RESUMEN
INTRODUCTION: Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats. METHODS: An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured. RESULTS: Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats. CONCLUSIONS: The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.
Asunto(s)
Benzamidas/uso terapéutico , Hidrazonas/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Arteria Pulmonar/efectos de los fármacos , Citrato de Sildenafil/uso terapéutico , Agonistas del Receptor de Adenosina A2/farmacología , Agonistas del Receptor de Adenosina A2/uso terapéutico , Animales , Benzamidas/farmacología , Sinergismo Farmacológico , Hidrazonas/farmacología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Masculino , Monocrotalina , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Arteria Pulmonar/fisiopatología , Ratas , Ratas Wistar , Citrato de Sildenafil/farmacología , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). METHODS: Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg-1.d-1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. RESULTS: Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg-1.d-1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg-1.d-1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg-1.d-1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. CONCLUSION: In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound's potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension.
Asunto(s)
Agonistas del Receptor de Adenosina A2/uso terapéutico , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/prevención & control , Hidrazonas/uso terapéutico , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Tiofenos/uso terapéutico , Agonistas del Receptor de Adenosina A2/administración & dosificación , Administración Oral , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Insuficiencia Cardíaca/fisiopatología , Hidrazonas/administración & dosificación , Masculino , Infarto del Miocardio/patología , Ratas , Ratas Endogámicas SHR , Tiofenos/administración & dosificaciónRESUMEN
Adenosine receptors are expressed in adipose tissue and control physiological and pathological events such as lipolysis and inflammation. The aim of this study was to evaluate the activity of N6-cyclopentyladenosine (CPA), a potent and selective A1 adenosine receptor agonist; 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine hydrochloride (CGS-21680), an A2A adenosine receptor agonist; and 5'-N-ethylcarboxamidoadenosine (NECA), a potent non-selective adenosine receptor agonist on adipose tissue inflammatory alterations induced by obesity in mice. Swiss mice were fed with a high-fat diet for 12 weeks and agonists were administered in the last two weeks. Body weight, adiposity and glucose homeostasis were evaluated. Inflammation in adipose tissue was assessed by evaluation of adipokine production and macrophage infiltration. Adenosine receptor signaling in adipose tissue was also evaluated. Mice that received CGS21680 presented an improvement in glucose homeostasis in association with systemically reduced inflammatory markers (TNF-α, PAI-1) and in the visceral adipose tissue (TNF-α, MCP-1, macrophage infiltration). Activation of p38 signaling was found in adipose tissue of this group of mice. NECA-treated mice presented some improvements in glucose homeostasis associated with an observed weight loss. Mice that received CPA presented only a reduction in the ex vivo basal lipolysis rate measured within visceral adipose tissue. In conclusion, administration of the A2A receptor agonist to obese mice resulted in improvements in glucose homeostasis and adipose tissue inflammation, corroborating the idea that new therapeutics to treat obesity could emerge from these compounds.
Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Tejido Adiposo/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/patología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Agonistas del Receptor de Adenosina A1/uso terapéutico , Agonistas del Receptor de Adenosina A2/uso terapéutico , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adiposidad/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Inflamación/complicaciones , Lipólisis/efectos de los fármacos , Masculino , Ratones , Obesidad/complicaciones , Obesidad/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Pulmonary 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 APPROACH: PAH 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 RESULTS: MCT 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 IMPLICATIONS: In 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.