Study On The Effect Of Compound 658 On Pulmonary Arterial Hypertension And The Pharmacokinetics And Anti-arthritis Effects Of Compound HOEC

The research containedin this paper is divided into two parts.The first part mainly studies the pharmacodynamics and mechanism of compound 658 in the treatment of pulmonary arterial hypertension.The second part mainly studies the drug metabolism parameters of'IIOEC,and its effecton rat arthritis model.In the first part of the experiment,this chapter mainly studied the pharinacodynamics and mechanism of compound 658 on monocrotaline-induced pulmonary hypertension on rats.Rats with pulmonary arterial hypertension induced by monocrotaline were given different doses of compound 658 for 21 days.The right ventricular pressure and mean pressure were measured by right heart catheterization,and the middle membrane was observed by lung tissue staining.The results showed that compound 658 reduced right ventricular systolic pressure and mean right ventricular pressure in pulmonary arterial hypertension rats after 21 days of administration,and reduced right ventricular hypertrophy and pulmonary vascular remodeling.In order to further explore the specific mechanism of compound 658 in the treatment of pulmonary hypertension,we used MTT and wound healing assays respectively to investigate the anti-proliferation/migration effects of compound 658on hypoxia-induced pulmonary artery endothelial cells.And then the influence of compound 658 on STAT3 phosphorylation was investigated by western blot.The results showed that compound 658 dose-dependently inhibited hypoxia-induced proliferation and migration of pulmonary artery endothelial cells,whichmight be achieved by inhibiting overphosphorylation of STATS.The second part is to study the pharmacokinetics of HOEC and the drug effect on collagen-induced arthritis model.The pharmacokinetic behaviors of single intravenous and oral administration of HOEC in rats were first investigated.The concentration of the metabolite—caffeic acid of the test substance HOEC in plasma at different times was determined by liquid chromatography-mass spectrometry-mass spectrometry.The effect of the compound HOEC on collagen-induced arthritis was then investigated.In the experiment,collagen-induced arthritis model rats were given intraperitoneal injection of HOEC for 36 days,and the arthritis score and H&E staining were investigated.The results showed that HOEC was rapidly metabolized into caffeic acid in the bodyand only the intraperitoneal injection or intravenous injectionhad function.Moreover,the compound HOEC can reduce the score of arthritis after 36 days of administration,and is an effective drug candidate for treating arthritis.