Allan K Alencar

Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats.

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.

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

Rationale: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right‐ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein‐coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. Objectives: To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)‐induced PH. Methods: Rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were as follows: control, MCT + vehicle, and MCT + G1 (400 &mgr;g/kg/day subcutaneous). Animals (n = 5 per group) were treated with vehicle or G1 for 14 days after disease onset. Measurements and Main Results: Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left‐ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH‐related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2 + handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Conclusions: G1 was effective to reverse PH‐induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease. Graphical Abstract GPER activation by G1 reverses pulmonary hypertension in male rats by promoting pulmonary endothelial nitric oxide synthesis, Ca2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Figure. No caption available.

Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases.

Novel Agonist of Adenosine Receptor Induces Relaxation of Corpus Cavernosum in Guinea Pigs: An In Vitro and In Vivo Study

OBJECTIVE To test the relaxation effect of a new adenosine receptor agonist N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on in vitro and in vivo preparation of corpus cavernosum (CC), and its interaction with type-5 phosphodiesterase enzyme inhibitor, sildenafil. METHODS For in vitro study, an increasing concentration of LASSBio-1359 was added in the solution at the plateau isometric tension recording of isolated guinea pig CC induced by phenylephrine (30 μM). Concentration-response curve was repeated in the presence of A2A receptor antagonist, ZM 241385 (10 μM). Sildenafil-induced CC relaxing effect was compared with that of LASSBio-1359. Isobolographic analysis was performed to identify possible synergistic interaction between LASSBio-1359 and sildenafil. For in vivo study, blood pressure response in the CC of guinea pig was measured after administration of LASSBio-1359 (10 mg/kg intravenously) or sildenafil (10 mg/kg intravenously). RESULTS LASSBio-1359 caused relaxation of phenylephrine-induced contraction of isolated CC in a concentration-dependent manner (IC50 = 10.1 ± 1.8 μM), which was shifted to the right in the presence of ZM 241385 (IC50 = 27.1 ± 1.4 μM; P <.05). Isobolographic analysis showed synergistic interaction between LASSBio-1359 and sildenafil. As sildenafil, LASSBio-1359 increased blood pressure oscillation in the CC confirming its systemic efficacy. CONCLUSION CC relaxing effects induced by the adenosine A2A receptor agonist, LASSBio-1359, demonstrated in vitro and in vivo experimental protocols, represent a promise therapeutic option for the treatment of erectile dysfunction. Synergistic interaction of LASSBio-1359 with sildenafil suggests a combined use to reach a higher population of patients with erectile dysfunction.

Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats

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.

Cardioprotection Induced by Activation of GPER in Ovariectomized Rats With Pulmonary Hypertension

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.