Viagra for Impotence of Pulmonary Vasodilator Therapy?

Robert F. Lodato

University of Texas Science Health Center, Houston, Texas

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To date, the efficacy of pulmonary vasodilator therapy has been limited. The limitation is due in part to the lack of potency of pulmonary vasodilator agents in many patients and in part to the lack of selectivity of these agents for the pulmonary circulation. Nearly all pulmonary vasodilators are also systemic vasodilators. The most important exception is oxygen, which selectively dilates the pulmonary vasculature while constricting the systemic vasculature.

Despite the limitations of pulmonary vasodilator therapy, it has seen significant advances in recent years. One of the most important developments has been the explosion of information on the biology of nitric oxide (NO). NO is a potent, short-acting vasodilator. It is a gas and readily diffusible across cell membranes. Within vascular smooth-muscle cells, NO activates soluble guanylate cyclase, which generates cyclic guanosine 3',5'-monophosphate (cGMP), which in turn relaxes smooth muscle. cGMP is degraded by phosphodiesterase (PDE) enzymes. The concentration of cGMP, and thus the level of smooth-muscle tone, is the result of a balance between the rate of cGMP production by guanylate cyclase and its rate of degradation by PDEs.

Mammalian PDEs are a superfamily of enzymes consisting of at least 11 families of PDEs, PDE-1 through PDE-11, that differ in their amino acid sequences, substrate specificities, inhibitor sensitivities, modes of regulation, and tissue distribution. They inactivate cGMP and/or cyclic adenosine 3',5'-monophosphate (cAMP).

Because cGMP and cAMP mediate the regulation of a great variety of physiologic processes, PDEs have emerged as important targets for drug development. Several PDE families have received attention for their influence in the cardiovascular and respiratory systems. PDE-3 inactivates cAMP and is inhibited by milrinone, amrinone, and theophylline (nonspecifically). PDE-3 is also inhibited by cGMP, providing the possibility of crosstalk between the cAMP and cGMP pathways. PDE-3 inhibitors increase the level of cAMP, thereby increasing cardiac contractility and vascular and airway relaxation. PDE-5 inactivates cGMP specifically and is inhibited by the experimental agents zaprinast, E4021, and DMPPO, and by the clinically available agents, dipyridamole (nonspecifically) and sildenafil (Viagra). Sildenafil, a potent and selective inhibitor of PDE-5, is best known for its use as a treatment for male erectile dysfunction. In addition to its high concentration in the corpora cavernosa, PDE-5 is abundant in vascular, tracheal, and visceral smooth muscle and in platelets (1).

A number of recent studies have explored the therapeutic potential of PDE-5 inhibitors in pulmonary hypertension. In 1993, Braner and colleagues (2) showed in lambs that zaprinast dilated the pulmonary vasculature selectively (without a decrease in systemic arterial pressure) and augmented acetylcholine-induced, NO-mediated pulmonary vasodilation. In other animal models, zaprinast has been shown to increase the duration (3, 4) or the magnitude (4, 5) of NO-dependent pulmonary vasodilation. Results similar to those for zaprinast have been reported in animal models with the PDE-5 inhibitors E4021, DMPPO, dipyridamole, and sildenafil.

The clinically approved PDE-5 inhibitors dipyridamole and sildenafil have been studied in patients with pulmonary hypertension. Patients who failed to respond to inhaled NO responded to the combination of inhaled NO plus dipyridamole (6). In some patients the combination of dipyridamole plus inhaled NO was a more effective pulmonary vasodilator than either agent alone (7). In one patient, sildenafil was as effective as inhaled NO, but the combination of the two was more effective than either agent alone (8). Both dipyridamole and sildenafil can attenuate the rebound pulmonary hypertension associated with withdrawal of inhaled NO (9, 10). Long-term (3 mo) treatment with oral sildenafil alone improved exercise capacity and quality of life in a patient with severe pulmonary hypertension (11).

The work done to date with PDE-5 inhibitors in pulmonary hypertension documents their exciting potential for improving hemodynamics. Their effects on gas exchange, however, have been less well studied. In this issue of the Journal (pp. 339- 343), Kleinsasser and colleagues (12) report their study of the hemodynamics and gas-exchange effects of sildenafil in pigs. They found that sildenafil decreased pulmonary artery pressure and increased cardiac output (CO), but that it also increased pulmonary shunt, resulting in a decrease in arterial oxygen tension. Similar findings were reported for zaprinast in an experimental model of ARDS (13). Kleinsasser and colleagues did not investigate the mechanism of the increase in CO with sildenafil, but it is likely to have been related in part to systemic arterial vasodilation. However, as they speculate, it may be related to an indirect positive inotropic effect of sildenafil on the heart. That is, if sildenafil increased cGMP in the heart, then cGMP could inhibit PDE-3 (1), thereby increasing cAMP and thus cardiac contractility. In addition, as Kleinsasser and colleagues state, it is not clear whether the increased shunt is a direct result of the pulmonary vasodilation or in part related to the increase in CO. Extrapolating Kleinsasser and colleagues' results to humans is not straightforward. The baseline shunt in their study was high (5%), and the systemic hemodynamic effects of sildenafil in healthy humansin the absence of nitrate therapyare minor (1).

The rapid growth of information about PDE biology and PDE inhibitors is already broadening our view of potential novel therapeutic approaches to cardiovascular and pulmonary diseases. Many areas remain to be explored: newer and more potent, selective, and tissue-specific PDEs; the effects of PDE-5 inhibitors on gas exchange in healthy humans and patients, the role of PDE-5 in pulmonary hypertension and the role of PDE-5 inhibitors in the treatment of pulmonary hypertension, especially that which is refractory to established vasodilator therapy; the potential cardiac inotropic effect of PDE-5 inhibitors; and the potential synergy of combining PDE-5 inhibitors with NO; the potential synergy (14, 15) of combining PDE-5 inhibitors with PDE-3 (or other) inhibitors; and the potential limitations of PDE-5 inhibitor therapy in critically ill patients (e.g., those with sepsis, in whom endogenous NO production is increased). Meanwhile, new potent cGMP-specific PDE-5 inhibitors are indeed providing novel approaches to overcoming the limited potency of current pulmonary vasodilator therapy.

Acknowledgments: Supported by grants from the Department of Veterans Affairs (Merit Review), the National Institute of Environmental Health Sciences (ES07498 and ES09607), and the National Heart, Lung, and Blood Institute (HL62628 and HL64855).

Supported by the National Institutes of Health (RO1-HL64937, RO1-HL 58115, and P6-HL58418; to B.A.F.), the American Heart Association (J.P.E.), and the Deutsche Herzstiftung (S.B).

	References

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