The Prevention Role Of Irbesartan In An Rat Model Of Chronic Thromboembolic Pulmonary Hypertension

Part I:Establishment of a rat model of chronic thromboembolic pulmonary hypertensionPurpose:Chronic thromboembolic pulmonary hypertension (CTEPH) develops from the obstruction of pulmonary artery branches following acute pulmonary embolism(APE). Incomplete thrombus resolution and remodelling of pulmonary blood vessels lead to pulmonary vascular resistance (PVR) increasing, and progressive right heart failure. It is not yet understood how PE progresses to CTEPH. Consequently, for a simple and reproducible CTEPH animal models is needed for the research of molecular signals involved in the pathology of this disease and for the evaluation of new therapeutic strategies.Methods:10-week-old male Sprague-Dawley rats were randomized into sham (n=8) and PE (n= 8) groups. Pulmonary embolization was performed by injections of a PVA suspension (Polyvinyl alcohol,90-180μm) via the left femoral vein at a dosage of 45 particle/g body weight. Control animals underwent the same protocol but were treated with saline solution instead of the thrombotic material. Organ collection was performed after euthanasia under isoflurane anesthesia. Right ventricles and lungs were prepared for histological analysis.Results:We generated and standardized a rat model that resembles functional and histological features of CTEPH. The APE was induced by left femoral vein injection of PVA particles into 10-week-old male SD rats. Seven days after the introduction of APE, rats developed characteristic features of CTEPH including elevated right ventricular systolic pressure, right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, and increased serum Angiotensin Ⅱ.Conclusion:The current animal model seems suitable for detailed study of CTEPH pathophysiology and permits preclinical testing of new pharmacological therapies against CTEPHPart II:The prevention role of Irbesartan on pulmonary artery remodeling in an rat model of chronic thromboembolic pulmonary hypertensionPurpose:Chronic thromboembolic pulmonary hypertension (CTEPH) may develop from acute pulmonary embolism (APE). Incomplete thrombus resolution and remodeling of pulmonary blood vessels contribute to the increased pulmonary vascular resistance (PVR).Blocking the angiotensin II receptor exerts beneficial effects in the prevention of primary arterial hypertension, while no previous study has examined whether angiotensin Ⅱ receptor blockers protect against the hemodynamic changes associated with the formation of CTEPH. We aimed to examine the effects exerted by irbesartan on APE-induced CTEPH.Methods:10-week-old male Sprague-Dawley rats were randomized into 5 groups: CON (n=8), IR (n=8), PE (n=8),PE+IR (n=8), and A779 (n=8) groups. Group PE, PE+IR and A779 received injection of a PVA suspension (Polyvinyl alcohol, 90-180μm) via the left femoral vein at a dosage of 45 particle/g body weight. Group CON and IR received the same volume of saline solution instead of the thrombotic material. Group IR, PE+IR and A779 were treated with irbesartan over a 7-day period. Group A779 were implanted with mini osmotic pumps to deliver A779 (200 ng/kg/min) over the 7-day period. Hemodynamic (right ventricle systolic pressure, RVSP; blood pressure, BP) evaluations were performed on day 7 and organ collection was performed. Right ventricles and lungs were prepared for histological analysis.Results:CTEPH was generated 7 days after the introduction of APE. Irbesartan decreased RVSP significantly in PE+IR group (PE group vs. PE+IR group, 48.89±4.05mmHg vs.35.68±4.43mmHg, P<0.05), while have no effect on the normal pulmonary artery pressure. Right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, and increased serum Angiotensin Ⅱ all could be reversed by irbesarta. A779 could diminish the effect caused by irbesartan.Conclusion:Our findings show that the activation of the renin-angiotensin system participates in the pathogenesis of CTEPH after APE. Irbesartan exert protection effect against on APE-induced CTEPH.