of the mitochondrion, as the site of action, not unlikely. Using the previous assumption and available data, an estimate was made of the toxic level of oxygen in the brain of man as being of the order of 40-85 min. Hg. at the mitochondria, or 70-100 min. Hg. in the venous blood. It was shown that the dose-response curve might be interpreted as resulting from a process leading to convulsions. It was further suggested that this hypothetical process to convulsions represented the rate-limiting step of a cyclic or chain reaction involved in tissue oxidations and that the kinetics of this process might help to identify the site or sites at which oxygen acts to produce convulsions. The existence of interactions between oxygen and other gases has been confirmed and it has been suggested that these interactions may represent interference with tissue oxidations either at the same sites as those involved in oxygen toxicity or at adjacent sites. The evidence suggested that there were two principal modes of interaction, the first represented by the anaesthetic gases and the second by the action of helium, although alterations in intra-cellular pH. may also be of some importance.

No description available.

Asthma is characterised by airway inflammation, remodelling and bronchial hyperresponsiveness to normally innocuous stimuli. There is growing evidence that the airway smooth muscle (ASM) in asthmatic patients is altered and contributes to all three of these central pillars of the disease. Intracellular free calcium ions act as a secondary messenger within ASM in all of these processes and the expression of proteins regulating this tightly controlled process are altered in the disease. It has further been suggested that the long-term detrimental effect observed with some asthma therapies maybe associated with changes in calcium handling. The hypothesis of this study was that the calcium handling proteins SERCA2, TRPC3 and TRPC6 are altered by cytokines associated with asthma, or current therapies, leading to changes in calcium dynamics in the cell which contribute to the asthmatic phenotype. To investigate this hypothesis human primary healthy ASM cells were grown in culture and stimulated with either IL-13, TGF-β, TNF-α or a combination thereof or β2-adrenergic receptor agonists. The RNA and protein expression of the aforementioned calcium regulators were measured by qPCR and western blot and the calcium dynamics assessed by loading cells with fura-2. The impact of reduced SERCA2 expression, as observed in ASM derived from asthmatics, was investigated in a murine model of ovalbumin induced allergic airway disease using SERCA2+/- mice. End-points included lung function measurements and inflammatory cell and cytokine infiltration. The key results found were that TGF-β differentially upregulates the expression of TRPC6 splice variants in a Smad2/3 dependent manner resulting in a reduction in flufenamic acid induced calcium entry. TNF-α upregulates TRPC3 expression while concomitantly down-regulating TRPC6 possibly conferring a switch in signalling from receptor operated calcium entry to store operated calcium entry. A reduction in SERCA2 in an in vivo model of asthma results in enhanced neutrophilia and an increase in sensitivity to methacholine to increase total airway resistance and decrease dynamic compliance. Finally it appears that chronic administration of β2-adrenergic receptor agonists can lead to a variable decrease in SERCA2 expression however cAMP formation significantly increases it. Therefore β-arrestins may play a role in the detrimental effects observed with chronic dosing of this class of compounds. In conclusion the calcium handling proteins TRPC3 and TRPC6 are differentially altered by both TNF-α and TGF-β but unaffected by IL-13. The protein expression of SERCA2 on the other hand appears to be less regulated by the presence of asthmatic cytokines and its continued reduced expression in cultured asthmatic cells could be the result of genetic or epigenetic regulatory mechanisms.

No description available.

No description available.

The circulatory and metabolic effects of high oxygen pressures have fascinated research workers virtually since the time of Lavoisier. This interest has been more marked in the past decade or so with the application of hyparbaric oxygen to clinical practice (Boerema, 1965, Smith, 1964, 1966), In this respect, however, the major limiting factor to the therapeutic use of hyperbaric oxygen has been the phenomenon of oxygen toxicity. This thesis is concerned with the study of the setiological factors concerned in oxygen toxicity and the possible relationship between the metabolic affects of oxygen and oxygen toxicity. In order to achieve a meaningful assessment of the effects of high oxygen tensions, it was felt that the accuracy of the system of measurement of oxygen tension to be utilised in later experiments should first be validated. The accuracy of using 100 ul. samples of blood for P02 measurement on the Radiometer micro oxygen electrode over the range of oxygen tension 2-2400mm. Hg. was confirmed. It was shown that, if measurement of P02 could not be carried out Immediately after sampling, blood samples should be stored in glass capillary tubes or glass syringes at 4C in melting ice. A method of obtaining arterialised capillary blood samples from the ear lobe by means of massage with Thurfyl nicotinate was developed. Such samples give values of P02 which were in close agreement with values of arterial P02 in normal hyperoxic and hypoxic 'shocked' individuals, thus providing an alternative to the use of arterial blood senile. The addition of nitrogen as a supporting gas for the alveoli when high inspired oxygen tensions were administered to mice, postponed the onset of severe lung damage and death but could not prevent the manifestations of pulmonary oxygen poisoning. Abolition of systomic hyperoxia, whilst maintaining a high intra alveolar oxygen tension, did not prevent pulmonary oxygen poisoning. The more severe morphological and histological changes produced by oxygen poisoning to the lungs correlated with a diminution In surfactant activity of lung extracts and an unstable alveolar structure as diminution by volume/ pressure relationships of excised lungs. Oxygen at high tension appears to produce toxicity in the lungs by an intra pulmonary effect. Although there is no definitive proof of the mechanism whereby the pulmonary damage is produced, it appears that this may be due to a primary effect on the pulmonary vasculature. The renal blood flow In dogs was reduced by approximately one third when the animals breathed high oxygen tension. This diminution in renal perfusion was not abolished by selective pharmacological blockade of the renal sympathetic nerves. When the kidney was underperfused by inducing hypovolsemic hypotension in the animals the renal blood flow was still reduced hyporoxia. The reduction in perfusion did not occur until the renal tissue, as indicated by the renal venous oxygen tension, became super saturated with oxygen and the haemodynamic changes did not follow directly changes in arterial oxygen tension. There was no evidence to show that the conges in renal blood flow were secondary to changes in renal metabolism Induced hyperoxia. The changes in renal perfusion due to oxygen, however, appear to be due to a direct intra-renal effect of oxygen. Increased carbon dioxide tensions in the blood did not produce changes In renal blood flow or renal function until the carbon dioxide tension was above 70 MM. Hg. The changes in renal handling of electrolytes, which were studied, appeared only to reflect the reduction in total renal perfusion which occurred with gross hypercapnia. The effects of hypercapnia on the renal circulation could be abolished by renal nerve blockade and appeared to be mediated through the sympathetic Nervous system as part of an extra-renal effect. Infusion of mannitol prevented the changes in renal blood flow produced by hypercapnia. Carbon dioxide does not appear to play an important effect in the normal psychological control of renal blood flow. The responses produced in the renal circulation by changes in the blood tension of carbon dioxide and oxygen were different. The responses of the kidney following renal nerve blockade in the presence of high tensions of these gases were also dissimilar. Thus it must be concluded that their modes of action and importance in physiological control over renal blood flow are entirely dissimilar.

No description available.

The aim of the present thesis was to experimentally test hypotheses originally forwarded by Burnley and Jones (2007): that the kinetics interact with an individual’s capacity for substrate-level phosphorylation and maximal oxygen uptake to determine the power-duration relationship. Experiments were designed to manipulate the kinetics, the “anaerobic capacity,” and/or the maximal oxygen uptake, and determine the effect of these manipulations on the power-duration relationship. Prior high-intensity exercise was used to investigate the classic priming effect during subsequent high-intensity exercise. Both heavy- and severe-intensity exercise ‘primed’ the kinetics (i.e., increased primary amplitude, reduced the slow component trajectory and amplitude). Following 10 min recovery, prior heavy-intensity exercise increased exercise tolerance as a result of an increase in W (C: 16.0  4.8 vs. PHE: 18.7  4.8 kJ; 95% CI, 0.3, 5.2 kJ). In contrast, following the same recovery period, no difference was seen in performance or the power-duration relationship after prior severe-intensity exercise. It was considered that the accumulation of H+ ions (thereby reducing pH) during high-intensity exercise may be implicated in the fatigue process. Sodium bicarbonate ingestion was used to increase the buffering capacity of the blood. This intervention had no effect on the kinetics or , but increased CO2 production, , and blood [lactate] at exhaustion. Despite these results, no overall difference was seen in exercise tolerance between conditions; however, CP was reduced (Pl: 303 ± 48 vs. Na: 296 ± 53 W; 95% CI, 0,14 W) and W increased (Pl: 19.5 ± 8.6 vs. Na: 22.4 ± 9.2 kJ; 95% CI, -5.2, -0.7 kJ), following alkalosis. The final two studies were designed to reduce muscle O2 availability by lowering the O2 carrying capacity of the blood (Blood donation), or through a reduction in perfusion pressure (Supine exercise). Each of these interventions has similar effects on the kinetics: a reduction in the primary amplitude (and a longer time constant; supine only); no change in the slow component trajectory; and a reduction in its amplitude and . Blood donation reduced exercise tolerance, and supine exercise was performed at the same relative intensity, so no difference was seen in time to exhaustion. Each of these interventions reduced CP for blood donation and supine exercise (C: 259 ± 54; vs. BD: 246 ± 42 W; 95% CI: 2, 26W) and (UP: 275 ± 36 vs. SUP: 216 ± 13 W; 95% CI, 40, 78 W), while W was unchanged following each intervention. The experiments conducted in the current programme of research demonstrate that manipulating the kinetics, , or the parameters of the power-duration relationship have predictable effects on exercise tolerance. Hence, these data support the notion that the interaction between the kinetics, the maximal oxygen uptake, and substrate-level phosphorylation determines exercise tolerance and therefore shapes the power-duration relationship.