The Effect of Hypoxia on Airway Smooth Muscle Function

Clayton, Robert Alan (1998) The Effect of Hypoxia on Airway Smooth Muscle Function. PhD thesis, University of Glasgow.

Abstract

Resistance to airflow in the respiratory tract is largely determined by the degree of tone in the smooth muscle layer surrounding the airways. The tone of the airway smooth muscle in vivo is regulated by neural control mechanisms, locally released mediators as well as humoral factors. Environmental factors, such as hypoxia, may also influence the tone of the airway smooth muscle and in addition, alter its responsiveness to various pharmacological agonists. Since hypoxia can be a feature of respiratory disorders, such as asthma and chronic obstructive pulmonary disease, it may be of importance to determine if airway smooth muscle function is altered under hypoxic conditions. Using various techniques, I assessed: (i) The effect of acute changes in oxygen tension on responses to contractile agents and relaxatory agents in bovine isolated bronchi. (ii) The effect of chronic hypoxia on contractile responses in rat isolated airways. (iii) The effect of chronic hypoxia on endothelin receptor-mediated responses in rat isolated airways. (iv) The effect of hypoxia on the proliferation of cultured human airway smooth muscle cells. (v) The effect of changes in inspired oxygen tension on salbutamol-mediated bronchodilation and methacholine- and histamine-mediated bronchoconstriction in asthmatic patients in vivo. In rings of bovine bronchi (3rd-5th order, 3-5mm internal diameter), isometric contractions were significantly potentiated when the oxygen tension in the Krebs- Henseleit solution was lowered from 524mm Hg (hyperoxia) to either 147 mm Hg (normoxia) or 26mm Hg (hypoxia). The ability of the dilator agents salbutamol, atrial natriuretic peptide (ANP), sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) to reverse methacholine-induced tone was also altered by changing the oxygen tension, although the pattern of response differed between the various agents: The ability of salbutamol to reverse the induced tone was attenuated in hypoxia, whereas ANP was more effective in hypoxia than either hyperoxia or normoxia. ISDN and SNP were similar in that they were both more effective in either hypoxia or normoxia than in hyperoxia. In addition, the ability of these four dilators to confer protection against subsequent challenge with methacholine was compared under hyperoxic, normoxic and hypoxic conditions. Salbutamol attenuated responses to methacholine, but only under hyperoxic conditions, in normoxia and hypoxia it was ineffective. In hyperoxia, ANP protected against methacholine challenge, but in hypoxia, ANP actually potentiated the methacholine-induced contractions. The ability of both SNP and ISDN to protect against methacholine challenge was enhanced when the oxygen tension was reduced from hyperoxia to either normoxia or hypoxia. Tracheal rings (internal diameter ~2mm) isolated from rats exposed to 14 days of chronic hypobaric hypoxia (500-550mBar) produced contractions to methacholine, endothelin-1 (ET-1) and potassium chloride which were significantly less than responses in control rats. In both control and hypoxic rats, responses to methacholine and ET-1 were not altered by indomethacin (a cyclooxygenase inhibitor) but were potentiated by either L-NAME (a nitric oxide synthase inhibitor) or by removal of the epithelium. Responses to the nitric oxide donor, SNP, but not the beta adrenoceptor agonist salbutamol were enhanced in chronically hypoxic rats. Taken together, these results indicate that nitric oxide or a nitric oxide-like substance is released from the epithelium of both control and chronically hypoxic rats and that this subsequently attenuates the contractile responses to methacholine and ET-1. In chronically hypoxic rats, however, the airway smooth muscle appears to be more sensitive to nitric oxide than control rats, which may explain why contractile responses are significantly smaller in the chronically hypoxic rats. ET-1 acts via at least two G protein-coupled receptor subtypes, termed ETA and ETB- Contractile responses to ET-1 were attenuated in chronically hypoxic rats, whereas responses to sarafotoxin S6c (an ETB receptor agonist) were not altered. The ETA receptor antagonist, FR 139317 at a concentration of 10-8M potentiated contractile responses to ET-1 in trachea from control but not chronically hypoxic rats. The ETB receptor antagonist, BQ 788, potentiated responses to ET-1 in both control and chronically hypoxic rat trachea. It was found that ET-1 responses were only blocked by simultaneous blockade of both ETA and ETB receptors, either by using the non-selective ET receptor antagonist, SB 209670, or by combining BQ 788 and FR 139317. The proliferative response of cultured human airway smooth muscle cells was examined under different environmental oxygen tensions.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Margaret MacLean
• Keywords: Physiology
• Date of Award: 1998
• Depositing User: Enlighten Team
• Unique ID: glathesis:1998-75940
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 17:14
• Last Modified: 19 Nov 2019 17:14
• URI: https://theses.gla.ac.uk/id/eprint/75940