Pulmonary artery hypertension is usually a secondary event caused by cardiac disorders, pulmonary disorders such as COPD or both in combination. Although extremely common, the incidence of pulmonary hypertension has not been accurately determined due in part to the fact that many patients are undiagnosed. 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. Cardiac diseases produce pulmonary hypertension via volume or pressure overload; although subsequent intimal proliferation of pulmonary resistance vessels adds an obstructive element. Perivascular parenchymal changes along with pulmonary vasoconstriction are the mechanism of pulmonary hypertension in respiratory diseases. Symptoms of pulmonary hypertension include shortness of breath with minimal exertion, fatigue, chest pain, dizzy spells and fainting. In patients with secondary pulmonary hypertension, management is directed at early recognition and treatment of the underlying disease. Few options are available for the treatment of pulmonary hypertension per se. Epoprostenol (Flolan), or prostacyclin have been investigated as possible treatments as have inhibitors of platelet aggregation. Inhaled nitric oxide (NO) has also been established as a selective pulmonary vasodilator although problems associated with long-term use of NO inhalation, including its potential toxicity and difficulty in ambulatory inhalation limit its use in the treatment of pulmonary hypertension. Thus other strategies for increasing NO levels or the activity of its signal transduction pathway have been investigated. NO increases cGMP thereby mediating vasodilatation, an effect terminated by the catalytic degradation by PDE5. This enzyme as well as PDE3 which degrades cAMP, a second relaxatory molecule, are expressed in the human pulmonary vasulature artery. The activities of both PDE isoforms are increased in models of pulmonary hypertension. This finding along with observations that arterial preparations taken from hypoxic animals respond to PDE5 inhibition (zaprinast) as well as PDE3 inhibition (milrinone and SCA40) with a relaxation supports the targeting of these enzymes in human disease. Moreover a recent clinical study has shown that the PDE5 inhibitor sildenafil was able to decrease mean pulmonary arterial pressure in patients with pulmonary hypertension alone and, furthermore it also increased the efficacy of iloprost. Most recently, Scottish researchers have investigated the mechanism by which PDE3 and PDE5 activity is increased following chronic hypoxia. PDE3A was found to be over-expressed through a protein kinase A-dependent mechanism. PDE5, probably the PDE5A2 splice variant was also over-expressed through a mechanism likely involving NF-kappaB. These data further implicate PDE3 and PDE5 in the pathophysiology of pulmonary hypertension, delineate new strategies for targeting these enzymes and support the use of such strategies as therapeutic approaches.

Entry date January 2003

Adapted from Murray et al, Br J Pharmacol 2002 Dec;137(8):1187-94 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? CContact peter.barfoot@bioportfolio.com