Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension

AbstractImbalanced matrix metalloproteinase (MMP)-2 activity and transforming growth factor expression (TGF-β) are involved in vascular remodeling of hypertension. Atorvastatin and sildenafil exert antioxidant and pleiotropic effects that may result in cardiovascular protection. We hypothesized that atorvastatin and sildenafil alone or in association exert antiproliferative effects by down-regulating MMP-2 and TGF-β, thus reducing the vascular hypertrophy induced by two kidney, one clip (2K1C) hypertension.Sham and 2K1C rats were treated with oral atorvastatin 50mg/kg, sildenafil 45mg/kg, or both, daily for 8 weeks. Blood pressure was monitored weekly. Morphologic changes in the aortas were studied. TGF-β levels were determined by immunofluorescence. MMP-2 activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence. The effects of both drugs on proliferative responses of aortic smooth muscle cells to PDGF and on on MMP-2 activity in vitro were determined. Atorvastatin, sildenafil, or both drugs exerted antiproliferative effects in vitro. All treatments attenuated 2K1C-induced hypertension and prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats. Aortas from 2K1C rats showed higher collagen deposition, TGF-β levels and MMP-2 activity and expression when compared with Sham-operated animals. Treatment with atorvastatin and/or sildenafil was associated with attenuation of 2K1C hypertension-induced increases in these pro-fibrotic factors. However, these drugs had no in vitro effects on hr-MMP-2 activity.Atorvastatin and sildenafil was associated with decreased vascular TGF-β levels and MMP-2 activity in renovascular hypertensive rats, thus ameliorating the vascular remodeling. These novel pleiotropic effects of both drugs may translate into protective effects in patients

Morpho-anatomy and histochemistry of the leaves of Luehea divaricata Mart.

Foram determinados parâmetros morfo-anatômicos por análises macro e microscópicas das folhas de Luehea divaricata Mart., planta reconhecida tradicionalmente como medicinal, objetivando sua diagnose como insumo farmacêutico. Macroscopicamente a folha é discolor, com margem serrilhada e com três nervuras principais desde a base. Quando desidratada apresenta os bordos enrolados sobre a nervura principal. Microscopicamente, a presença de cristais de oxalato de cálcio na forma de drusas e monocristais prismáticos, de células mucilaginosas, de bainhas vasculares com extensões que ocasionam partições transversais do mesofilo face a face e parênquima esponjoso com células braciformes, são características significativas no controle botânico de qualidade desta espécie para a indústria farmacêutica, quando analisadas em conjunto.Morpho-anatomical parameters of Luehea divaricata Mart. leaves were determined aiming its diagnosis as a pharmaceutical drug. This plant is traditionally known as medicinal. The macroscopic characteristics shown that the leaves were discolors, with serrated edges and three principals nervures from the base. When dehydrated it presents edges rolled on the principal nervure. The microscopic characteristics showed the presence of crystals of calcium oxalate in the form of druses and prismatic monocrystals, mucilaginous cells, vascular form extensions that cause to transversal partitions of mesophyll face the face and present too, spongy parenchyma with brachyforms cells, which are significative characteristics in the botanical quality control of this plant for the pharmaceutical industry, when analyzed together.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Pharmacology activity and quercetin content of Mirabilis jalapa L.

Mirabilis jalapa (Nyctaginaceae), conhecida popularmente em Brasil como "bonina" ou "maravilha", é utilizada popularmente para o tratamento de infecções, inflamações e dores. O extrato bruto etanólico (70%) foi preparado por maceração e fracionado com solventes orgânicos de polaridade crescente (hexano, diclorometano, acetato de etila e butanol). As melhores respostas para a atividade antimicrobiana foram obtidas para Staphylococcus aureus com a fração diclorometano e para Saccharomyces cerevisiae com a fração acetato de etila. Os extratos brutos e frações apresentaram atividade antioxidante pelo método do DPPH, sendo que as frações acetato de etila e butanólica das folhas demonstraram excelente atividade com CI50 de 20,40 μg/ml e 25,41 μg/ml, respectivamente. O teor de quercetina (0,19%) foi dosado no extrato das folhas através de cromatografia líquida de alta eficiência. A fração hexânica das folhas apresentou-se altamente tóxica frente a Artemia salina com uma CL50 de 1,27 μg/ml.Mirabilis jalapa (Nyctaginaceae), popularly known in Brazil as "bonina" or "maravilha", is popularly used to treat infections, inflammations and pains. The crude extract ethanolic (70%) was prepared by maceration and fractionated with organic solvents of increasing polarity (hexane, dichloromethane, ethyl acetate and butanol). The best answer to the antimicrobial activity were obtained for Staphylococcus aureus with the dichloromethane fraction and Saccharomyces cerevisiae with ethyl acetate fraction. The extracts and fractions showed antioxidant activity by the method of DPPH, where the leaf ethyl acetate and butanol fractions showed excellent antioxidant activity with IC50 of 20.40 μg/ml and 25.41 μg/ml, respectively. The content of quercetin (0,19%) was determined in extracts from the leaves of liquid chromatography with high efficiency. The leaf hexanic fraction proved to be highly toxic front of Artemia salina with a LC50 of 1.27 μg/ml.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Data on the effects of losartan on protein expression, vascular reactivity and antioxidant capacity in the aorta of ethanol-treated rats

We describe the effects of losartan, a selective AT1 receptor antagonist on the alterations induced by treatment with ethanol in the rat aorta. The data shown here are related to the article entitled “Angiotensin type 1 receptor mediates chronic ethanol consumption-induced hypertension and vascular oxidative stress” (P. Passaglia, C.S. Ceron, A.S. Mecawi, J. Antunes-Rodrigues, E.B. Coelho, C.R. Tirapelli, 2015) [1]. Here we include new data on the protective effect of losartan against ethanol-induced oxidative stress. Male Wistar rats treated for 2 weeks with ethanol (20%, vol./vol.) exhibited increased aortic production of reactive oxygen species (ROS) and losartan (10 mg/kg/day; p.o. gavage) prevented this response. Ethanol did not alter the expression of eNOS in the rat aorta. Losartan prevented ethanol-induced increase in the aortic expression of nNOS. Neither ethanol nor losartan affected superoxide dismutase (SOD) or catalase (CAT) activities in the rat aorta. Treatment with ethanol increased the contraction induced by phenylephrine in both endothelium-intact and endothelium-denuded aortas and these responses were prevented by losartan. Conversely, neither ethanol nor losartan affected the endothelium-dependent relaxation induced by acetylcholine

Atorvastatin and sildenafil lower blood pressure and improve endothelial dysfunction, but only atorvastatin increases vascular stores of nitric oxide in hypertension

Nitric oxide (NO)-derived metabolites including the anion nitrite can recycle back to NO and thus complement NO formation independent of NO synthases. While nitrite is as a major vascular storage pool and source of NO, little is known about drugs that increase tissue nitrite concentrations. This study examined the effects of atorvastatin or sildenafil, or the combination, on vascular nitrite concentrations and on endothelial dysfunction in the 2 kidney-1 clip (2K1C) hypertension model. Sham-operated or 2K1C hypertensive rats were treated with vehicle, atorvastatin (50 mg/Kg), sildenafil (45 mg/Kg), or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Nitrite concentrations were assessed in the aortas and in plasma samples by ozone-based reductive chemiluminescence assay. Aortic rings were isolated to assess endothelium-dependent and independent relaxation. Aortic NADPH activity and ROS production were evaluated by luminescence and dihydroethidium, respectively, and plasma TBARS levels were measured. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. Atorvastatin and sildenafil, alone or combined, significantly lowered SBP by approximately 40 mmHg. Atorvastatin significantly increased vascular nitrite levels by 70% in hypertensive rats, whereas sildenafil had no effects. Both drugs significantly improved the vascular function, and decreased vascular NADPH activity, ROS, and nitrotyrosine levels. Lower plasma TBARS concentrations were found with both treatments. The combination of drugs showed no improved responses compared to each drug alone. These findings show evidence that atorvastatin, but not sildenafil, increases vascular NO stores, although both drugs exert antioxidant effects, improve endothelial function, and lower blood pressure in 2K1C hypertension

Consistent alterations of circulating matrix metalloproteinases levels in untreated hypertensives and in spontaneously hypertensive rats : a relevant pharmacological target

Inconsistent matrix metalloproteinases (MMPs) levels have been reported in hypertension, with higher, similar and lower MMPs levels reported in hypertensives compared with normotensives. Differences between studies may reflect lack of control of drug effects, accompanying diseases and pre‐analytical issues. We compared MMP‐2, MMP‐8 and MMP‐9 levels in 38 untreated hypertensive patients (with no other diseases) with those found in 33 normotensive controls. We also studied endogenous MMPs inhibitors (TIMP‐1, TIMP‐2 and alpha‐2‐macroglobulin‐A2M). Additionally, we assessed MMPs and A2M levels in spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto (WKY) rats. We hypothesized that similar MMPs/endogenous inhibitors’ profiles would be found in this animal model of hypertension and in clinical hypertension. MMPs, TIMPs and A2M were measured in plasma samples with commercially available ELISA and gelatin zymography. We found unaltered MMP‐2, MMP‐8, TIMP‐1, TIMP‐2 and A2M levels in hypertension. However, hypertensives had higher MMP‐9 levels and MMP‐9/A2M ratios than normotensives. Moreover, while we found similar MMP‐2 and A2M levels in SHR and WKY rats, we found higher MMP‐9 levels and MMP‐9/A2M ratios in SHR versus WKY rats. These findings show consistent abnormal net plasma MMP‐9 (but not MMP‐2) activity in clinical and experimental hypertension. These parallel alterations in clinical hypertension and in SHR suggest an important role for MMPs in hypertension. While MMPs may be a relevant pharmacological target, antihypertensive drugs that down‐regulate MMPs may offer advantages in the management of this disease1092130137CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPNão temNão te