Preeclampsia pravastatin early VS late treatment: Effects on oxidative stress and vascular reactivity.

Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative stress. There is evidence that statins show antioxidant effects that can improve endothelial function without adverse perinatal effects. We aimed to compare early vs. late pravastatin treatment on the oxidative stress and cardiovascular features of an experimental model of preeclampsia. Female Wistar rats were randomly divided into preeclampsia phenotype rats (PEP) developed by sub renal aortic coarctation (SRAC) and healthy pregnant rats (C). Each group received pravastatin (5 mg/Kg) p.o. either for one week before and during the first week or during the last two weeks of gestation. Blood pressure was determined using the plethysmographic method. Phenylephrine (Phe)-induced contractility was evaluated in isolated thoracic and abdominal aortic rings with or without endothelium. Blood samples were obtained to determine anion superoxide concentration as indicator of NADPH activity. Two-way ANOVA and Bonferroni post hoc tests were used to define statistical significance. Early or late pravastatin treatment decreased hypertension of PEP animals but did not change BP of the healthy pregnant group. Thoracic and abdominal aorta from PEP rats showed increased contractility that was reverted by pravastatin early treatment in endothelium intact rings. Pravastatin did not significantly change contractility neither in the thoracic nor in the abdominal aorta segments from healthy pregnant control rats (C), and decrease anion superoxide concentration by NADPH activity. We conclude pravastatin can improve both blood pressure and endothelium-dependent Phe-induced contractility in an experimental model of preeclampsia by reducing oxidative stress.

Impact of Normal and Overweight Pregnancy in GLUT4 and Glucose-Dependent Vascular Contractility.

INTRODUCTION: Obesity during pregnancy can contribute to hypertensive complications through changes in glucose utilization. We investigated the impact of vascular glucose uptake, GLUT4 density, and endothelium on agonist-induced vasoconstriction in the aortas of overweight pregnant rats. METHODS: Isolated aortic rings with or without endothelium from pregnant or nonpregnant rats fed a standard (SD) or hypercaloric diet (HD) were contracted with phenylephrine or serotonin (10-9 to 10-4M) using standard (11 mm) or without (0 mm) glucose Krebs solution. GLUT4 density in the aortas was measured using the en face method. RESULTS: Aortas from overweight pregnant animals (PHD) showed increased Phe-induced vasoconstriction (p < 0.05 vs. pregnant standard diet [PSD]), which was endothelium-independent. The contraction decreased significantly in the absence of glucose. In contrast, vessels from pregnant SD rats maintained their contraction in glucose-free Krebs solution. 5-HT increases PHD aortic contraction only in the absence of glucose. The fetal aortas from PHD mothers showed blunted vasoconstriction. Overweight significantly reduced GLUT4 expression in maternal and fetal aortas (p < 0.05 vs. PSD). CONCLUSIONS: Aortic contractility is independent of glucose uptake during healthy pregnancy. In contrast, overweight pregnancy increases contractility. This increase depends directly on smooth muscle glucose uptake and inversely on GLUT-4 density. The increased contraction observed in the vasculature of overweight mothers was inverted in the fetal aortas.

AT1R antagonism improves metabolic and vascular changes of obesity-induced gestational diabetes mellitus.

Obesity can overload glucose homeostasis and physiological insulin resistance during gestation which increases the risk of complications like diabetes mellitus or preeclampsia. Angiotensin II /AT1 receptors are involved in the pathogenesis of vascular effects of obesity/insulin resistance but its role during gestation is not as clear. We sought to determine angiotensin II- AT1R participation on a diet-induced gestational diabetes mellitus (GDM) experimental model. Female Wistar rats were fed with a standard or hypercaloric diet for 7 weeks. Half of the animals were mated and became pregnant from week 4-7. Animals were treated with saline, irbesartan (30 mg/kg) or metformin (320 mg/kg) for the last two weeks of the protocol. Weight gain, systolic blood pressure (BP), oral glucose tolerance test and vascular contractility were measured at the last day of the protocol (day 19-20 of pregnancy). Hypercaloric diet increased blood glucose, impaired glucose tolerance test, and increased BP in pregnant rats, fulfilling criteria for GDM. Both drugs decreased impaired GTT and relative hyperglycemia. Metformin had no effect on BP but prevented weight increase. In isolated aortas, irbesartan and metformin decreased vasoconstriction only of non-pregnant hypercaloric diet fed animals. Results support angiotensin II/ AT1R involvement in BP and glucose homeostasis disturbances observed in present GDM model. Also, provide evidence that a hypercaloric diet can mask pregnancy´s physiological hypoglycemia and hypotension without surpassing non-pregnant values. Then, we conclude overweight during pregnancy causes subtle but significant vascular and metabolic damage that might be dismissed in clinical practice.

Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-related Liver Diseases and Hepatocellular Carcinoma.

BACKGROUND: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs. Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

Beneficial effects of phycobiliproteins from Spirulina maxima in a preeclampsia model.

AIMS: Considering phycobiliproteins of Spirulina maxima has shown a wide margin of security in pregnant and non-pregnant animals as well as antioxidant properties, present study aimed to investigate if the cardiovascular and metabolic effects of an experimental model of preeclampsia can be prevented by the administration of this compound. MAIN METHODS: Subrenal aortic coarctation (SRAC) practiced to female Wistar rats of 8 weeks of age. Animals were divided randomly to conform non-pregnant and pregnant groups and pregnant with SRAC showed fetoplacental ischemia and were considered preeclamptic (PE). Groups were treated with saline solution (control group) or phycobiliproteins solution (100 mg/kg/day ig) for the last 7, 14 or 20 days of pregnancy. KEY FINDINGS: PE animals showed increased systolic blood pressure, weight gain, glucose and GTT as well as vascular contractility. Also, PE animals showed decreased SOD, GPx activities while MDA was increased. Phycobiliproteins oral treatment for 3 weeks significantly decreased systolic blood pressure and reestablished glucose, weight gain and vascular contractility as well as enzyme activities of PE rats to those of normal pregnant animals. SIGNIFICANCE: Our results show that phycobiliproteins can prevent the damage produced by fetoplacental ischemia and provides evidence of free radical species contribution to the physiopathology of the disease. Also, we conclude phycobiliproteins can be an alternative to reduce preeclampsia manifestations, however, more studies are recommended.

Time course of angiotensin II dependent vascular and metabolic effects of preeclampsia.

Pregnancy is characterized by a blunted pressor response to angiotensin II that is progressively lost during preeclampsia complicated pregnancies. Renin angiotensin system (RAS) plays a pivotal role in cardiovascular and renal function but its role in normal and pathological pregnancy is far from being clarified. It is not as clear if hypertension and particularly pregnancy-induced hypertension as the initial event, can trigger some of the metabolic syndrome components, and if these changes are angiotensin II mediated. The aim of this study was to determine the time course of angiotensin II contribution to the vascular and eventual metabolic changes of preeclampsia. An experimental model was developed by reducing feto-placental circulation through a subrenal aorta coarctation before pregnancy in rats. Control and pregnant (preeclamptic) animals were treated with captopril (5mg/kgpo) or saline solution for 21, 14 or 7days before delivery, and their body weight, plasma glucose andblood pressure were registered. Phenylephrine (Phe) induced contraction was evaluated using isolated aorta rings. Preeclampsia increased blood pressure (2nd and 3rd wk) but also weight (3rd wk) and glucose values (2nd and 3rd week). Captopril (for 21 or 14days) treatment prevented increases in blood pressure and plasma glucose but not in body weight. Also, captopril treatment significantly increased aorta contractility. These results provide evidence that cardiovascular and metabolic disturbances of preeclampsia appear simultaneously and are angiotensin II dependent.

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p < 0.01 hypercaloric diet vs standard diet) in the presence of both prazosin and losartan but only in endothelium-intact vessels. Diet-induced obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p < 0.05 vs standard diet). Seven-week hypercaloric diet-induced obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

Oxychlorine species suppress postsurgical adhesions in rats.

BACKGROUND: Surgically induced adhesions complicate up to 100% of abdominal surgeries. Food and Drug Administration-approved treatments are generally not only less effective than desired but they also have major contraindications. Oxychlorine species, including chlorine dioxide (ClO2), suppress scar formation in infected wounds without affecting keratinocytes while reducing fibroblast proliferation. The aim of the present study was to evaluate the effect of oxychlorine solutions containing ClO2 on adhesion formation. METHODS: Male Wistar rats were subjected to Buckenmaier model of surgical adhesions and treated with either oxychlorine solutions containing ClO2 (40-150 ppm) or isotonic saline solution. To increase the severity of adhesions, peritonitis was produced by intraperitoneal administration of a diluted nonlethal dose of feces (50 mg/kg). Wound strength of the healed wound was measured to evaluate the effects of oxychlorine solutions. In addition, an oxychlorine solution of lesser efficacy (at 100 ppm) was compared with three available anti-adhesion materials. RESULTS: Reproducibility of the model was validated in 26 rats. Oxychlorine solutions containing ClO2 (40-110 ppm) significantly reduced postsurgical adhesion formation without affecting the strength of the healed wound. Higher concentrations (120 and 150 ppm) had no effect. Fecal peritonitis significantly increased, and solutions with ClO2 at 110 ppm significantly reduced adhesion formation. The effect of the oxychlorine solution was significantly greater than that of Interceed, Guardix, Seprafilm, and isotonic saline solution. CONCLUSIONS: ClO2-containing oxychlorine solutions could be an innovative strategy for the suppression of surgical adhesion formation, with the additional advantage of contributing antiseptic properties.

Effect of pregnancy and diabetes on vascular receptors for angiotensin II.

Both gestation and diabetes mellitus (DM) are conditions associated with an increased participation of renin-angiotensin system (RAS) as well as with changes in the vascular response to angiotensin II (Ang II). We sought to establish the impact of gestational diabetes mellitus (GDM) on Ang II- induced vasoconstriction and its correlation with the expression of angiotensin II receptors (AT(1)R, AT(2) R). Female Wistar rats, virgin, or on day 3 after mating, received randomly streptozotocin (STZ) 60 mg/kgor saline ip.Streptozotocin-treated animals developed hyperglycemia (25.6 ± 1.42 mM). Ang II-induced vasoconstriction was evaluated on isolated aortas with (e+) and without (e-) endothelium and the protein expression of AT(1)R and AT(2)R was measured by western blot. Gestational diabetes mellitus significantly increased vasoconstriction with respect to all the other groups. Changes were observed only on e+ vessels. Interestingly, GDM moved AT(1)R: AT(2)R balance towards AT(1) R, while both pregnancy and diabetes towards AT(2)R expression. In conclusion, GDM increases the possibility of an hypertensive complication by an increased AT(1)R expression.

Angiotensin-II-dependent changes in alpha-1 adrenoceptor vascular expression in pregnant rats.

Vessels from pregnant animals show a blunted response to adrenergic agonists. In this work, we explored if pregnancy reduces alpha(1)-adrenergic receptor (alpha(1)-AR)-mediated vascular smooth muscle protein expression as well as agonist-induced contraction in rat aorta, and if angiotensin II (Ang II) levels during pregnancy are related to these changes. Female Wistar rats were divided randomly into nonpregnant (NP) and pregnant groups (first week: P1, second week: P2, third week: P3). Subsets of animals were treated with captopril (5 mg kg(-1) day(-1) for 7 days; n = 6). Phenylephrine (PHE) concentration-response curves were constructed (1 x 10(-9) to 3.1 x 10(-5) mol/l) and alpha(1A)-, alpha(1B)- and alpha(1D)-AR were measured in the aorta by immunoblot. Captopril decreased alpha-AR expression in the NP group. In contrast, pregnancy decreased alpha(1A)-, alpha(1B)- and alpha(1D)-AR levels and captopril prevented this reduction. PHE sensitivity was decreased in the thoracic and abdominal aorta in the P2 group, with no changes in E(max ), and E(max) was decreased in the abdominal aorta in all experimental groups. Our results suggest that Ang II levels during pregnancy are related to a decrease in aortic alpha(1)-AR expression. The physiological meaning of this finding remains to be established.

Increased alpha-1 adrenoceptor expression in pregnant rats with subrenal aortic coarctation.

UNLABELLED: The progression of pregnancy is associated with attenuation in vasopressor response to adrenergic agonists. In pregnancy-induced hypertension this attenuation is reverted. It is not known if this reversion involves alpha-1 adrenoceptor expression. OBJECTIVE: In this work we propose that in pregnant rats with subrenal aortic coarctation there are changes in the expression of alpha-1 adrenergic receptors in the thoracic and abdominal aorta during pregnancy. METHODS: We used non-pregnant, normal pregnant and pregnant with subrenal aortic coarctation female Wistar rats. Pregnancy-induced hypertension indicators, systolic blood pressure, 24 hours proteinuria, pup weight and maternal weight were measured. Dose response curves to phenylephrine were carried out to determine vascular reactivity along pregnancy. Alpha 1-adrenoceptors were detected from thoracic and abdominal aorta using immunoblot. RESULTS: Results show significant increases in arterial pressure and proteinuria in pregnant rats with SRAC at the end of the third week. Pregnancy reduces alpha-(1-A, -B) and (-D) adrenoceptor expression and this event is reverted by subrenal aortic coarctation. This phenomenon is more apparent in the abdominal segment of the aorta. CONCLUSIONS: These findings suggest that subrenal aortic coarctation is a good animal model of pregnancy-induced hypertension and that alpha1-adrenoceptors participate in its physiopathology increasing their expression in a segment-dependent manner.

Renal angiotensin-II receptors expression changes in a model of preeclampsia.

The blunted response to angiotensin II (Ang II) during pregnancy is lost in patients by preeclampsia. This impaired response has been attributed to a change in one or both of the Ang II receptors, type 1 (AT(1)R) and type 2 (AT(2)R). The ratio of the Ang II receptor types in the kidney has not been studied. We postulated that an imbalance exists between AT(1)R/AT(2)R receptors in the renal cortex from rats subjected to an experimental model of preeclampsia, and that this altered ratio can modify the characteristic blunted pressor response to Ang II during pregnancy. The feto-placental units of Wistar rats were made ischemic by subrenal aortic coarctation, thus creating an experimental model of preeclampsia. We measured the AT(1)R and AT(2)R protein expression and the presence of the heterodimer AT(1)R/AT(2)R in the renal cortex and evaluated the pressor response to Ang II in an isolated kidney preparation from non-pregnant, healthy pregnant, and preeclampsia model rats. Pregnancy increased AT(2)R and AT(1)R/AT(2)R heterodimer expression and decreased the pressor response to Ang II. In contrast, AT(1)R increased, while AT(2)R and AT(1)R/AT(2)R heterodimer decreased in the preeclampsia model group. Thus, Ang II hypersensitivity observed in preeclampsia might be related to an increased expression of AT(1)R over AT(2)R and to a decreased presence of the AT(1)R/AT(2)R heterodimer in renal cortex.

Vasoactive properties of antidepressant N-alkyl derivatives.

Hypotension is a principal side effect of antidepressant therapy. In addition to serotonin and noradrenalin reuptake inhibition, some antidepressants have shown ion channel interactions which are thought to be related to the vascular effects of these agents. Methylation of the pharmacophore has shown to change the pharmacological properties of a variety of compounds. The purpose of this work was to evaluate whether methylation of the amino group of imipramine (TCA's) and fluoxetine (SSRI) could change their vasodilator properties. N-methyl imipramine (NMI), N-methyl fluoxetine and (NMF) N-N dimethyl fluoxetine (NNDF) were synthesized and compared with desipramine (DES), imipramine (IMI) and fluoxetine (F) in their ability to relax rat aortic rings pre-contracted with 80mM KCl using an isolated bath preparation. Drugs were evaluated in thoracic aorta rings with and without endothelium. All compounds displayed a vasorelaxant effect. Endothelium-denuded aortic rings showed an increased relaxant response for IMI and derivatives compared with endothelium-intact vessels, while no endothelium-dependent effect was observed with F and its methyl derivatives. Maximal relaxant potency was displayed by dimethylated derivatives (IMI and NMF), while NMI in the TCA series and NNDF in the SSRI series (both with 3 methyl groups), had the least potency to relax either preparation. Endothelium plays an important role inhibiting the vasodilatation induced by IMI and its derivatives. Vascular relaxation is increased in the compounds tested with 2 methyl groups in their structure, while the presence of 3 methyl groups (positive charge) importantly reduced the relaxant potency.