Abstract
Carbon monoxide (CO) has in the past been considered only in respect of its acute toxic properties. Possible pathological effects of prolonged exposure to low concentrations of the gas (chronic exposure) have more recently been thought to be of importance. The thesis investigates the likely pathological effects of CO in terms of demonstrable physiological effects of chronic exposure. The most widespread source of chronic CO exposure has been identified by a number of workers as cigarette smoking. In the present study smokers had up to 13% carboxyhaemoglobin (COHb), the blood concentration depending among other factors on the number of cigarettes smoked per day and activity levels whilst smoking. Rabbits chronically exposed to between 200 and 400 parts per million (p. p. m) CO were shown to have many haematological features of acclimatisation to hypoxic hypoxia including an increase in red cell count and haemoglobin. After prolonged exposure the haematological changes were seen to reverse. Initial exposure to 200 p. p. m CO produced in rabbits a mean blood concentration of 17% COHb. At 300 p. p. m the initial concentration was 24% and at 400 p. p. m 32%. After 30 days continuous exposure the COHb concentration fell to about 50% of these initial concentrations. Further experiments demonstrated that a rise in blood oxygen saturation and PO2 accompanies prolonged exposure and may explain this phenomenon. Another aspect of acclimatisation was demonstrated as a lowered rate of uptake of the gas after an animal had been chronically exposed. Experiments showed that this can be partly simulated by acclimatisation to hypoxic hypoxia or by red cell transfusion. However CO exposure lowered the uptake rate over and above that which can be explained solely as a result of an increase in red cell numbers. Most workers consider that the fundamental physiological property of 60 is to cause tissue hypoxia. The suspected mechanisms by which CO can bring this about were identified in the present study as including a reduction in the quantity of functional haemoglobin, a shift to the left of the oxyhaemoglobin dissociation curve and a fall in arterial partial pressure of oxygon (PO2) and oxygen saturation. Acclimatisation was seen to reverse some of these hypoxic stresses but the shifted dissociation curve remained even after prolonged exposure. In the non-anaesthetised rabbit, a small but significant rise in blood glucose was observed within the first three hours of exposure to 200 p. p. m CO, however this had returned to normal after 48 hours continuous exposure. A similar glycogenic effect of CO was observed in anaesthetised rabbits and this could also be reproduced by exposure to a low inspired PO2. This glycogenic effect was not inhibited by a dose of Hydergine (a catecholemine inhibitor)sufficient to reduce by 50% the hyperglycaemic effect of a large dose of adrenaline. Many recent suggestions have been made that chronic CO exposure resulting from cigarette smoking may be responsible for some of the known pathological consequences of smoking. The present study includes investigations into some aspects of the implications of CO in the consequences of smoking in pregnancy and in the aetiology of atherosclerosis. The present study illustrates that the human foetus acquires about 1. 8 times the COHb concentration of the mother and it was also demonstrated that the foetal oxyhaemoglobin dislocation curve is shifted to the left in the presence of CO in a similar way to the adult curve. The possible significance of these observations in the retarded intra-uterine growth of the foetus, known to result from cigarette smoking, is discussed. In a series of experiments with rabbits, CO was seen to enhance the deposition of cholesterol in the arterial wall. Cholesterol feeding and CO exposure for four months resulted in a marked increase in the severity of arterial lesions compared to either cholesterol feeding alone or CO exposure alone. A study of the arterial intima after chronic CO exposure reveated structural alterations characterised by flattening of the normal ridge pattern, and endothelial ulceration. The possible significance of these observations in the known association between cigarette smoking and arterial pathology is discussed.