Background-The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. Methods and Results-We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by Ն1 class in all patients. Pretreatment versus posttreatment values (meanϮSEM) were as follows: 6-minute walk, 376Ϯ30 versus 504Ϯ27 m, PϽ0.0001; mean PA pressure, 70Ϯ3 versus 52Ϯ3 mm Hg, PϽ0.007; pulmonary vascular resistance index 1702Ϯ151 versus 996Ϯ92 dyne · s · cm Ϫ5 · m
Ϫ2, PϽ0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. Figure 1. Short-term inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in PAH, 4,5 but ambulatory delivery in humans is cumbersome. Another strategy is to prolong the survival of cGMP in PASMCs by inhibiting type-5 phosphodiesterase (PD-5), an isoform that is primarily located in the penis and lungs, which rapidly degrades cGMP. Because of PD-5's tissue distribution (pulmonaryϾsystemic vasculature), PD-5 inhibitors are attractive candidate pulmonary vasodilators that minimally decrease systemic blood pressure. (75 mg) is an effective and relatively selective pulmonary vasodilator. 4,5 We hypothesized that PD-5 inhibition acutely causes human PA dilatation, in part by opening of BK Ca channels, and that it chronically improves hemodynamics and functional capacity in moderately severe PAH.
Conclusion-This
MethodsWe studied 5 consecutive patients with PAH (nϭ4 New York Heart Association [NYHA] class III; patient 3 class II). All subjects provided informed consent. Patients with class IV PAH were excluded because they often require epoprostenol, which could confound the assessment of sildenafil's effects. All the patients had been stable for Ͼ3 months, and their standard therapy was not altered before initiation of sildenafil. All were on diuretics and coumadin, and patients 2 and 4 were on Ca 2ϩ channel blockers because they had been shown to respond to iNO with Ͼ20% decrease in pulmonary vascular resistance (Figure 2). No patient was taking nitrates. All patients had primary pulmonary hypertension (PPH) except patient 2, w...
