Effects of sildenafil on pulmonary vascular remodeling in a rat model of pulmonary hypertension

Objective To investigate the effects of sildenafil on pulmonary vascular remodeling in a rat model of pulmonary hypertension and the possible mechanism.Methods Forty SD rats weighing 220-230 g were randomly divided into 4 groups (n=10 each):groupⅠcontrol (C);groupⅡpulmonary hypertension (PH); groupⅢsildenafil 25 mg·kg~(-1)·d~(-1)+PH (S1) and groupⅣsildenafil 50 mg·kg~(-1)·d~(-1)+ PH (S2).Pulmonary hypertension was induced by intraperitoneal injection of monocrotaline 60 mg·kg~(-1)(in normal saline 1 ml) in group PH,S1 and S2 (groupⅡ,ⅢandⅣ).In control group normal saline 1 ml was given IP instead of monocrotaline. Fourteen days after IP monocrotaline sildenafil was given IP every day for 6 weeks.The animals were then tracheostomized,intubated and mechanically ventilated under pentobarbital anesthesia.Left common carotid artery and pulmonary artery (through right ventricle) were cannulated for MAP and MPAP monitoring.The animals were then killed and the hearts and lungs were removed.Right ventricular hypertrophy index (the ratio between the weight of right ventricle and the total weight of left ventricle and septum RV/LV+S) and the ratio between the thickness of the wall and the diameter of the lumen of pulmonary arterioles were calculated.The lung tissues were examined with light microscope.The expression of vascular endothelial growth factor (VEGF) mRNA (by RT-PCR),ERK_1/ERK_2 and MKP1 (by western blot) in the lung were determined.Results Monocrotaline could induce pulmonary hypertension,pulmonary vascular remodeling and upregulate expression of VEGF mRNA, phosphorylated ERK_1/ERK_2 and MKP1.Sildenafil could attenuate the changes induced by monocrotaline as mentioned above except up-regulation of MKP1 expression in the lung.Conclusion Sidenafil,a phosphodiesterase type 5 inhibitor,can attenuate puhuonary vascular remodeling induced by pulmonary hypertension.The down- regulation of expression of VEGF mRNA and phosphorylated ERK_1/ERK_2 is involved in the mechanism.