Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD
Introduction
A reduced exercise capacity is one of the main symptoms in chronic obstructive pulmonary disease (COPD), with important impact on quality of life and a strong relation with mortality [1], [2]. Altered exercise hemodynamics, most markedly an excessive increase in pulmonary artery pressure, have been shown in COPD [3], [4], [5], [6] and may contribute to the exercise limitation. One of the proposed mechanisms responsible for the increase in pulmonary artery pressure is a reduced production of the endothelium relaxing factor nitric oxide (NO), leading to an impaired pulmonary artery dilator response to increased flow [7]. Strategies that enhance NO signalling may therefore attenuate the exercise-induced increase in pulmonary artery pressure, thereby improving stroke volume, cardiac output (CO) and exercise capacity. For this particular purpose, phosphodiesterase 5 inhibitors seem well suited. They stimulate NO-mediated pulmonary vasodilatation by preventing the degradation of NO's second messenger cyclic guanosine monophosphate (cGMP) [8]. cGMP activates transmembrane potassium channels, which indirectly inhibits calcium entry into vascular smooth muscle cells. The result is a decrease in intracellular free calcium, smooth muscle cell relaxation and vasodilatation. Accordingly, the phosphodiesterase 5 inhibitor sildenafil reduces pulmonary artery pressure in different types of pulmonary hypertension [9], [10], [11], [12], [13], [14]. A single dose of sildenafil attenuates the exercise-induced rise in pulmonary artery pressure in hypoxic human volunteers [11], [15] and patients with systolic heart failure [14].
The primary aim of our study was to investigate the acute effects of sildenafil on pulmonary artery pressure, stroke volume and CO at rest and during exercise in COPD patients. Our second aim was to assess whether a possible attenuation of right ventricular afterload by sildenafil translates into an increase in maximal exercise capacity.
Section snippets
Patients
The committee on research involving human subjects of the VU University medical center approved of this study. Written informed consent was obtained from each patient prior to the start of the study. Eighteen stable COPD patients (GOLD II/IV) were included [16]. Patients with a history of systemic hypertension or left-sided heart failure were excluded, as were patients with a history of pulmonary embolism or an acute exacerbation of COPD within the previous year. Prior to the study, pulmonary
Patient characteristics
Eighteen COPD patients were included in this study. Patient characteristics and pulmonary function data are shown in Table 1. The patients had moderate to severe airflow obstruction, increased TLC and a moderate to severe reduction in TLCO. Eleven patients were diagnosed with COPD-associated PH, which is defined as mean pulmonary artery pressure (mPpa)⩾25 mmHg with a wedge pressure below 15 mmHg at rest, or mPpa⩾30 mmHg during exercise [21]. Five out of these 11 patients had pulmonary hypertension
Discussion
This is the first study to evaluate the acute effects of sildenafil on pulmonary artery pressure during exercise in COPD patients. The most relevant finding is that sildenafil attenuates the submaximal exercise-induced increase in mPpa in COPD patients (GOLD stages III and IV) with absent or mild pulmonary hypertension at rest. However, this reduction was not accompanied by an increase in stroke volume or CO (Table 2). Moreover, sildenafil has no effect on maximal exercise capacity (Table 3).
Conclusion
This study showed that sildenafil, given as a single dose, attenuates the increase in mPpa during submaximal exercise in COPD patients with moderate to severe airflow limitation regardless of mPpa at rest. This acute reduction in right heart afterload is neither accompanied by an increase in stroke volume, CO, nor by an improved exercise tolerance. Future research is warranted on the chronic effects of sildenafil on cardiac function and exercise capacity in COPD patients.
Acknowledgments
The authors thank I. van der Mark-Goebielje and F. Oosterveer for their assistance in right heart catheterization.
Conflict of Interest Statement
Dr. AB has served on advisory boards of Actelion (2005 and 2006, $600 per year), Glaxo Smith Kline (2006; $1500) and Pfizer (2005; $800) and received a lecture fees form Encysive (2006; $800). He received an educational grant from GSK of $31,000. The remaining authors have no conflicts to disclose.
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These authors contributed equally to this work.