Cardiac Uses of Phosphodiesterase-5 Inhibitors

Abstract

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.

Signaling effectors underlying pathologic growth and remodeling of the heart

“…Indeed, mice subjected to pressure overload stimulation show almost no cardiac hypertrophy when treated with sildenafil before (81,82) and even after signs of heart failure have developed (83). Sildenafil has been evaluated in numerous human clinical trials of heart disease, including congestive heart failure, diabetic cardiomyopathy, and pulmonary hypertension, most of which showed improved endpoints and outcomes (84,85). The molecular mechanism whereby sildenafil achieves this beneficial cardiovascular profile remains controversial, as it appears that PDE5 is not basally expressed in adult cardiomyocytes (86), and sildenafil may have some effect on PDE1 (80) and PDE3 (87) that could produce a mild increase in cAMP and an increase in inotropy (Figure 2).…”

An in vitro and in vivo comparative study of directly compressed solid dispersions and freeze dried sildenafil citrate sublingual tablets for management of pulmonary arterial hypertension

“…This improves symptoms of right-sided heart failure by reducing the workload of the right ventricle of the heart. Since PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, SILD acts selectively in both of these areas without inducing vasodilation in other areas of the body,which is considered to be an advantage of SILD (2)(3). SILD decreases myocardial apoptosis, fibrosis, and hypertrophy by activating protein kinase G, inhibiting Rho kinase, and increasing Blc-2 (4-5).…”

Pharmacologic Therapy That Simulates Conditioning for Cardiac Ischemic/Reperfusion Injury

“…101 There is also evidence for its beneficial effect in congestive cardiac failure, high-altitude pulmonary edema, and high-altitude pulmonary hypertension. 102 With regard to the conditioning effects of sildenafil, there are several animal studies showing a beneficial effect on infarct size. However, there are no clinical trials in humans to date examining the role of PDE-5 inhibitors in the context of ischemia/reperfusion.…”