Niflumic Acid Attenuated Pulmonary Artery Tone and Vascular Structural Remodeling of Pulmonary Arterial Hypertension Induced by High Pulmonary Blood Flow In Vivo

Abstract

Calcium-activated chloride channels (CaCCs) play a vital role in regulating pulmonary artery tone during pulmonary arterial hypertension (PAH) induced by high blood flow. The role of CaCCs inhibitor niflumic acid (NFA) in vivo during this process requires further investigation. We established the PAH model by abdominal shunt surgery and treated with NFA in vivo. Fifty rats were randomly divided into normal, sham, shunt, NFA group 1 (0.2 mg/kg), and NFA group 2 (0.4 mg/kg). Pathological changes, right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter were analyzed. Then contraction reactions of pulmonary arteries were measured. Finally, the electrophysiological characteristics of pulmonary arterial smooth muscle cells were investigated using patch-clamp technology. After 11 weeks of shunting, PAH developed, accompanied with increased right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter. In the NFA treatment groups, the pressure and pathological changes were alleviated. The pulmonary artery tone in the shunt group increased, whereas it decreased after NFA treatment. The current density of CaCC was higher in the shunt group, and it was decreased in the NFA treatment groups. In conclusion, NFA attenuated pulmonary artery tone and structural remodeling in PAH induced by high pulmonary blood flow in vivo. CaCCs were involved and the augmented current density was alleviated by NFA treatment.

TMEM16A regulates the cell cycle of pulmonary artery smooth muscle cells in high‑flow‑induced pulmonary arterial hypertension rat model

“…Under aberrant levels of mechanical shear stress caused by excessive blood flow, pulmonary arteriole endothelial and smooth muscle cells undergo progressive dysfunction. A previous study (16,18) in our laboratory in the Pediatric department, The First Affiliated Hospital of Guangxi Medical University (Nanning, China) demonstrated that CaCCs contribute to elevated pulmonary artery pressure and structural remodeling in PAH induced by high pulmonary flow. TMEM16A was reported as a candidate for the molecular basis of CaCCs in 2008 (8)(9)(10), and there is accumulating evidence revealing that TMEM16A is involved in a variety of physical and pathophysiological processes (15,(19)(20)(21)(22).…”

“…Right ventricular (RV) pressure (RVP), right ventricular hypertrophy index (RVHI) and pulmonary structural remodeling measurements. RVP, including systolic right ventricular pressure (SRVP), diastolic right ventricular pressure (DRVP) and mean right ventricular pressure (MRVP) were measured 11 weeks after surgery using a cardiac function analyzer (MP160; Bipoac Systems, Inc.) as previously described (16,17). Weights of the RV and left ventricle (LV) with the septum (S) of the hearts were measured after sacrifice.…”

“…PASMC isolation and culture. Primary PASMCs from control, sham and shunt groups were isolated and cultured for in vitro assessment as previously described (16,17). Pulmonary arteriole tissue was removed and immersed in ice-cold HEPES-buffered salt solution.…”

“…TMEM16A has been revealed to be overexpressed in PASMCs in a number of different pulmonary hypertension models (14,15). A previous study from our laboratory at the Pediatric department, The First Affiliated Hospital Of Guangxi Medical University (Nanning, China) demonstrated that the CaCC inhibitor, niflumic acid, attenuated pulmonary artery structural remodeling in PAH induced by high pulmonary blood flow in vivo (16). However, the role and mechanism of TMEM16A in PAH induced by high pulmonary blood flow remains unclear.…”

“…Rats were anaesthetized by intraperitoneal injection of sodium pentobarbital (0.25%; 40 mg/kg). According to methods reported previously (16,17), an abdominal aorta and inferior vena cava arteriovenous fistulization was performed to establish PAH induced by high pulmonary blood flow from the systemic circulation. Laparotomy was performed in the sham and shunt groups, and the abdominal aorta was clamped for 3 min.…”