A Novel Adenosine A2a Receptor Agonist Attenuates the Progression of Monocrotaline-induced Pulmonary Hypertension in Rats

Allan Kn Alencar Sharlene L Pereira

doi:10.4172/2161-105x.s4-005

Abstract

Background and purpose: Pulmonary hypertension is characterized by enhanced pulmonary vascular resistance, Right Ventricular Hypertrophy (RVH), and increased Right Ventricular Systolic Pressure (RVSP). This study examined the therapeutic effects of (E)-N'-(3,4-dimethoxybenzylidene)-3,4-dimethoxy-N-methylbenzohydrazide (LASSBio-1366) on monocrotaline-induced pulmonary hypertension in rats. Experimental approach: Pulmonary hypertension was induced in male Wistar rats by a single intraperitoneal injection of monocrotaline (MCT) at a dose of 60 mg/kg. Rats were divided into the following groups: control (saline injection only), MCT, MCT+vehicle (dimethyl sulfoxide (DMSO)), and MCT+LASSBio-1366. Starting 14 days after MCT injection, rats were treated daily with orally administered LASSBio-1366 (50 mg/kg/day) or vehicle for 14 days. Experiments were performed at the end of the 2-week treatment period (28 days post-MCT). Hemodynamics, vascular activity, and expression of endothelial nitric oxide synthase (eNOS), adenosine A 2A receptor (A 2A R), and sarcoplasmic/ endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) were evaluated in each group. Results: MCT increased the RVSP, RVH, and endothelial dysfunction in the pulmonary artery rings. These changes were attenuated by LASSBio-1366. The RVSP was reduced from 49.59 ± 5.08 mmHg in the MCT group, to 35.50 ± 1.17 mmHg in the LASSBio-1366-treated group (P<0.05). MCT also reduced eNOS, A 2A R, and SERCA2a levels compared with control, but treatment with LASSBio-1366 rescued their expression. Conclusion: LASSBio-1366 activated A 2A R and attenuated RVH, endothelial dysfunction, and pulmonary vascular remodeling that occurs in rats with pulmonary hypertension.

Highlights

Pulmonary Arterial Hypertension (PAH) is a rare disorder, with a prevalence of 15-50 people per million [1,2]
The Right Ventricular Systolic Pressure (RVSP) was reduced from 49.59 ± 5.08 mmHg in the MCT group, to 35.50 ± 1.17 mmHg in the LASSBio-1366-treated group (P
MCT reduced endothelial nitric oxide synthase (eNOS), A2A receptor (A2AR), and sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) levels compared with control, but treatment with LASSBio-1366 rescued their expression

Summary

Introduction

Pulmonary Arterial Hypertension (PAH) is a rare disorder, with a prevalence of 15-50 people per million [1,2]. PAH is characterized by endothelial cell dysfunction, proliferation of endothelial and pulmonary arterial smooth muscle cells, pulmonary vasoconstriction, and in situ thrombosis. These changes lead to a sustained increase in pulmonary vascular resistance and pulmonary arterial pressure, culminating in progressive Right Ventricular (RV) dysfunction and death [3]. This study examined the therapeutic effects of (E)-N’-(3,4-dimethoxybenzylidene)-3,4-dimethoxy-N-methylbenzohydrazide (LASSBio-1366) on monocrotaline-induced pulmonary hypertension in rats. Experimental approach: Pulmonary hypertension was induced in male Wistar rats by a single intraperitoneal injection of monocrotaline (MCT) at a dose of 60 mg/kg. Starting 14 days after MCT injection, rats were treated daily with orally administered LASSBio-1366 (50 mg/kg/day) or vehicle for 14 days. Hemodynamics, vascular activity, and expression of endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), and sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) were evaluated in each group

Methods

Results

Discussion

Conclusion