Sildenafil attenuates pulmonary vascular remodeling and upregulates Kv1.5 mRNA expression in pulmonary hypertension secondary to left-to-right shunt in rats

Introduction

Sildenafil is a phosphodiesterase-type-5 inhibitor and selectively decreases pulmonary artery pressure. So far, the mechanism underlying sildenafil's effects on pulmonary vascular remodeling and potassium channel activity in pulmonary artery smooth muscle cells (PASMCs) has not been clearly addressed in pulmonary hypertension secondary to increased pulmonary blood flow.

Methods

A total of 27 male SD rats were randomly divided into a sham group (n = 9), a shunt group (n = 9) and a shunt + sildenafil group (n = 9). A left-to-right shunt was established by performing an abdominal aorta to inferior vena cava fistula both in the shunt group and the shunt + sildenafil group. Rats in the shunt + sildenafil group received oral sildenafil 10 mg/kg/day, whereas the rats in the sham group and the shunt group were fed with normal saline of the same volume. Eleven weeks later, mean pulmonary artery pressure (mPAP) was measured. Meanwhile, the ratio of right ventricular mass to left ventricular plus septal mass (RV/(LV+S)) was detected as a marker of the degree of right ventricular hypertrophy. The relative medial thickness (RMT) of middle and small pulmonary muscularized arteries was calculated as a sign of pathological changes of pulmonary vasculature. The voltage-gated potassium channel Kv1.5 mRNA expression of pulmonary vasculature was detected using real-time PCR.

Results

Eleven weeks later, the rats in the shunt group developed pulmonary hypertension as evidenced by significantly increased mPAP, RV/(LV+S), as well as higher RMT of middle and small pulmonary muscularized arteries (all P = 0.01). In addition, the rats in shunt group had decreased Kv1.5 mRNA expression in pulmonary vasculature (P = 0.01). The rats in the shunt + sildenafil group had a significantly decreased mPAP, and RV/(LV+S) ratio, and a lower RMT as well (all P = 0.01), whereas the levels of Kv1.5 mRNA expression were significantly upregulated (P = 0.01). Furthermore, there were no statistically significant difference in mPAP, in RV/(LV+S) ratio, RMT of middle and small pulmonary muscularized arteries and Kv1.5 mRNA expression between the shunt + sildenafil group and the sham group (all P = NS).

Conclusions

Oral sildenafil attenuated pulmonary vascular remodeling and upregulated Kv1.5 mRNA expression in the rats with pulmonary hypertension secondary to left-to-right shunt.