The Renin–Angiotensin System in Pulmonary Hypertension

To the Editor:

We read with interest the article by de Man and coworkers (1) on the potential beneficial effects of angiotensin type 1 (AT1) receptor inhibition in animal models of pulmonary arterial hypertension (PAH). The article also describes systemic activation of the renin–angiotensin–aldosterone system in patients with idiopathic PAH and demonstrates evidence for increased expression and activation of AT1 receptors in these patients. The authors went on to show that AT1 receptor blockade with losartan improves hemodynamics in the monocrotaline rat model of PAH, and stated that very few studies have previously used AT1 inhibition in these models. In our view, the authors have overlooked a very significant previous body of work in this area. In 1995, we reported that inhibition of angiotensin-converting enzyme (ACE) with captopril, or the AT1 receptor with losartan, reduced the hemodynamic and structural indices of pulmonary hypertension in the chronically hypoxic rat model (2, 3). In addition, we showed that local pulmonary vascular expression of ACE was specifically associated with remodeling of small pulmonary arteries in the chronically hypoxic rat (3) and various forms of human (4) PAH. Moreover, we demonstrated that angiotensin stimulates proliferation of human pulmonary artery smooth muscle cells via the AT1 receptor and activation of extracellular-regulated kinase (5). We also published the first characterization of ACE expression and activity in the setting of right ventricular (RV) hypertrophy (6). ACE activity was increased and correlated with the degree of RV hypertrophy in the chronically hypoxic rat (6). The results of these studies led to the first double-blind placebo-controlled trial of losartan in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (7). Although this trial was underpowered, a post hoc analysis suggested benefit in patients with more severely elevated pulmonary hemodynamics.

We agree with the general conclusions of the article by de Man and colleagues, and believe that their article advances our knowledge of the potential contribution of the renin–angiotensin–aldosterone system in idiopathic PAH. Their work also highlights the potential impact of AT1 receptor blockade on the RV hypertrophic response, which may be deleterious unless pulmonary vascular resistance is also decreased by this approach. We suggest that a full evaluation of angiotensin receptor blockade in various forms of PAH is long overdue based on the findings of the present manuscript and the wealth of data from previous studies.