Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension

Abstract

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical diabetogenesis

“…There is substantial evidence that long-term treatment with other PDE5 inhibitors has a positive effect on antioxidant capacity, relief of symptoms, and restoration of erectile function in human and animal studies. For instance, sildenafil reduces malondialdehyde levels and potentiates the total antioxidant capacity of plasma in STZ-induced diabetic rats [29], induces symptomatic improvement in pulmonary hypertension [30] and prevents myocyte hypertrophy [31]. Moreover, erectile function, protein expression of phosphorylated eNOS and NOS enzymatic activity are improved in normal rats by sildenafil treatment [32][33][34].…”

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

“…In a recently published study by Preston et al, 81 10 HF patients in NYHA classes III-IV were followed after an average course of 1271.6 months of sildenafil therapy. Six of the 10 patients reported improvement in NYHA functional score by at least one class and nine patients reported improvement in exertional dyspnea.…”

Inhaled NO and Sildenafil Combination in Cardiac Surgery Patients With Out-of-Proportion Pulmonary Hypertension

“…Preston et al 26 showed that in patients with acute and chronic PH, the addition of iNO potentates the pulmonary vasodilator effects of sildenafil lowering PVR more than each agent alone. 26 In patients who are candidates for heart/lung transplantation, the pulmonary vasodilator effects of oral sildenafil were found to be as effective as iNO, but it was more effective when the 2 were combined.…”

“…Preston et al 26 showed that in patients with acute and chronic PH, the addition of iNO potentates the pulmonary vasodilator effects of sildenafil lowering PVR more than each agent alone. 26 In patients who are candidates for heart/lung transplantation, the pulmonary vasodilator effects of oral sildenafil were found to be as effective as iNO, but it was more effective when the 2 were combined. 27 These additive effects induced by the combination of the 2 drugs may indicate a synergistic effect, providing pulmonary vascular smooth muscle relaxation due to mechanisms mediated by cGMP.…”