Targeting PDE5 for the treatment of pulmonary hypertension

Secondary pulmonary hypertension is a common consequence of cardiac disorders, pulmonary disorders (COPD), or both in combination. Both of these groups of conditions are extremely common and the number of patients with secondary pulmonary hypertension is large however many of these are undiagnosed and the actual frequency of secondary pulmonary hypertension is therefore unknown. As an indicator however, in individuals older than 50 years of age, cor pulmonale, the consequence of untreated pulmonary hypertension, is the third most common cardiac disorder.

Unrelieved pulmonary hypertension, regardless of the underlying cause, leads to right ventricular failure. Cardiac diseases produce pulmonary hypertension via volume or pressure overload although subsequent intimal proliferation of pulmonary resistance vessels adds an obstructive element.

In patients with secondary pulmonary hypertension, management is directed at early recognition and treatment of the underlying disease (while it is still potentially reversible). Few options are however available for the treatment of pulmonary hypertension per se. NO has been implicated in the cause and treatment of pulmonary hypertension and since PDE5 is expressed in the human pulmonary artery this condition is emerging as a possible new indication for PDE5 inhibitors (see "Phosphodiesterase 4 (PDE4) & Phosphodiesterase 5 (PDE5): Pharmaceutical advances and new therapeutic targets" click here for access). Early clinical studies demonstrated that sildenafil was able to decrease mean pulmonary arterial pressure in patients with primary pulmonary hypertension alone and, furthermore it also increased the efficacy of iloprost, one of the few treatments in use.

More recently DongA researchers have evaluated the efficacy of a second PDE5 inhibitor, DA-8159 in a monocrotaline model of rat pulmonary hypertension. Control animals demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and plasma cGMP levels, along with decreased body weight gains. However, oral DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the untreated disease group. Morphologically, DA-8159 prevented the myocardial fibrosis characteristic of this model. These results further confirm the utility of PDE5 inhibitors as an oral treatment option for pulmonary hypertension and suggest that clinical trial of DA-8159 may be warranted in addition to studies in patients with erectile dysfunction which are currently underway.

Entry date Monday, November 10, 2003

Adapted from Kang et al, Arch Pharm Res. 2003 Aug;26(8):612-9.