Combined effects of the ATP-sensitive potassium channel opener pinacidil and simvastatin on pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension.

The drugs that are currently used to treat pulmonary hypertension (PH) lack the ability to inhibit or reverse the pulmonary vascular remodeling that occurs during the course of the disease. We propose a novel method that combines the therapeutic powers of the potassium channel opener pinacidil and the statin drug simvastatin. These two drugs do not share similar mechanisms of treating PH. We used rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) as a model and examined the combined effects of pinacidil and simvastatin on pulmonary vascular remodeling. A series of indicators, including those for pulmonary vascular obstruction, proliferation, and cell phenotype, pulmonary vascular matrix and pulmonary vascular smooth muscle cell phenotype were used to monitor changes in pulmonary structure over the course of disease and treatment in normal controls, untreated PAH rats, pinacidil-treated subjects, simvastatin-treated subjects, and combination-treated subjects. We found that levels of mPAP, right ventricle Fulton index, pulmonary arteriolar wall thickness and muscularization, cell growth rate, transforming growth factor beta (TGF-beta), lung tissue matrix metalloproteinase-2 (MMP-2), MMP-9 and lung tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), vascular smooth muscle cell (VSMC) contractile protein SM-alpha-actin, and SM-alpha-actin mRNA of these different groups were all significantly lower in the combination-treated group than in the untreated group. Subjects in the combination-treated group also showed lower levels than those in either the pinacidil-treated or simvastatin-treated group. These results support our hypothesis and provide basis for a new, more effective therapeutic methods of treating PAH in human patients.