We investigated long-lasting changes in endothelial and vascular function in adult rat survivors of severe sepsis induced by cecal ligation and puncture (CLP) model. For this, male Wistar rats (200–350 g) had their cecum punctured once (non-transfixing hole) with a 14-gauge needle. Performed in this way, a mortality rate around 30% was achieved in the first 72 h. The survivors, together with age-matched control rats (not subjected to CLP), were maintained in our holding room for 60 days (S60 group) and had the descending thoracic aorta processed for functional, histological, biochemical or molecular analyses. Endothelium-intact aortic rings obtained from sepsis-surviving S60 group displayed increased angiotensin II-induced contraction, accompanied by decreased activity of the endogenous superoxide dismutase, augmented reactive oxygen species generation, and increased levels of tyrosine nitration compared with vessels from control group. The superoxide scavengers superoxide dismutase and tempol, and the antioxidant apocynin, were able to avoid this enhanced contractility to angiotensin II in aortic rings from the S60 group. In addition, aortic rings from the S60 group presented reduced sensitivity to Y-27632, a Rho-kinase (ROCK) inhibitor. Immunoblot analyses revealed augmented RhoA and ROCK II, and high levels of phosphorylation of myosin phosphatase target subunit 1 in vessels from S60 rats. In conclusion, aortic rings from sepsis-surviving rats display endothelial dysfunction mediated by the increased production of reactive oxygen species, which in turn reduces the bioavailability of nitric oxide and increases the formation of peroxynitrite, and enhances RhoA-ROCK-mediated calcium sensitization, leading to augmented contractile responses to angiotensin II. Notably, this is the first study demonstrating long-term dysfunction in the vasculature of sepsis-surviving rats, which take place or remain beyond the acute septic insult.

Our data suggest that activation of Rho-kinase potentiates the vascular effects of vasopressin in the kidneys, contributing to the maintenance of the hypertensive effects of this agent during septic shock.

The aim of the present study was to investigate the existence of gender-related differences in the profile of changes that occur in cardiac functionality during endotoxic shock. For this, both male and female Wistar rats received a single injection of lipopolysaccharide (LPS; 10 mg/kg, i.p.) at 6 h (LPS 6-h group) or 24 h (LPS 24-h group) before the induction of anesthesia and insertion of a pressure-volume catheter using the closed-chest method. Control animals received sterile saline. Hemodynamic parameters were recorded under basal conditions and during the peak of the pressor effect of phenylephrine (30 nmol/kg i.v.). Body temperature, hematologic parameters, blood glucose, and diuresis were also evaluated. There were unremarkable differences between male and female rats in the general aspects of sepsis evaluated in our study. Both male and female rats from the LPS 6-h group presented hypotension, depressed left ventricular ejection fraction, decreased stroke work, reduced dP/dtmax (maximal rate of left ventricle pressure change), P@dP/dtmax (pressure value at the maximum dP/dtmax), dP/dtmin (minimal rate of left ventricle pressure change), and preload-recruitable stroke work indices, as well as increased end-systolic volume. Nevertheless, only male rats from the LPS 24-h group still presented decreased stroke work and reduced dP/dtmax, P@dP/dtmax, and preload-recruitable stroke work indices. The end-systolic volume presented slight changes during the pressor effects of phenylephrine in all groups of male rats, as well as in females from the control and LPS 6-h groups, but it was significantly increased in females from the LPS 24-h group. These findings suggest that after induction of endotoxic shock female rats may recover the inotropic cardiac function earlier than males, as well as present improved adaptation of their left ventricle to the pressure-loading effects of phenylephrine.

BackgroundExtracellular superoxide dismutase (ECSOD) protects nitric oxide (NO) bioavailability by decreasing superoxide levels and preventing peroxynitrite generation, which is important in maintaining renal blood flow and in preventing acute kidney injury. However, the profile of ECSOD expression after sepsis is not fully understood. Therefore, we intended to evaluate the content and gene expression of superoxide dismutase (SOD) isoforms in the renal artery and their relation to renal blood flow.MethodsSepsis was induced in Wistar rats by caecal ligation and perforation. Several times after sepsis induction, renal blood flow (12, 24 and 48 h); the renal arterial content of SOD isoforms, nitrotyrosine, endothelial and inducible nitric oxide synthase (e-NOS and i-NOS), and phosphorylated vasodilator-stimulated phosphoprotein (pVASP); and SOD activity (3, 6 and 12 h) were measured. The influence of a SOD inhibitor was also evaluated.ResultsAn increase in ECSOD content was associated with decreased 3-nitrotyrosine levels. These events were associated with an increase in pVASP content and maintenance of renal blood flow. Moreover, previous treatment with a SOD inhibitor increased nitrotyrosine content and reduced renal blood flow.ConclusionsECSOD appears to have a major role in decreasing peroxynitrite formation in the renal artery during the early stages of sepsis development, and its application can be important in renal blood flow control and maintenance during septic insult.

RESUMO:A utilização de plantas medicinais sempre foi bem difundida, porém hoje se faz necessária uma abordagem científica para comprovar sua eficácia. Este estudo foi realizado para avaliar a possível toxicidade materna e teratogenicidade do óleo de copaíba, um óleo resina exudado do tronco de Copaifera langsdorfii, muito utilizado na medicina natural. Três doses de óleo de copaíba, administradas por gavage durante 5 dias do período gestacional de fêmeas de camundongos, foram testadas 0,3 mL Kg -1 , 0,6 mL Kg -1 e 0,9 mL Kg -1 (p.c.). Em relação ao ganho de peso materno, peso dos órgãos, número de fetos vivos e implantes e viabilidade fetal, não houve diferença estatística entre os grupos. Os dados demonstram que este fitoterápico não apresenta toxicidade materna. Com relação às médias de peso e comprimento fetal dos grupos tratados, houve diferença estatística quando comparados ao controle, mas os fetos ainda se encontravam dentro do peso adequado à idade de prenhez. A prole das fêmeas tratadas não apresentou malformações ou alterações externas, viscerais e esqueléticas. Os resultados deste estudo indicam que o óleo de copaíba, nas doses administradas e período estudado, não apresentou toxicidade materna ou causou teratogenicidade na prole das fêmeas tratadas. Portanto, podemos considerar seu uso seguro durante o período gestacional. Palavras-chave: Copaifera langsdorfii, plantas medicinais, toxicidade, teratogenicidade, gestaçãoABSTRACT: Copaiba oil (Copaifera langsdorfii Desf.) on mouse reproductive patterns and embryonic or fetal development. The use of medicinal plants has always been widely spread, but today a scientific approach is needed to prove their efficiency. The present study was performed to evaluate the possible maternal toxicity and teratogenicity of copaiba oil, a resin oil exudate from the trunk of Copaifera sp., extensively used in natural medicine. Three copaiba oil levels, administered through gavage for 5 days during the gestational period of female mice, were tested: 0.3 mL Kg -1 , 0.6 mL Kg -1 and 0.9 mL Kg -1 (b.w.). As regards maternal weight gain, organ weight, live fetus number, implants and fetal viability, there was no statistical difference among groups. Data indicate that this phytotherapic drug does not show maternal toxicity. Considering the means of fetal weight and length of treated groups, there was statistical difference when compared with the control group, but the fetuses were still within the appropriate weight to that pregnancy age. The offspring from treated females did not present external, visceral and skeletal alterations or malformations. The results from this study indicate that copaiba oil at the administered levels and studied period did not present maternal toxicity or cause teratogenicity to the offspring of treated females. Therefore, its use can be considered safe during pregnancy. INTRODUÇÃOO uso de plantas medicinais para tratamento, cura e prevenção de doenças tem sido descrito por muitos povos desde os tempos mais remotos. Devido a esse uso, surgiram in...