Pulmonary hypertension (PHT) exists in a rare primary form (which occurs in familial and sporadic forms) called pulmonary arterial hypertension (PAH) and a relatively common form of secondary PHT, as occurs in patients with heart disease, chronic lung disease (COPD), sleep apnea etc. Due to the high incidence of these conditions the number of patients with secondary PHT is large however many of these are undiagnosed and the actual frequency of secondary PHT is therefore unknown. As an indicator however, in individuals older than 50 years of age, cor pulmonale, the consequence of untreated PHT, is the third most common cardiac disorder. Cardiac diseases produce secondary PHT via volume or pressure overload; although vascular remodeling of pulmonary resistance vessels adds an obstructive element. The pulmonary circulation manifests, in varying degrees, excessive vasoconstriction, obstructive vascular remodeling, inflammation and thrombosis in situ. These changes narrow or obliterate the pulmonary artery lumen, which increases right ventricular afterload and ultimately precipitates failure of the afterload-intolerant right heart. Vascular remodelling changes along with pulmonary vasoconstriction are the mechanism of PHT in respiratory diseases. Unrelieved PHT, regardless of the underlying cause, leads to right ventricular failure and can cause death.

Although the pathophysiology of PHT is unclear, K+ channels appear to be involved in this disease. Hypoxia has been shown to selectively inhibit the function and expression of voltage-gated K+ channels (Kv) in pulmonary arterial smooth muscle cells. Acute hypoxia inhibits Kv channel function, inducing membrane depolarization and a rise in cytosolic Ca2+ that triggers vasoconstriction. Chronic hypoxia may inhibit Kv channel activity by directly or indirectly downregulating mRNA and protein expression of Kv channel subunits. In particular the expression of O2- and 4-aminopyridine (4-AP)–sensitive, voltage-gated K channels (Kv1.5 and Kv2.1) is reduced. Hence gene therapy strategies that reintroduce Kv channel activity may be of therapeutic use. Field leaders from the Vascular Biology Group at the University of Alberta in Canada have recently investigated this possibility.

In their recent publication, Drs. Stephen Archer, Evangelos Michelakis and colleagues report the effects of Kv1.5 gene therapy in a chronic hypoxia model of rat PHT. Nebulization of rats with the human Kv1.5 gene (delivered in an adenoviral vector with a GFP reporter) produced an airway selective overexpression of the Kv1.5 channel and reversed changes in cardiac indices of rats subjected to chronic hypoxia back towards normoxic levels; in particular, changes in pulmonary vascular resistance. This study not only demonstrates the feasibility of airway delivery of the Kv1.5 gene but it also establishes a therapeutic proof of concept for this approach. Further advances in this technology that may allow prolonged overexpression of Kv1.5 through gene therapy are eagerly awaited. Alternatively the development of Kv1.5 channel openers may offer an alternative approach to the treatment of PHT and readers may be interested to learn about the "Potassium channel Enterprise library" an assay ready library of candidate potassium channel modulators which may be used to screen for therapeutic candidates targeting multiple potassium channels and indications.

Entry date Monday, May 19, 2003

Adapted from Pozeg et al, Circulation 2003 Apr 22;107(15):2037-44 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk