Sildenafil Attenuate Pulmonary Vascular Remodeling And Increase Kv1.5 MRNA Expression In Pulmonary Hypertension Secondary To High Pulmonary Blood Flow In Rats

Objectives To investigate the effects of sildenafil on pulmonary vascular remodeling in pulmonary hypertension secondary to high pulmonary blood flow with left-to-right shunt in rats and to elucidate the mechanism of sildenafil on pulmonary vascular Kv1.5 mRNA expression as well.Methods Male twenty-seven SD rats were randomly divided into control group(n=9),shunt group(n=9)and shunt+sildenafil group(n=9).A left-to -right shunt was performed by an abdominal aorta to inferior vena cava fistula both in shunt group and shunt+sildenafil group.Rats in shunt+sildenafil group received oral sildenafil 10 mg·kg^-1·d^-1,whereas the rats in the control group and the shunt group were fed with a same volume of normal saline.Eleven weeks later,mean pulmonary artery pressure(mPAP)was measured by using a right cardiac catheterization procedure.The ratio of right ventricular mass to left ventricular plus septal mass[RV/(LV+S)]was detected and calculated.The pathological changes in pulmonary vasculature were observed.The Kv1.5 mRNA expression of pulmonary vasculature was detected using real-time PCR.Results 1.Compared with the control group,the rats in shunt group had asignificantly increasedmPAP(21.7±0.4 vs.14.6±0.2,P＜0.01),and the mass ratio of RV/(LV+S)were significantly increased as well(0.33±0.01 vs.0.270±0.008,P＜0.01).Meanwhile relative medial thickness (RMT)of middle and small pulmonary muscularized arteries were significantly increased in shunt group(27.12±0.97 vs.13.29±0.29,P＜0.01).2.Compared with the shunt group,the rats in shunt+sildenafil group had a significantly decreased mPAP(15.6±0.3 vs.21.7±0.4,P＜0.01),a lower mass ratio of RV/(LV+S)(0.28±0.01 vs.0.33±0.01, P＜0.01),and a lower RMT(13.53±0.38 vs.27.12±0.97,P＜0.01).3. Between the control group and the shunt+sildenafil group,there were no statistically significant difference in mPAP(15.6±0.3 vs.14.6±0.2, P＞0.05),the ratio of RV/(LV+S)(0.28±0.01 vs.0.27±0.01,P＞0.05), and the relative medial thickness(RMT)of middle and small pulmonary muscularizedarteries(13.53±0.38 vs.13.29±0.29,P＞0.05).4.Compared with the control group,the rats in the shunt group had an decreased Kv1.5 mRNA expression in pulmonary vasculature(9.83±0.49 vs.3.02±0.31,P＜0.01).Compared with the shunt group,the levels of Kv1.5 mRNA expression were significantly up-regulated in shunt+sildenafil group(3.04±0.31 vs.9.83±0.49,P＜0.01).There was no statistically significant difference of the levels of Kv1.5 mRNA expression between the control group and the shunt+sildenafil group(3.02±0.31 vs.3.04±0.31,P＞0.05).Conclusions1.Shunts from aorta-inferior vene cava fistula in rats caused increased pulmonary blood flow and led to pulmonary hypertension and pulmonary vascular remodeling.2.Sidenafil,a phosphodiesterase type 5 inhibitor,can attenuate pulmonary hypertension and pulmonary vascular remodeling in rats with pulmonary hypertension secondary to high pulmonary blood flow.3.The rats with pulmonary hypertension secondary to high pulmonary blood flow had an decreased Kv1.5 mRNA expression in pulmonary vasculature, whereas the levels of Kv1.5 mRNA were significantly up-regulated after treatment with oral sildenafil.