Augmenting pulmonary rehabilitation in chronic obstructive pulmonary disease: studies of ACE-inhibition and nitrate supplementation

Abstract

This thesis addresses two approaches to enhancing exercise capacity in chronic obstructive pulmonary disease (COPD). The first is by manipulation of the renin-angiotensin system through angiotensin-converting enzyme (ACE) inhibition to establish if this can augment the response to pulmonary rehabilitation. The second is nitrate supplementation, assessed for its effects on endurance exercise parameters.

In a cross-sectional study of 78 patients with at least moderate severity COPD I found no association between ACE genotype and exercise parameters during incremental cycle ergometry, in contrast to previous work from a Chinese group. The role of the renin-angiotensin pathway in skeletal muscle impairment in COPD is likely to be highly complex, and there are both potential beneficial and adverse effects of angiotensin II, and potentially conflicting effects on strength and endurance exercise capacity. The absence of differences in a cross-sectional study do not preclude the possibility that the ACE genotype may influence the response to both training and detraining through physical inactivity, and this remains an area of possible future research.

I went on to test the effect of the ACE-inhibitor enalapril on the response to pulmonary rehabilitation, focussing on the change in peak exercise capacity. I undertook a double-blind randomised controlled trial of 80 COPD patients with at least moderate airflow obstruction referred for pulmonary rehabilitation. There was evidence of adequate suppression of ACE activity through both the suppression of serum ACE levels and alteration in blood pressure parameters in the enalapril treated arm. Contrary to expectations the peak power achieved on incremental cycle ergometry increased more in the placebo arm of the study than the ACE-inhibitor treated arm. No significant differences were noted in computed tomography measures of muscle bulk, quadriceps strength or health-related quality of life. Thus, in subjects without a pre-existing clinical indication for ACE-inhibition, use of the ACE-inhibitor enalapril reduced the response to exercise training in COPD.

I also conducted a pilot study to investigate the role of acute nitrate supplementation on endurance exercise characteristics and oxygen consumption during endurance exercise in COPD. I recruited 25 subjects into a double-blind, placebo-controlled, single-dose cross-over study. Nitrate supplementation, in the form of beetroot juice at a dose of 12.9 mmoles, significantly lowered resting diastolic blood pressure and isotime pulmonary oxygen consumption. This did not translate into an improvement in endurance time. This preliminary work will provide the basis for further studies, including the potential role of nitrate supplementation in enhancing the response to pulmonary rehabilitation and the role of nitrate supplementation on exercise capacity in individuals with exercise induced hypoxaemia.