Sharlene L Pereira

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.

Vasodilator Activity of the Essential Oil from Aerial Parts of Pectis brevipedunculata and Its Main Constituent Citral in Rat Aorta

The essential oil of Pectis brevipedunculata (EOPB), a Brazilian ornamental aromatic grass, is characterized by its high content of citral (81.9%: neral 32.7% and geranial 49.2%), limonene (4.7%) and α-pinene (3.4%). Vasodilation induced by EOPB and isolated citral was investigated in pre-contracted vascular smooth muscle, using thoracic aorta from Wistar Kyoto (WKY) rats which was prepared for isometric tension recording. EOPB promoted intense relaxation of endothelium-intact and denuded aortic rings with the concentration to induce 50% of the maximal relaxation (IC50) of 0.044% ± 0.006% and 0.093% ± 0.015% (p < 0.05), respectively. The IC50 values for citral in endothelium-intact and denuded rings were 0.024% ± 0.004% and 0.021% ± 0.004%, respectively (p > 0.05). In endothelium-intact aorta, EOPB-induced vasorelaxation was significantly reduced by l-NAME, a nitric oxide synthase inhibitor. The vasodilator activity of citral was increased in the KCl-contracted aorta and citral attenuated the contracture elicited by Ca2+ in depolarized aorta. EOPB and citral elicited vasorelaxation on thoracic aorta by affecting the NO/cyclic GMP pathway and the calcium influx through voltage-dependent l-type Ca2+ channels, respectively.

Docking, Synthesis and Anti-Diabetic Activity of Novel Sulfonylhydrazone Derivatives Designed as PPAR-Gamma Agonists

Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.

Vasodilator and antihypertensive effects of a novel N-acylhydrazone derivative mediated by the inhibition of L-type Ca2+ channels

New bioactive N‐acylhydrazone derivatives synthesized from safrole previously have been found to promote intense vasodilation and antihypertensive activity. In this study, we describe the synthesis and the cardiovascular effects of the new N‐acylhydrazone derivative (E)‐N‐methyl‐N′‐(thiophen‐3‐ylmethylene)benzo[d][1,3]dioxole‐5‐carbohydrazide (LASSBio‐1289). Thoracic aorta and left papillary muscles from Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. LASSBio‐1289 promoted relaxation of endothelium‐intact and denuded aortic rings with respective pIC50 (−log IC50) values of 5.07 ± 0.09 and 4.26 ± 0.09 (P < 0.001) for WKY rats and 5.43 ± 0.05 and 5.58 ± 0.07 (P > 0.05) for SHR. The vasodilator activity of LASSBio‐1289 was increased in the KCl‐contracted aorta. LASSBio‐1289 attenuated the contracture elicited by Ca2+ in depolarized aorta from both WKY rats and SHR. In endothelium‐intact aorta from WKY rats, LASSBio‐1289‐induced relaxation was unchanged after incubation with propranolol, ZM 241385, atropine, diphenhydramine, and HOE140, but was significantly reduced by L‐NAME and ODQ. LASSBio‐1289 decreased papillary muscles contractility only at concentrations above 200 μm. Acute intravenous injection of LASSBio‐1289 (3 mg/kg) produced a significant hypotensive response in SHR but not in WKY rats, suggesting its antihypertensive profile. The antihypertensive effect was also observed in SHR during 14 days of intraperitoneal and oral administration. In conclusion, our data demonstrated that LASSBio‐1289 induces both endothelium‐independent vasorelaxation involving the inhibition of Ca2+ influx through L‐type Ca2+ channels in aorta from WKY rats and SHR, and endothelium‐dependent relaxation mediated by the NO/cyclic GMP pathway in WKY rats.

N-acylhydrazone improves exercise intolerance in rats submitted to myocardial infarction by the recovery of calcium homeostasis in skeletal muscle.

AIMS This work investigated the effects of 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294) treatment on the contractile response of soleus (SOL) muscle from rats submitted to myocardial infarction (MI). MAIN METHODS Following coronary artery ligation, LASSBio-294 (2mg/kg, i.p.) or vehicle was administrated once daily for 4 weeks. KEY FINDINGS The run time to fatigue for sham rats was 17.9 ±2.6 min, and it was reduced to 3.3 ± 0.8 min (P<0.05) in MI rats. In MI rats treated with LASSBio-294, the time to fatigue was 15.1 ± 3.6 min. During the contractile test, SOL muscles from sham rats showed a response of 7.12 ± 0.54N/cm(2) at 60 Hz, which was decreased to 5.45 ± 0.49 N/cm(2) (P<0.05) in MI rats. The contractility of SOL muscles from the MI-LASSBio-294 group was increased to 9.01 ± 0.65N/cm(2). At 16 mM caffeine, the contractility was reduced from 2.31 ± 0.33 to 1.60 ± 0.21 N/cm(2) (P<0.05) in the MI group. In SOL muscles from MI-LASSBio-294 rats, the caffeine response was increased to 2.62 ± 0.33 N/cm(2). Moreover, SERCA2a expression in SOL muscles was decreased by 0.31-fold (31%) in the MI group compared to the Sham group (P<0.05). In the MI-LASSBio-294 group, it was increased by 1.53-fold (153%) compared to the MI group (P<0.05). Meanwhile, the nuclear density in SOL muscles was increased in the MI group compared to the Sham group. Treatment with LASSBio-294 prevented this enhancement of cellular infiltrate. SIGNIFICANCE LASSBio-294 treatment prevented the development of muscular fatigue and improved exercise intolerance in rats submitted to MI.