Oral treatment with Euterpe oleracea Mart. (açaí) extract improves cardiac dysfunction and exercise intolerance in rats subjected to myocardial infarction.

BACKGROUND: This study was designed to evaluate the cardioprotective effects of Euterpe oleracea Mart., popularly known as "açaí", on rats subjected to myocardial infarction (MI). METHODS: Hydroalcoholic extracts of açaí were obtained from a decoction of the seeds. Two male Wistar rat groups were delineated: 1) the sham-operated group (control, n = 6), with no surgical amendment, and 2) the MI group (n = 12), in which the anterior descendent coronary artery was occluded during surgery. MI group was divided into two subgroups, in which rats were either treated with hydroalcoholic extract of Euterpe oleracea seeds (100 mg/kg/day p.o.) or received no treatment. Treatment began on the day of surgery, and lasted 4 weeks. Subsequently, rats were subject to an exercise test protocol, hemodynamic evaluation, and histological analysis of the left ventricle. Groups were compared using one-way analysis of variance (ANOVA), followed by Dunnett's test. RESULTS: The total running distance of sham rats was 1339.0 ± 276.6 m, MI rats was 177.6 ± 15.8 m (P < 0.05), and MI-açaí rats was 969.9 ± 362.2 m. Systolic arterial pressure was significantly decreased in MI rats (86.88 ± 4.62 mmHg) compared to sham rats (115.30 ± 7.24 mmHg; P < 0.05). Açaí treatment prevented a reduction in systolic arterial pressure (130.00 ± 8.16 mmHg) compared to MI rats (P < 0.05). Left ventricular (LV) end-diastolic pressure was significantly augmented in MI rats (17.62 ± 1.21 mmHg) compared to sham rats (4.15 ± 1.60 mmHg; P < 0.05), but was 3.69 ± 2.69 mmHg in açaí-treated rats (P < 0.05 vs. MI). The LV relaxation rate (-dp/dt) was reduced in MI rats compared to the sham group, whereas açaí treatment prevented this reduction. Açaí treatment prevented cardiac hypertrophy and LV fibrosis in MI rats. CONCLUSIONS: Euterpe oleracea treatment of MI rats prevented the development of exercise intolerance, cardiac hypertrophy, fibrosis, and dysfunction.

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH. METHODS: Male Wistar rats were injected with a single dose (60mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca(2+)-ATPase activity and vascular activity of LASSBio-1386 were evaluated. RESULTS AND CONCLUSIONS: The RV systolic pressure was elevated in the PAH model and reduced from 49.6 ± 5.0 mm Hg (MCT group) to 27.2 ± 2.1 mm Hg (MCT+LASSBio-1386 group; P<0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca(2+)-ATPase activity was reduced. These alterations were related with MCT-injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A2AR agonists for the treatment of PAH.

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

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.

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.

Pharmacological characterization of (3-thienylidene)-3,4-methylenedioxybenzoylhydrazide: a novel muscarinic agonist with antihypertensive profile.

BACKGROUND: Several new bioactive compounds of the N-acylhydrazone class were developed from the safrole, a Brazilian natural product obtained from sassafras oil (Ocotea pretiosa). This work investigated the effects on cardiovascular system of LASSBio-897, a new analogue of the lead compound 3,4-methylenedioxybenzoyl-2-thienylhydrazone named LASSBio-294. METHODS: Thoracic aorta from Wistar-Kyoto (WKY) rats was prepared for isometric tension recording and for cGMP content determination. Blood pressure (BP) was measured in WKY rats and spontaneously hypertensive rats (SHR) after treatment with 1 mg/kg intravenously of LASSBio-897 and during 14 days' treatment of SHR with 1 mg/kg/day perorally. RESULTS: LASSBio-897 (0.05-1 micromol/l) exhibited a potent vasodilatory activity in phenylephrine (Phe)-contracted aortic rings from WKY rats. This effect was abolished in endothelium-denuded aortic rings and after treatment with the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Also, LASSBio 897 (1 micromol/l) increased about 15 times the intracellular content of cGMP. LASSBio-897-induced vasodilation was totally inhibited by the muscarinic antagonist atropine and by the M(3) subtype selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), indicating the involvement of M(3) receptors. Intravenous administration of LASSBio-897 (1 mg/kg) produced significant hypotensive response in both WKY and SHR. The hypotensive effect of LASSBio-897 was also observed during the 14 days of oral administration. CONCLUSIONS: The novel N-acylhydrazone derivative LASSBio-897 exhibited a potent vasodilatory activity in aortic rings mediated by the NO/cGMP pathway via activation of endothelial M(3) receptors and was orally effective in reducing BP on SHR.