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Title: The autonomic mechanisms in extrinsic bronchial asthma
Author: Patel, Kantilal Rambhai
ISNI:       0000 0001 3475 7392
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1975
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Although the bronchial hyper-reactivity to specific and non-specific stimuli in asthma has been well recognised for many years, the factors involved in its pathogenesis are still unresolved. The theme of work presented in this thesis is to examine the autonomic mechanisms in patients with extrinsic asthma, and in particular the role of alpha adrenergic activity in the control of bronchoraotor tone both in normal subjects and asthmatic patients. In sixteen patients with extrinsic bronchial asthma alpha stimulation in presence of beta blockade caused a significant bronchoconstriction both in the central and neripheral airways Whereas in ten normal subjects alpha stimulation or beta blockade had no effect on the bronchial calibre. The bronchoconstriction caused by pharmacological stimulation of alpha receptors could be inhibited by pretreatment of these patients with alpha receptor blocking drugs, phenoxybenzamine and thymoxamine. The results of this investigation confirm the presence of alpha receptors in human airways and that the stimulation of these receptors can cause bronchoconstriction in asthmatic patients. Further, it is shown that thymoxamine can effectively inhibit histamine, allergen and exercise induced bronchoconstriction whereas it had no effect in methacholine and Prostaglandin F2 alpha induced bronchoconstriction. It is suggested that inhibitory effect of thymoxamine in histamine, allergen and exercise provoked asthma is mediated by increase in the intracellular levels of cyclic AMP which prevents the effect of some of the pharmacological mediators released in the type I reaction on the bronchial smooth muscle. On the other hand, methacholine and Prostaglandin alpha are now known to catise bronchial smooth muscle contraction through stimulation of cholinergic receptors which are unaffected by alpha receptor blocking drugs. Further, it is shown that thymoxamine and phentolamine when administered with isourenaline cause significantly greater bronchodilation compared to bronchodilation achieved with isourenaline alone. This observation may have, therapeutic significance in the management of patients with chronic labile airways obstruction and especially in those patients in whom beta agonists alone fall to produce significant bronchodilatation. In Part II of this thesis biochemical studies of leucocyte adenyl cyclase and lymphocyte guanyl cyclase activities in normal and asthmatic patients are described. It is now well recognised that the membrane bound enzyme, adenyl cyclase-cyclic AMP system, mediates beta adrenergic responses and that guanyl cyclase-cyclic GMP system is activated by cholinergic and possibly alpha receutor stimulation. The presence of both these enzyme activities on the peripheral leucocytes has paved the way for more fundamental and basic research to study atitonomic mechanisms in asthma. Conflicting results had been reported previously on the leucocyte adenyl cyclase response to isoorenaline in patients with asthma. Logsdon et al. observed diminished leucocyte adenyl cyclase activity in all patients they had examined whereas Grillespie et al failed to show any significant difference in the leucocyte adenyl cyclase activity of normals or asthmatic patients. Parker and Smith, in more detailed studies, have reported diminished adenyl cyclase activity in patients with acute asthma whereas in patients in remission the activity of this enzyme was normal. In none of these studies was there any objective assessment of degree of airways obstruction or detailed account of the clinical state of the patients. In this carefully conducted investigation it is shown that the basal leucocyte adenyl cyclase activity is increased in patients with acute asthma and the response of this enzyme system to isoprenaline is inversely related to the basal levels. These observations indicate that adenyl cyclase activity in acute asthma is maximally stimulated by endogenous factors and further stimulation becomes increasingly difficult.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available