Sildenafil is a drug that treats cardiovascular disease and male erectile dysfunction. Its structure is:

Sildenafil, the first US FDA-approved, oral phosphodiesterase type-5 inhibitor, has revolutionized the treatment of erectile dysfunction sine its approval in 1998. Since sildenafil is a potent inhibitor of cyclic guanosine monophosphate in the corpus cavernosum and therefore increases the penile response to sexual stimulation. Goldstein I et al[1]. evaluated the efficacy and safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, or mixed causes. Research indicates oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction. Little W N et al [2] also conducted a similar study.

Mechanism of action of sildenafil: The pelvic parasympathetic nerves control the relaxation of corporal smooth muscle through nonadrenergic, noncholinergic neurons. Sexual arousal stimulates these efferents, causing the release of nitric oxide from smooth muscle cells in the corpus cavernosum. Nitric oxide activates guanylate cyclase, causing an increase in levels of cGMP, which results in smooth muscle relaxation and inflow of blood. Through inhibition of PED-5, sildenafil blocks the hydrolysis of cGMP, thereby increasing cGMP locally and potentiating the effects on the cavernosal smooth muscle.

The most common adverse effects reflect the pharmacologic nature of sildenafil as a phosphodiesterase-type-5 inhibitor (headache, flushing, and dyspepsia) and as a weak phosphodiesterase-type-6 inhibitor (visual effects). Sildenafil has modest vasodilator properties but no effect on heart rate.

The association of endothelial dysfunction with vascular inflammation, platelet activation and atherosclerosis has led  researchers to evaluate the role of sildenafil in enhancing cGMP-mediated vasodilation. Multiple studies have demonstrated the favorable effect of acute and chronic sildenafil on flow-mediated vascular dilatation in smoking, diabetes[3], congestive heart failure[4], myocardial ischemia[5], ischemia-reperfusion injury and other diseases.

Cardiovascular diseases such as pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. Tantini B et al [6] evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. Studies by Nazzareno Galiè et al.[7] show that Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. Ghofrani H A et al[8] have compared acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

References

[1] Goldstein I , Lue T F , Padma-Nathan H , et al. Oral Sildenafil in the Treatment of Erectile Dysfunction[J]. New England Journal of Medicine, 1998, 338(20):1397-1404.
[2] Little W N , Park G T , Patton H M . Sildenafil in the treatment of erectile dysfunction[J]. New England Journal of Medicine, 1998, 339(10):700; author reply 701-2.
[3] Desouza C , Parulkar A , Lumpkin D , et al. Acute and Prolonged Effects of Sildenafil on Brachial Artery Flow-Mediated Dilatation in Type 2 Diabetes[J]. Diabetes Care, 2002, 25(8):1336-1339.
[4] https://pubchem.ncbi.nlm.nih.gov/compound/135398744
[5] Katz S D , Balidemaj K , Homma S , et al. Acute Type 5 Phosphodiesterase Inhibition With Sildenafil Enhances Flow-Mediated Vasodilation in Patients With Chronic Heart Failure[J]. Journal of the American College of Cardiology, 2000, 36(3):845-851.
[6] Halcox J P J , Nour K R A , Zalos G , et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia[J]. Journal of the American College of Cardiology, 2002, 40(7):1232-1240.
[7] https://pubs.acs.org/doi/10.1021/mp300479r