Ângela Castro Resende

Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension.

BACKGROUND Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K-1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects.

Involvement of nitric oxide in acute lung inflammation induced by cigarette smoke in the mouse

Short-term exposure to cigarette smoke (CS) leads to acute lung inflammation (ALI) by disturbing oxidant/antioxidant balance. Both CS exposure and lung inflammation are important risk factors in the pathogenesis of chronic obstructive pulmonary disease. Nitric oxide (NO) is an oxidant both present in CS and produced in the inflammatory response, but its role in the effects of CS exposure is unclear. Our aim was to study involvement of NO in a model of CS exposure. Groups of mice (male C57BL/6) exposed to CS (six cigarettes per day over five days) were simultaneously subjected to treatment with vehicle (CS), 60mg/kg/day omega-nitro-l-arginine methyl ester (CS+l-NAME), 20mg/kg/day nitroglycerine (CS+NTG), or 120mg/kg/day l-arginine (CS+l-arg). Bronchoalveolar lavage fluid was then aspirated to perform cell counts, and malondialdehyde (MDA), nitrite, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were measured in lung homogenates. Macrophage and neutrophil counts were increased in the CS (p<0.001) and CS+l-NAME groups (p<0.05 and p<0.01, respectively); the CS+NTG and CS+l-arg groups showed no differences from the control group. MDA was increased in the CS (p<0.05) and CS+l-NAME (p<0.01) groups when compared to the control group. Nitrite levels were decreased in the CS and CS+l-NAME groups (p<0.001) and increased in the CS+NTG (p<0.001) and CS+l-arg (p<0.01) groups when compared to the control. CAT, SOD and GPx activities in the CS and CS+l-NAME groups were all significantly increased compared to the control group. Our results suggest that administration of NO donors or substrates may be a useful therapy in the treatment of ALI caused by CS.

L -arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia

Pre-eclampsia (PE), a syndrome of pregnancy-induced hypertension, continues to be a leading cause of maternal and fetal morbidity and mortality. The aim of this study was to investigate whether changes in oxidative status are correlated with alterations in the L-arginine-nitric oxide pathway and platelet aggregation in PE. Plasma and platelets from women with PE (n=24) or normotensive pregnancy (NP, n=27) recruited in the third trimester of gestation were used to measure oxidative damage assessed by protein carbonyl content, antioxidant activities of superoxide dismutase (SOD), catalase (CAT) and nitrite levels. Transport of L-[3H]-arginine, as well as the activities of the nitric oxide (NO) synthase (eNOS and inducible NO synthase (iNOS)) and platelet aggregation, were also evaluated. Plasma nitrite levels and the activities of SOD and CAT were reduced in PE (5.2±2.7, 3.4±0.8, 0.3±0.4, respectively, P<0.05) compared with NP (8.7±2.3, 6.7±3.1, 1.0±0.5, respectively), whereas protein carbonyl content and L-arginine levels were not significantly different between PE and NP groups. In platelets, L-arginine transport was reduced in PE (19.2±10.5, P<0.05) compared with NP (62.0±31.1), whereas the NOS activity, eNOS and iNOS expression, nitrite levels and platelet aggregation were unaffected. Protein carbonyl content was increased, and CAT activity was reduced in platelets from PE (0.03±0.02, 0.55±0.30, respectively, P<0.05), compared with NP (0.005±0.005, 1.01±0.36, respectively). The data suggest that a systemic impairment of antioxidant defense mechanisms is associated with decreased plasma nitrite levels, which may contribute to hypertension in PE. Oxidative stress may contribute to the reduced influx of L-arginine in platelets. Compensatory mechanisms may contribute to the maintenance of NO production and its modulatory role on platelet function.

Relaxant Effects of Sildenafil on the Human Isolated Bladder Neck

OBJECTIVE To evaluate potential in vitro relaxant actions of sildenafil on human isolated bladder neck smooth muscle. METHODS Bladder neck strips were sampled from patients (aged 55-77 years) submitted to prostatic surgery (6 adenomectomies and 1 radical prostatectomy). These were carefully dissected into 1-2 x 0.5-cm pieces and suspended in an organ bath containing 30 mL of a modified Krebs Henseleit solution, bubbled with 95% O(2)/5% CO(2). After tissue stabilization and viability test with KCl, the tissue was precontracted with phenylephrine, and a concentration-response relaxant curve to sildenafil was constructed. The effect of sildenafil was also assessed in tissues treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (inhibitors of nitric oxide synthase and guanylyl cyclase, respectively). RESULT Sildenafil induced significant bladder neck relaxation at all concentrations tested. The maximum relaxation was 86.97% +/- 6.69%, obtained with a high concentration of sildenafil (5.1 x 10(-4) M). Both L-NAME and ODQ significantly reduced sildenafil-induced relaxation. CONCLUSIONS Sildenafil was effective in inducing bladder neck smooth muscle relaxation in vitro. This effect was almost abolished by L-NAME and ODQ, clearly demonstrating a dependence of the nitric oxide-cyclic guanosine monophosphate pathway. Our in-vitro results suggest that sildenafil might be useful in improving lower urinary tract symptoms due to benign prostatic hyperplasia.

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice

Objectives  This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin‐signalling cascade in alloxan‐treated mice.

Role of the NO-cGMP pathway in the systemic antinociceptive effect of clonidine in rats and mice

The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.

Protective action of a hydroalcoholic extract of a vinifera grape skin on experimental preeclampsia in rats.

Objective: This study was designed to determine the protective effects of a vinifera grape skins extract (GSE, 200 mg/kg/day) on the deleterious effect observed in experimental preeclampsia, a condition where reduced nitric oxide production and increase in oxidative stress are present. Methods: A condition similar to preeclampsia was induced by chronic inhibition of nitric oxide synthesis by L-NAME (60 mg/kg/day, orally) in pregnant rats. Blood pressure (systolic, mean and diastolic) was measured with the tail cuff method on day 20 of pregnant control rats; pregnant rats treated with L-NAME, L-NAME plus GSE or GSE from day 13 to day 20 of pregnancy. Glucose was infused in anesthetized pregnant rats at day 20 and blood glucose and insulin were estimated at time zero, 15, 30, 45 and 60 minutes after beginning of glucose infusion. The number of fetus alive was also estimated at day 20 of pregnancy. In parallel, blood pressure was measured in non-pregnant and in non-pregnant rats treated with L-NAME during 7 days. Results: Increase in arterial pressure, reduction of alive fetus at the end of pregnancy and increase in insulin resistance was observed in pregnant L-NAME rats but not in pregnant L-NAME plus GSE rats or in pregnant GSE rats. Increase in arterial pressure was also observed in non-pregnant L-NAME rats. Conclusion: The present study demonstrated a protective effect of GSE in experimental preeclampsia since the deleterious effect induced by L‐NAME that is, increased in stillbirth, hypertension and insulin resistance were significantly reduced by oral treatment with the extract. Probably an endothelium-dependent vasodilator effect and an antioxidant action play an important role on the effects of GSE in experimental preeclampsia.

Cardiovascular and Metabolic Effects of Açaí, an Amazon Plant.

Abstract: Despite being used for a long time as food and beverage by Brazilian people who live on the Amazon bay, only in the beginning of this century, açaí berries have been the object of scientific research. Açaí berries are rich in polyphenols that probably explains its versatile pharmacological actions and huge consumption, not only in Brazil but also in Europe and United States. In this review, not all but some pharmacological aspects of açaí berries are analyzed. Chemical and pharmacological differences between extracts obtained from the skin and seed of açaí are considered. Polyphenols from the seed of açaí increase endothelial nitric oxide production leading to endothelium-dependent relaxation, reduce reactive oxygen species and regulate key targets associated with lipid metabolism in different conditions such as hypertension, renal failure, and metabolic syndrome. We review the novel mechanisms of actions of açaí on different targets which could trigger the health benefits of açaí such as antioxidant, vasodilator, antihypertensive, cardioprotector, renal protector, antidyslipidemic, antiobesity, and antidiabetic effects in cardiovascular and metabolic disturbances.

Inhibitory effect of sildenafil on the human isolated seminal vesicle

To investigate the effects of sildenafil on noradrenaline‐ and potassium‐induced contractions of isolated human seminal vesicles (SVs), as premature ejaculation is a relatively common male sexual dysfunction that currently lacks an adequate therapy, and recent in vitro tests showed that sildenafil induces relaxation of rodent isolated SVs, but it is not known whether it also inhibits isolated human SV.

Role of renin–angiotensin system and oxidative status on the maternal cardiovascular regulation in spontaneously hypertensive rats

BACKGROUND The purpose of this study was to investigate the contribution of renin-angiotensin system (RAS) and oxidative status on the maternal cardiovascular regulation at the end of pregnancy in normotensive and spontaneously hypertensive rats (SHR). METHODS Blood pressure (BP), mesenteric arterial bed (MAB) reactivity, mesenteric oxidative damage, protein expression, and antioxidant activities were compared between four groups: SHR (SHR-P) and normotensive Wistar controls (W-P) in the 20th day of pregnancy or age-matched nonpregnant rats (SHR-NP and W-NP). RESULTS BP in W-P and SHR-P was reduced at the end of pregnancy. The vasodilator effects of angiotensin II (Ang II) and angiotensin 1-7 (Ang-(1-7)) were higher in SHR-P than in other groups. Endothelial nitric oxide synthase (eNOS) expression was increased in W-P and SHR-P compared to nonpregnant groups. Angiotensin-converting enzyme (ACE) and AT(1) receptor expressions were increased in SHR-NP compared to normotensive groups and pregnancy reduced their expressions in SHR. No difference was observed in AT(2) receptor expression among the groups. ACE2 expression was higher in hypertensive than normotensive groups. The levels of thiobarbituric acid-reactive substances (TBARS) were reduced in pregnant compared to nonpregnant groups. Superoxide dismutase (SOD) activity was reduced in SHR-P compared to SHR-NP. However, pregnancy increased catalase (CAT) and glutathione peroxidase (GPx) activities in normotensive rats and SHR, respectively. CONCLUSIONS The results suggest that the reduction of BP to normal values at the end of pregnancy in SHR may be related to an increased NO production and vasorelaxation to Ang II and Ang-(1-7) associated with decreased expression of vascular ACE and AT(1) receptors and oxidative status.