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ACE in COPD: a therapeutic target?
  1. R Forth1,
  2. H Montgomery2
  1. 1Portex Anaesthesia, Intensive Therapy and Respiratory Unit, Institute of Child Health, London WC1N 1EH, UK
  2. 2Cardiovascular Genetics, Rayne Institute, London WC1E 6JJ, UK
  1. Correspondence to:
    Dr H Montgomery, Cardiovascular Genetics, 3rd Floor, Rayne Institute, 5 University Street, London WC1E 6JJ, UK;

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Chronic lowering of ACE activity may have profound benefits in the long term treatment of patients with chronic lung disease such as COPD.

As a component of the circulating (or endocrine) renin-angiotensin system (RAS), angiotensin converting enzyme (ACE) plays an important role in circulatory homeostasis. ACE cleaves angiotensin I to yield the potent vasopressor octapeptide angiotensin II while simultaneously cleaving vasodilator kinins, and angiotensin II drives renal salt/water retention through release of adrenal aldosterone. In this way, ACE exerts tonic influence on water balance and blood pressure. However, local cellular (autocrine) and organ (paracrine) RAS exist in tissues as diverse as human heart,1 skeletal muscle,2 fat,3 and brain,4 where they play a variety of roles. Whether in the circulation or the tissues,1,5 the presence (insertion, I allele) rather than the absence (deletion, D allele) of a 287 base pair fragment in the human ACE gene is associated with increased ACE activity.

Increasing RAS activity certainly exerts powerful proinflammatory effects in many systems,6–10 while angiotensin II has direct profibrotic actions.11 Local RAS has additional roles in the direct regulation of tissue metabolism.12 Postoperatively, bradykinin increases forearm glucose uptake and reduces both endogenous hepatic glucose production13 and protein catabolism.14 Angiotensin II has glycogenolytic actions15 and shifts lactate uptake to release.16 Such actions may be complemented by the potential indirect metabolic effects of altered steroid hormone metabolism.17 Increasing RAS activity may also detrimentally impact on endothelial function18,19 and exert vasoconstrictor and prothrombotic actions.20

What, then, of the lung? Given such diverse actions, could pulmonary ACE expression play an important role in the pathogenesis and progression of pulmonary disease, and of COPD in particular? A report in this issue of Thorax would support such a contention.21 ACE genotype was determined in 36 patients with COPD who underwent right heart catheterisation while exercising for 5 minutes at 60% of peak symptom limited bicycle ergometric work rate. Testing was repeated in a randomised double blind crossover trial of the ACE inhibitor captopril in a dose of 25 mg. Analyses are presented by ACE genotype and treatment, and this can be confusing. The authors also recognise that their results are preliminary. However, the data presented seem to confirm earlier related reports from the same group.22,23 Whether the patients in these earlier studies (n=19 and 39, respectively) represent the same patient cohort as those reported here is not clear. Nonetheless, the message seems interesting—lower ACE activity (whether defined by genotype or pharmacotherapy) is associated with lower exertional pulmonary artery pressure, lower pulmonary vascular resistance, higher mixed venous oxygen saturations, and lower blood lactate levels.

Caution must be extended to the interpretation of these data: we do not know precise measures of pulmonary function and true oxygen delivery in these patients, nor do we know that workload/oxygen delivery ratios were indeed the same across genotypes. However, the results would be consistent with known data suggesting benefits to low ACE activity in COPD. Firstly, the extent of lung damage in COPD may be higher among those of DD genotype: acute lung injury responses are certainly genotype dependent in this way.24 Secondly, respiratory drive may be better sustained in those of II genotype: arterial oxygen saturations in the face of acute hypobaric hypoxia are I allele dependent,25 an effect which may be partly due to increased chemoreceptor drive.26 In congestive heart failure, at least, ACE inhibition also increases respiratory muscle strength27 and exercise tolerance,28 while pulmonary vasoconstriction may be (at least in part) ACE dependent.29,30 Thirdly, ACE may also influence erythropoiesis and hence (putatively) red cell mass.31

Exertional minute ventilation may thus be better sustained in the presence of lower ACE activity and oxygen carriage increased. Once delivered, the oxygen may also be more efficiently used: it is known that the mechanical efficiency of lower limb muscle improves with training more in those of II genotype,32,33 with “less oxygen being burned per unit of work”. The ACE I allele is thus associated with fatigue resistance34 and endurance performance in skeletal muscle,35 an effect to which a genotype dependence in muscle fibre type may contribute.36 Whether due to better maintained oxygen delivery (pulmonary function, respiratory drive, and red cell mass) or more efficient oxygen use, II genotype may thus be associated with better performance in hypoxic environments,34 with consequent better long term adaptation to hypoxia.37

Chronic lowering of ACE activity may therefore have profound benefits in the long term treatment of patients with chronic lung disease such as COPD through (1) potential effects on pulmonary inflammation, architecture and vasculature; (2) effects on respiratory drive and respiratory muscle function; (3) effects on the efficiency of peripheral use of oxygen; and (4) improvements in skeletal muscle functional capacity in the face of reduced oxygen delivery. It is sad that such data should be accumulating just at the time when ACE inhibitors are losing their patent protection and commercial funding of appropriate trials will be harder to obtain. It falls to committed clinician-scientists to remain dedicated to the cause and to explore further the potential roles for ACE inhibitors and angiotensin II antagonists in the long term treatment of pulmonary disease.

Chronic lowering of ACE activity may have profound benefits in the long term treatment of patients with chronic lung disease such as COPD.


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