Additive effect of Tadalafil and Simvastatin on monocrotaline-induced pulmonary hypertension rats

Abstract

Objectives. Tadalafil, an oral phosphodiesterase type-5 inhibitor, induces pulmonary vasorelaxation by inhibiting the breakdown of cyclic guanosine monophosphate whereas simvastatin, an oral 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has been shown to reverse pulmonary hypertension (PH) and attenuate vascular remodeling in animal models of pulmonary hypertension. We investigated whether the combination of tadalafil and simvastatin, which has different mechanisms of action, is superior to either drug alone in a rat model of monocrotaline-induced PH. Methods. Male Sprague-Dawley rats were randomized to gavage with a vehicle, tadalafil (10 mg/kg/day), simvastatin (2 mg/kg/day), or tadalafi + simvastatin 21 days after the monocrotaline (60 mg/kg) injections. The hemodynamic and histological changes in the pulmonary arterioles, right heart hypertrophy, interleukin 6 (IL-6) levels and perivascular inflammation in the lungs were measured 35 days after monocrotaline exposure. Results. The combination of tadalafil and simvastatin showed significantly more improvement in the mean pulmonary hypertension pressure (mPAP) and right ventricular hypertrophy compared with each monotherapy (p < 0.05). Combination therapy had additive effects on the increases in lung IL-6 levels and the perivascular inflammation score. Conclusions. These results suggest that the combination of tadalafil and simvastatin bears promise as an approach to treat PH, especially PH associated with inflammation.