Beneficial effects of a novel agonist of the adenosine A_2A receptor on monocrotaline‐induced pulmonary hypertension in rats

Abstract

BACKGROUND AND PURPOSEPulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. EXPERIMENTAL APPROACHPAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg −1 ) and 2 weeks later, oral LASSBio-1359 (50 mg·kg −1 ) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. KEY RESULTSMCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. CONCLUSION AND IMPLICATIONSIn rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors.

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

“…Although lungs from MCT-treated PH rats do not sufficient generate angioobliteration that recapitulate human pulmonary vascular lesions (Vitali et al, 2014), we have chosen this model because it, similarly to that of hypoxia-induced PH, induces intense RV hypertrophy and dysfunction (Alencar et al, 2014; Alencar et al, 2013; van Suylen et al, 1998; Zapata-Sudo et al, 2012), the major determinants of life expectance in the clinical practice. Furthermore, as we aimed to investigate the specific potential of GPER independent of its activation by endogenous estrogens, the injection of MCT would low plasma E 2 levels by its gonadal actions (Tofovic and Jackson, 2013), reducing the physiologic stimulus of GPER and allowing to explore closely the effects of G1.…”

“…Rats in the MCT groups were given a single intraperitoneal (i.p.) injection of MCT at 60 mg/kg body weight to induce PH as published elsewhere (Alencar et al, 2014; Alencar et al, 2013; Zapata-Sudo et al, 2012). Rats in the control group were injected with the same volume of sterile saline.…”

“…RVs were treated in a similar way, except that the processing times were different (20 min in sequential baths with alcohol, xylene, and paraffin). Tissues were sectioned at 4 μm, stained, and analyzed in a blinded manner following the already published methods (Alencar et al, 2014; Alencar et al, 2013). …”

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

“…Activation of A1 and A2 receptors in neutrophils plays an important role in regulating inflammation. Data indicate the major role of A2A receptor in remodeling of the pulmonary circulation vessels, damaged by pulmonary hypertension [16]. Activation of these receptors on immune cells significantly weakens the release of cytokines and chemokines, which is the mechanism of antiinflammatory effect of adenosine [17].…”

Pharmacologic stress myocardial perfusion imaging in patients with pulmonary hypertension: What do we know, and what remains to be learned?

“…22 Stimulation of the A2a receptor may cause pulmonary vasodilation, and regression of PH in an experimental model. 23 …”