© 2004 American Thoracic Society
Sildenafil for Pulmonary Arterial HypertensionStill Waiting for EvidenceCentre des Maladies Vasculaires Pulmonaires Service de Pneumologie et Réanimation Respiratoire Hôpital Antoine-Béclère Université Paris-Sud, Assistance Publique-Hôpitaux de Paris Clamart, France Considerable evidence supports a key role for endothelial dysfunction leading to exaggerated vasoconstriction and impaired vasodilatation in pulmonary arterial hypertension (1–3). Chronically impaired production of vasodilators, such as nitric oxide and prostacyclin, along with prolonged overexpression of vasoconstrictors, such as endothelin-1, not only affect vascular tone, but also promote vascular remodeling and therefore represent a logical pharmacological target (3). One therapeutic strategy is aimed at increasing nitric oxide–dependent, cyclic guanosine monophosphate–mediated pulmonary vasodilatation through inhibition of the breakdown of cyclic guanosine monophosphate by phosphodiesterase type 5 (3–6). Novel experimental data published in the current issue of the Journal (pp. 39–45) demonstrate that sildenafil (Viagra), a phosphodiesterase type 5 inhibitor, may indeed improve pulmonary hemodynamics and survival in rats displaying severe monocrotaline-induced pulmonary hypertension (7). As stated by the authors, however, there is no ideal animal model of pulmonary arterial hypertension, and human studies are mandatory to analyze efficacy and safety of long-term sildenafil in pulmonary arterial hypertension (3, 4, 7). In their protocol, Schermuly and coworkers have used the monocrotaline model of pulmonary hypertension (7). Rats exposed to the pyrrolizidine alkaloid, monocrotaline, develop an acute pulmonary vascular inflammatory reaction with subsequent remodeling, leading to fatal pulmonary hypertension within weeks (7, 8). This is a reproducible and well established model of the disease, which may be of value for investigating some aspects of this condition (8). For instance, pulmonary vascular inflammation seems to play a key role in subjects developing pulmonary arterial hypertension in the context of toxic oil syndrome, autoimmune diseases, or infectious conditions (9). Pulmonary vascular inflammation may also play a key role in a subset of patients with primary (or idiopathic) pulmonary hypertension (9). Nevertheless, the history of the monocrotaline model of pulmonary hypertension also demonstrates the drawbacks of these animal studies. Drugs known to be definite inciters of pulmonary arterial hypertension in humans, such as fenfluramine derivatives, may, paradoxically, have a positive effect in this animal model (10). Moreover, drugs without value for most patients with established disease, such as methylprednisolone, can be effective in monocrotaline-exposed rats (11). Last, drugs effective in a small minority of patients with severe pulmonary arterial hypertension, such as calcium channel antagonists, are effective in most monocrotaline-exposed animals. These findings emphasize that the human disease may be quite distinct from the pulmonary vascular condition occurring in rats acutely exposed to this toxin (12). Accordingly, our interpretation of the data by Schermuly and colleagues is that the response is interesting, but we still have a long way to go before finding out the real value of sildenafil in humans with this devastating condition (3, 7). An interesting point of the present study is the timing of the therapeutic intervention because development of pulmonary hypertension had already commenced when sildenafil was given to the animals (7). This effect is more relevant than preventive treatment before monocrotaline exposure. The experimental design enabled Schermuly and colleagues to show that long-term sildenafil treatment in rats with established monocrotaline-induced pulmonary hypertension reduces muscularization of distal pulmonary arteries, indicating possible antiproliferative effects of this agent (7). The effect was further supported by the downregulation of matrix matalloproteinases-2 and -9 in the lungs of sildenafil-treated animals (7). Although statiscally significant, the effects of sildenafil on the survival rates of monocrotaline-exposed rats was far from striking as compared with the results obtained with a serine elastase inhibitor that allowed complete reversal of otherwise fatal pulmonary hypertension (7, 13). Confirming that phosphodiesterase inhibitors also possess antiremodeling potency, however, is of major importance. It is now widely accepted that vasoconstriction is not the predominant pathophysiological characteristic (3) in the vast majority of patients with pulmonary arterial hypertension. Indeed, most patients have little or no acute or chronic response to pure vasodilators, such as calcium channel blockers, presumably because the pulmonary arteriopathy includes fibrotic and proliferative changes that predominate over vasoconstriction (3). The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension (14). The difficulty with sildenafil therapy today is the lack of evidence-based information in pulmonary arterial hypertension despite a number of experimental reports (7), case reports (5), small series (6, 15), editorials (4), and breaking news (16) (more than 65 articles in Medline as of September 2003). We still await the results of the first 3-month international multicenter, randomized, double-blind, placebo-controlled study on sildenafil in pulmonary arterial hypertension (expected results, March 2004). We do not yet know if 3 months of sildenafil is effective, and we have no information on long-term effects, survival, and safety. Lastly, specific issues, such as tolerance (requiring dose increase with long-term exposure) and rebound effects after withdrawal of the drug remain also to be properly evaluated. Despite these words of caution, oral phosphodiesterase type 5 inhibitors are conceptually attractive for the treatment of pulmonary arterial hypertension, and this novel strategy provides tremendous hope for patients suffering from this devastating orphan disease (3, 4). FOOTNOTES Conflict of Interest Statement: M.H. has relationships with Actelion, Aventis, Astrazeneca, GlaxoSmithKline, Myogen, Pfizer, Schering, and United Therapeutics. He is an investigator on trials involving these companies, and also serves as a consultant and a member of scientific advisory boards. G.S. has relationships with drug companies including Actelion, Aventis, Encysive, GlaxoSmithKline, Myogen, Sanofi-Synthélabo, Schering, Pfizer, and United Therapeutics. He is an investigator on trials involving these companies, and also is a consultant and a member of scientific advisory boards. REFERENCES
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