AMSTERDAM – A new experimental study from the Amsterdam Pulmonary Hypertension Center  suggests that a novel candidate drug for the treatment of pulmonary arterial hypertension (PAH) is superior to two of the most potent anti-PAH drugs currently available. The new therapeutic concept involves inhibition of the enzyme Rho-kinase, which is believed to play a key role in the pathogenesis of the disease.

In an animal model, fasudil, an orally administered substance from a class called Rho-kinase inhibitors, performed better than current treatments for PAH, such as endothelin receptor blockers or phosphodiesterase-5 (PDE5) inhibitors, without any evidence of cardiac side-effects.

However, the study published ahead of print in the European Respiratory Journal has found no benefit from combining the new substance with current therapies.
Rho-kinase is an important regulator of vasoconstrictor tone. A potential new candidate in the treatment of PAH, the potent Rho-kinase inhibitor and vasodilator fasudil, has already been successfully used in over 150,000 Japanese patients suffering from cerebral vasospams, often secondary to a subarachnoid haemorrhage.

Idiopathic PAH is a severe progressive and fatal disease, which is characterised by an increased pulmonary vascular resistance, caused by remodeling of the blood vessels of the lungs. The right side of the heart typically adapts initially by hypertrophy to maintain cardiac output, but will eventually fail. Despite several available treatment options, the disease is still incurable and the prognosis grim, warranting the search for novel medications.

Rho-kinase is upregulated in experimental models of pulmonary hypertension. Various studies have shown that Rho-kinase is actively involved in the pathogenesis of PAH. Activation of Rho-kinase occurs both in endothelial cells and vascular smooth muscle cells, leading to altered cell adhesion properties and hypercontraction. Inhibition of Rho-kinase not only causes vasodilatation of pulmonary arteries, but also reduces structural remodeling by inhibiting proliferation of smooth muscle cells and fibroblasts.

Beneficial effects of Rho-kinase inhibition have been described in different cardiovascular diseases. However, potential adverse effects may also be envisaged. Rho-kinase is essential for the development of the heart. The developmental gene programme is partly reactivated in hypertrophied myocardium, and there is an increasing amount of evidence to suggest that Rho-kinase acts as an important mediator of the hypertrophic response. Inhibition of Rho-kinase might, therefore, harm the adaptive response of the right heart to pressure overload.

In the study, researchers investigated the effects of Rho-kinase inhibition in a rat model of PAH, with special attention to right heart function, and made comparisons with two commonly used therapies in PAH, namely endothelin receptor blockade by bosentan and PDE5 inhibition by sildenafil.
As expected, mean pulmonary arterial pressure and pulmonary vascular resistance significantly increased in the animals after pulmonary hypertension was induced by monocrotaline. The heart rate, stroke volume and right heart contractility deteriorated, with accompanying right heart hypertrophy and dilatation, and marked pulmonary arterial wall thickening.

In the first study to directly compare Rho-kinase inhibition with endothelin receptor blockade and PDE5 inhibition in a model of severe PAH, the animals received oral treatment with either the endothelin antagonist bosentan, the PDE5 inhibitor sildenafil, fasudil or combinations of fasudil with either bosentan or sildenafil for two weeks.
All treatments were successful in preserving heart rate, stroke volume and right heart contractility, and reducing pulmonary vascular resistance and right heart dilatation. Fasudil was superior in lowering the pulmonary arterial blood pressure, and in reducing the extent of pulmonary arterial remodeling and right heart hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect.

“This therapeutic option extends beyond symptomatic vasodilatation as fasudil decreases pulmonary arterial wall remodeling,” the authors conclude.
“The vasodilator effect of fasudil was limited to the pulmonary circulation, and no hypotension occurred as a side-effect,” explains Dr Anton Vonk Noordegraaf, Associate Professor of Pulmonology at the VU University Medical Center in Amsterdam.

Reference:
Mouchaers KT et al. Eur Respir J. 2010 Mar 29. [Epub ahead of print]