Abstract
Background: We hypothesized that inhibition of Rho-kinase by fasudil, together with tyrosine kinase platelet-derived growth factor (PDGF) receptor inhibition by imatinib, results in greater pulmonary arterial hypertension (PAH) improvement. Methods: The effects of such regimens were investigated on hemodynamics, right ventricle hypertrophy, PDGF and ROCK in experimental monocrotaline (MCT)-induced pulmonary hypertension. Fourteen days after MCT injection, male rats were treated orally for another 14 days with imatinib, fasudil or their combination. Results: Concurrent imatinib and fasudil administration reversed an MCT-induced increase in right ventricular pressure more than either drug alone and decreased right ventricle hypertrophy (right ventricle weight to left ventricle plus septum weight ratio) significantly. The simultaneous administration of fasudil and imatinib caused a further decrease in plasma PDGF-BB levels compared to either drug alone. Conclusions: Inhibition of Rho-kinase by fasudil in addition to tyrosine kinase PDGF inhibition by imatinib can result in further PAH improvement. Such outcome may result from additional impact of the Rho-kinase inhibitor on the decrease in PDGF-induced effects.
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