Regulatory role of calcium activated chloride channel in pulmonary vascular structural remodeling in rats with pulmonary arterial hypertension induced by high pulmonary blood flow

Abstract

To explore the regulatory role of calcium activated chloride channel (CaCC) in vascular structural remodeling in pathogenesis of pulmonary arterial hypertension (PAH) induced by high pulmonary blood flow. An abdominal aorta and inferior vena cava shunting operation was used to induce high pulmonary blood flow and establish a PAH rat model.Seventy-five SD rats were randomly divided into normal, sham, shunt, niflumic acid (NFA) 1(0.2 mg/(kg·d))and NFA 2 (0.4 mg/(kg·d)) groups. There were 15 rats in each group. Pulmonary artery pressure and vascular structural remodeling were measured, arteriole contraction ratio among these groups were compared using vascular tone analysis system, and the electrophysiology of pulmonary artery smooth muscle cell (PASMC) was recorded using patch clamp technology. Differences between multiple groups were compared through variance analysis and that between groups with q test. Compared with normal ((14.4±1.3 ) mmHg, 1 mmHg=0.133 kPa)and sham groups ((13.5±2.3 ) mmHg), mean pulmonary artery pressure in shunt group ((27.4±2.4 ) mmHg) increased significantly (P<0.05). Compared with shunt group, mean pulmonary artery pressure in NFA 1 group ((21.2±2.0) mmHg) and NFA 2 group ((22.3±2.0) mmHg) decreased significantly (P<0.05). Pulmonary vascular structural remodeling including pulmonary artery stenosis presented in shunt group. Compared with normal ((114.3±1.2)%) and sham ((115.5±1.1)%) groups, arteriole contraction ratio to 10(-5) mol/L phenylephrine in shunt group ((132.6±1.4)%) increased significantly (P<0.05). Compared with shunt group, pulmonary vascular structural remodeling alleviated in NFA 1 and NFA 2 groups. Arteriole contraction ratio in NFA 1 group ((126.4±1.3)%) and NFA 2 group ((124.6±1.0)%) decreased significantly compared with shunt group (P<0.05). Patch clamp technique recorded typical CaCC currents. Compared with normal ((32.3±2.3 ) pA/pF) and sham groups ((35.3±1.2) pA/pF), the CaCC current density of PASMC in shunt group ((51.3±2.7) pA/pF) increased significantly (P<0.05). Compared with shunt group, the CaCC current density of PASMC in NFA 1 group ((40.2±1.5 ) pA/pF) and NFA 2 group ((42.7±2.2) pA/pF) decreased significantly (P<0.05). CaCC is involved in pulmonary arterial hypertension induced by high pulmonary blood flow through regulating membrane potential. NFA attenuate pulmonary vascular structural remodeling and pulmonary pressure through decreasing CaCC current density of PASMC membrane.