Mercury-induced vascular dysfunction is mediated by angiotensin II AT-1 receptor upregulation.

Low doses of mercury (Hg) promote deleterious effects on cardiovascular system, but the mechanisms implicated remain unclear. This study analyzed whether angiotensin II AT-1 receptors are involved in the vascular dysfunction caused by chronic exposure to low HgCl2 doses. For this, rats were divided into four groups and untreated (saline by im injections and tap water by gavage) or treated for 30 days as follows: Mercury (HgCl2im, first dose of 4.6 µg kg-1 and subsequent doses of 0.07 µg kg-1 day-1, and tap water by gavage); Losartan (saline im and losartan, 15 mg kg-1 day-1, by gavage); Losartan-Mercury (HgCl2im and Losartan by gavage). Systolic blood pressure was measured by tail plethysmography, vascular reactivity in aorta by isolated organ bath, oxidative stress by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and antioxidant capacity (FRAP) and protein expression of AT-1 receptors by Western Blot. As results, co-treatment with losartan prevented the increased aortic vasoconstrictor responses to phenylephrine (Phe), the involvement of ROS and prostanoids on the response to Phe and the reduced negative endothelial modulation by nitric oxide on these responses. Moreover, this co-treatment avoided the increase in plasmatic and vascular oxidative stress and AT-1 protein expression in aorta. In conclusion, these results suggest that AT-1 receptors upregulation might play a key role in the vascular damage induced by Hg exposure by increasing oxidative stress and probably by reducing NO bioavailability.

Reproductive dysfunction after mercury exposure at low levels: evidence for a role of glutathione peroxidase (GPx) 1 and GPx4 in male rats.

Mercury is a ubiquitous environmental pollutant and mercury contamination and toxicity are serious hazards to human health. Some studies have shown that mercury impairs male reproductive function, but less is known about its effects following exposure at low doses and the possible mechanisms underlying its toxicity. Herein we show that exposure of rats to mercury chloride for 30 days (first dose 4.6µgkg-1, subsequent doses 0.07µgkg-1day-1) resulted in mean (±s.e.m.) blood mercury concentrations of 6.8±0.3ngmL-1, similar to that found in human blood after occupational exposure or released from removal of amalgam fillings. Even at these low concentrations, mercury was deposited in reproductive organs (testis, epididymis and prostate), impaired sperm membrane integrity, reduced the number of mature spermatozoa and, in the testes, promoted disorganisation, empty spaces and loss of germinal epithelium. Mercury increased levels of reactive oxygen species and the expression of glutathione peroxidase (GPx) 1 and GPx4. These results suggest that the toxic effects of mercury on the male reproductive system are due to its accumulation in reproductive organs and that the glutathione system is its potential target. The data also suggest, for the first time, a possible role of the selenoproteins GPx1 and GPx4 in the reproductive toxicity of mercury chloride.

Ouabain induces nitric oxide release by a PI3K/Akt-dependent pathway in isolated aortic rings from rats with heart failure.

BACKGROUND: Ouabain occurs in nanomolar concentrations in myocardial infarction and heart failure (HF). However, the effects of ouabain in vascular function in HF conditions were not investigated yet. Therefore, we analyzed the effects of acute administration of 3 nM ouabain in isolated aortic rings from rats with HF 4 weeks after myocardial infarction. METHODS AND RESULTS: Rats were submitted to sham operation or coronary artery occlusion. In HF rats, left ventricular positive and negative derivatives of intraventricular pressure reduced and left ventricular end diastolic pressure increased. Phenylephrine responses increased in HF rings when compared with controls. Ouabain incubation for 45 minutes reduced phenylephrine-induced contraction in both groups. Endothelial removal increased more phenylephrine response in ouabain-treated rings of sham rats. Ouabain potentiated the effect of L-NAME in both groups but more in sham rats. Wortmannin increased the phenylephrine response only in HF rings. The effect of tetraethylammonium was potentiated by ouabain only in HF rings. Ouabain increased phenylephrine-stimulated nitric oxide production in rings from both groups but increased the activation of Akt only in vessels from HF rats. CONCLUSIONS: Results demonstrate that low ouabain concentration can decrease vascular reactivity of aortic rings from HF rats. Ouabain was able to increase nitric oxide production in HF rats by triggering a signal transduction PI3K/Akt-dependent pathway and increasing an endothelium-hyperpolarizing factor release.

Flaxseed oil increases aortic reactivity to phenylephrine through reactive oxygen species and the cyclooxygenase-2 pathway in rats.

BACKGROUND: Flaxseed oil has the highest concentration of omega-3 α-linolenic acid, which has been associated with cardiovascular benefit. However, the mechanism underlying the vascular effects induced through flaxseed oil is not well known. Thus, in the present study, we investigated the effects of flaxseed oil on vascular function in isolated rat aortic rings. METHODS: Wistar rats were treated daily with flaxseed oil or a control (mineral oil) intramuscular (i.m.) for fifteen days. Isolated aortic segments were used to evaluate cyclooxygenase-2 (COX-2) protein expression, superoxide anion levels and vascular reactivity experiments. RESULTS: Flaxseed oil treatment increased the vasoconstrictor response of aortic rings to phenylephrine. Endothelium removal increased the response to phenylephrine in aortic segments isolated from both groups, but the effect was smaller in the treated group. L-NAME incubation similarly increased the phenylephrine response in segments from both groups. The TXA2 synthase inhibitor furegrelate, the selective COX-2 inhibitor NS 398, the TP receptor antagonist SQ 29.548, the reactive oxygen species (ROS) scavenger apocynin, the superoxide anion scavengers tiron and the phospholipase A2 inhibitor dexamethasone partially reversed the flaxseed oil-induced increase in reactivity to phenylephrine. CONCLUSIONS: These findings suggest that flaxseed oil treatment increased vascular reactivity to phenylephrine through an increase in ROS production and COX-2-derived TXA2 production. The results obtained in the present study provide new insight into the effects of flaxseed oil treatment (i.m.) on vascular function.

Chronic exposure to low doses of mercury impairs sperm quality and induces oxidative stress in rats.

Mercury (Hg) is a widespread environmental pollutant that adversely affects the male reproductive system. The precise mechanisms underlying mercuric chloride (HgCl2)-induced toxicity are not fully understood; however, evidence indicates that oxidative stress may be involved in this process. Although the adverse effects of high levels of inorganic Hg on the male reproductive system have been investigated, the effects of low levels of exposure are unknown. Therefore, the aim of this study was to investigate the effects of chronic exposure to low concentrations of HgCl2 on sperm parameters, lipid peroxidation, and antioxidant activity of male rats. Three-month-old male Wistar rats were treated for 30 d and divided into groups: control (saline, i.m.) and HgCl2 group (i.m., first dose 4.6 µg/kg, subsequent doses 0.07 µg/kg/d). Sperm parameters (count, motility and morphology) and biomarkers of oxidative stress in testis, epididymis, prostate, and vas deferens were analyzed. Mercury treatment produced a reduction in sperm quantity (testis and epididymis) and daily sperm production, following by decrease in sperm motility and increase on head and tail morphologic abnormalities. HgCl2 exposure was correlated with enhanced oxidative stress in reproductive organs, represented not only by augmented lipid peroxidation but also by changes in antioxidant enzymes activity superoxide dismutase (SOD) and catalase (CAT) and nonprotein thiol levels. In conclusion, chronic exposure to low doses of Hg impaired sperm quality and adversely affected male reproductive functions, which may be due, at least in part, to enhanced oxidative stress.

Myocardial contractility is preserved early but reduced late after ovariectomy in young female rats.

BACKGROUND: Ovarian sex hormones (OSHs) are implicated in cardiovascular function. It has been shown that OSHs play an important role in the long term regulation of cardiac sarcoplasmic reticulum (SR) function and contractility, although early effects of OSHs deprivation on myocardial contractility have not yet been determined. This study evaluated the early and late effects of OSHs deficiency on left ventricular contractility in rats after ovariectomy. METHODS: Young female Wistar rats were divided into 3 groups (n=9-15): sham operated (Sham), ovariectomized (Ovx) and Ovx treated with estradiol (1 mg/kg, i.m., once a week) (Ovx+E2). After 7, 15, 30 and 60 days post Ovx, left ventricle papillary muscle was mounted for isometric tension recordings. The inotropic response to Ca2+ (0.62 to 3.75 mM) and isoproterenol (Iso 10-8 to 10-2 M) and contractility changes in response to rate changes (0.25 to 3 Hz) were assessed. Protein expression of SR Ca2+-ATPase (SERCA2a) and phospholamban (PLB) in the heart was also examined. RESULTS: The positive inotropic response to Ca2+ and Iso at 7, 15, and 30 days after Ovx was preserved. However, at 60 days, the Ovx group had decreased myocardial contractility which was subsequently restored with E2 replacement. The reduction in SERCA2a and increase in PLB expression observed at 60 days after Ovx were restored with E2 replacement. CONCLUSION: This study demonstrated that myocardial contractility and expression of key Ca2+ handling proteins were preserved in the early phase and reduced at long-term during OSHs deprivation.

Chronic HgCl(2) treatment increases vasoconstriction induced by electrical field stimulation: role of adrenergic and nitrergic innervation.

In the present study, we have investigated the possible changes in rat mesenteric artery vascular innervation function caused by chronic exposure to low doses of HgCl(2) (mercuric chloride), as well as the mechanisms involved. Rats were divided into two groups: (i) control, and (ii) HgCl(2)-treated rats (30 days; first dose, 4.6 µg/kg of body weight; subsequent dose, 0.07 µg·kg-1 of body weight·day-1, intramuscularly). Vasomotor response to EFS (electrical field stimulation), NA (noradrenaline) and the NO donor DEA-NO (diethylamine NONOate) were studied, nNOS (neuronal NO synthase) and phospho-nNOS protein expression were analysed, and NO, O(2)- (superoxide anion) and NA release were also determined. EFS-induced contraction was higher in the HgCl(2)-treated group. Phentolamine (1 µmol/l) decreased the response to EFS to a greater extent in HgCl(2)-treated rats. HgCl(2) treatment increased vasoconstrictor response to exogenous NA and NA release. L-NAME (N(G)-nitro-L-arginine methyl ester; 0.1 mmol/l) increased the response to EFS in both experimental groups, but the increase was greater in segments from control animals. HgCl(2) treatment decreased NO release and increased O(2)- production. Vasodilator response to DEA-NO was lower in HgCl(2)-treated animals. Tempol increased DEA-NO-induced relaxation to a greater extent in HgCl(2)-treated animals. nNOS expression was similar in arteries from both experimental groups, whereas phospho-nNOS was decreased in segments from HgCl(2)-treated animals. HgCl(2) treatment increased vasoconstrictor response to EFS as a result of, in part, reduced NO bioavailability and increased adrenergic function. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

Bioactive Peptides and Hydrolysates from Egg Proteins as a New Tool for Protection Against Cardiovascular Problems.

The aim of the present work is to review the potential beneficial effects of dietary supplementation with bioactive egg protein hydrolysates or peptides on cardiometabolic changes associated with oxidative stress. The development of nutritionally improved food products designed to address specific health concerns is of particular interest because many bioactive food compounds can be potentially useful in various physiological functions such as for reducing oxidative stress. The results presented suggest that egg hydrolysates or derived peptides could be included in the diet to prevent and/or reduce some cardiometabolic complications associated with oxidative stress-related diseases.

Endothelium: A Target for Harmful Actions of Metals.

The use of heavy metals is closely linked to the history of mankind. They have been used as important materials in a wide variety of human activities such as manufacturing utensils and tools. Such extended use has significantly increased professional and environmental exposure to mercury, lead and cadmium. These metals are known to produce hypertension in humans and animals and, among other effects, they can also affect endothelial function. Results described here suggest that mercury, lead and cadmium affect vascular reactivity, even at low doses or concentrations. Several vascular actions are mediated by the endothelium via increasing the production of free radicals and angiotensin II by local ACE stimulation. These results provide further evidence that these toxic metals, even at low doses, are an environmental risk factor to the exposed population. These results also suggest that continuous exposure to these metals, followed by their absorption and progressive accumulation in the body, may be hazardous to cardiovascular function. Therefore, the current reference values, which are considered safe, need to be reduced.

Deleterious effects of chronic mercury exposure on in vitro LTP, memory process, and oxidative stress.

Heavy metal contamination in aquatic environments plays an important role in the exposure of humans to these toxicants. Among these pollutants, mercury (Hg) is one main concern due to its high neurotoxicity and environmental persistence. Even in low concentrations, Hg bioaccumulation is a major threat to human health, with higher impact on populations whose diet has fish as chief consumption. Mercury compounds have high affinity for neuronal receptors and proteins, which gives Hg its cumulative feature and have the ability to cross cell membranes and blood-brain barrier to show their neurotoxicity. Intoxication with Hg increases levels of reactive oxygen species (ROS), thus depleting faster the resource of antioxidant proteins. To evaluate Hg-induced hippocampal ROS production, synaptic plasticity, anxiety, and memory, a total of 11 male Wistar rats were exposed to HgCl2 (Hg30 group) to produce a residual concentration of 8 ng/mL at the end of 30 days. Behavioral tests (plus-maze discriminative avoidance task), in vitro electrophysiology, and ROS assays were performed. Western blot assay showed decreased levels of antioxidant proteins GPx and SOD in Hg30 group. Increased ROS production was observed in the CA1 and CA3 regions in the Hg-exposed group. Plus-maze task detected long-term memory impairment in Hg30 group, linked to poorer in vitro long-term potentiation as compared to control group. Hg intoxication also promoted higher anxiety-like behavior in the exposed animals. In conclusion, our data suggests that low doses of HgCl2 resulted in impaired long-term memory and unbalance between decreased antioxidant protein expression and increased ROS production in the hippocampus.

Activation of BKCa channels by nitric oxide prevents coronary artery endothelial dysfunction in ouabain-induced hypertensive rats.

OBJECTIVE: Chronic-ouabain administration to rats induces hypertension and increases the endothelial modulation of vasoconstrictor responses. The aim of this study was to analyze whether ouabain-treatment affects the mechanisms involved in endothelium-dependent relaxation of coronary arteries. METHODS: Coronary arteries from control and ouabain-treated rats (approximately 8.0 microg/day, 5 weeks) were used. Vascular reactivity was analyzed by isometric tension recording and membrane currents were measured using the whole-cell configuration of the patch-clamp technique. RESULTS: In 5-hydroxytryptamine (5-HT) precontracted arteries, acetylcholine (ACh, 1 nmol/l-10 micromol/l) induced a similar relaxant response in coronary arteries from both groups that was abolished by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (100 micromol/l). However, when arteries were contracted with high KCl (60 mmol/l) or preincubated with the large-conductance Ca2+-activated K+ (BKCa) channels-blocker iberiotoxin (0.1 micromol/l), the relaxation elicited by ACh was more reduced in ouabain-treated than control rats. After iberiotoxin preincubation, the relaxant response of the nitric-oxide donor, DEA-NO (10 nmol/l-100 micromol/l) was significantly inhibited in ouabain-treated coronary arteries but not in control vessels. The soluble guanylyl cyclase activator BAY 41-2272 (10 nmol/l-30 micromol/l) induced relaxant responses that were inhibited by iberiotoxin. In coronary-artery myocytes isolated from ouabain-treated rats DEA-NO (1 micromol/l) markedly increased the amplitude of the iberiotoxin-sensitive current in the whole range of test potentials, compared with nontreated rats. CONCLUSION: Our results indicate that chronic ouabain treatment increases activation of BKCa currents by nitric oxide and this effect might contribute to preserve the endothelial function in coronary arteries in this hypertension model.

Mercury leads to features of polycystic ovary syndrome in rats.

Mercury (Hg) is a heavy metal and Hg exposure is associated with various neural, immune, and cardiovascular abnormalities. However, few studies have evaluated Hg's toxicologic effect on reproductive and metabolic functions. In this study, we assessed whether Hg exposure results in reproductive and metabolic abnormalities. Hg was administered to adult female Wistar rats, mimicking the Hg levels found in exposed human blood, and their reproductive and metabolic function was assessed. Rats exposed to Hg displayed abnormal estrous cyclicity and ovarian follicular development, with a reduction in ovarian antral follicles and an increase in atretic and cystic ovarian follicles. Uterine atrophy with the presence of inflammatory cells was observed in Hg-exposed rats. The presence of abnormal ovarian fat accumulation, as well as increased ovarian lipid drops accumulation, was observed in Hg-exposed rats. Ovarian oxidative stress was also present in the Hg-exposed rats. High fasting glucose levels, glucose, and insulin intolerance were observed in Hg-exposed rats. Thus, these data suggest that Hg exposure led to abnormal reproductive and metabolic features similar to those found in the polycystic ovary syndrome (PCOS) rat models.

Impaired participation of potassium channels and Na+ /K+ -ATPase in vasodilatation due to reduced nitric oxide bioavailability in rats exposed to mercury.

Mercury intoxication is a public health risk factor due to its hazardous effect to several organs, including the cardiovascular system. There is evidence of endothelial dysfunction after exposure to mercury, but the effects on endothelium-dependent vasodilatation are still unknown. In the present study, we aimed to evaluate the chronic effects of high HgCl2 doses on the mechanisms of vasodilatation. Wistar rats were injected with HgCl2 (1st dose 10.86 µg/kg, and daily doses 0.014 µg/kg for 30 days i.m.), and saline was used as control. Mercury exposure reduced the acetylcholine-induced vasodilatation in aortic rings, which was restored by incubation with antioxidant tiron. Inhibition of the NO synthase, Na+ /K+ -ATPase and K+ channels indicates reduced participation of these factors. In the mercury group, there were an increased local anion superoxide and a reduced NO. The vasodilatation to exogenous NO was partially inhibited by co-incubation with TEA plus tiron, suggesting that reduced NO bioavailability is the responsible to that decreased the participation of K+ channels. Moreover, there was an increased participation of the Na+ /K+ -ATPase associated with an up-regulation of its alpha-1 subunit. In conclusion, reduced NO bioavailability plays a major role in the impaired participation of K+ channels and Na+ /K+ -ATPase in the acetylcholine-mediated relaxation, although sodium pump is up-regulated probably as a compensatory mechanism.

Chronic ouabain treatment enhances cardiac myosin ATPase activity in rats.

1. Chronic ouabain administration increases blood pressure and produces a positive inotropic effect. However, the temporal changes capable of affecting both arterial and ventricular pressures and myosin ATPase activity during the induced hypertension have not been determined. 2. The aim of the present study was to investigate the time-course of the induction of hypertension to define when changes occur in Wistar rats treated with 25 mg/kg per day, s.c., ouabain for 3, 7, 15 or 30 days. 3. In anaesthetized rats, diastolic blood pressure increased after 7 days treatment with ouabain and after 15 and 30 days treatment, increases were observed in systolic blood pressure, left ventricular systolic pressure and myosin ATPase activity. After 15 days treatment, heart rate (HR) also increased, but after 30 days treatment HR returned to control levels. However, only after 30 days treatment did the left ventricular positive and negative first derivatives of intraventricular pressure (dP/dt(max) and dP/dt(min), respectively) increase. Increased arterial and left ventricular systolic pressures and myosin ATPase activity observed after 15 days treatment maintained similar levels as those after 30 days treatment. 4. The results suggest that changes in arterial and left ventricular pressures, HR and myosin ATPase activity induced by chronic ouabain treatment are time dependent, increasing after 15 days treatment. After 30 days treatment, the increase in systolic and diastolic arterial and ventricular pressures remained stable, as did inotropism. Normalization of HR after 30 days treatment suggests that during the period from Day 16 to Day 30 ouabain-induced hypertension is dependent, at least in part, on increased sympathetic activity.

Preliminary Studies of Acute Cadmium Administration Effects on the Calcium-Activated Potassium (SKCa and BKCa) Channels and Na+/K+-ATPase Activity in Isolated Aortic Rings of Rats.

Cadmium is an environmental pollutant closely linked with cardiovascular diseases that seems to involve endothelium dysfunction and reduced nitric oxide (NO) bioavailability. Knowing that NO causes dilatation through the activation of potassium channels and Na+/K+-ATPase, we aimed to determine whether acute cadmium administration (10 µM) alters the participation of K+ channels, voltage-activated calcium channel, and Na+/K+-ATPase activity in vascular function of isolated aortic rings of rats. Cadmium did not modify the acetylcholine-induced relaxation. After L-NAME addition, the relaxation induced by acetylcholine was abolished in presence or absence of cadmium, suggesting that acutely, this metal did not change NO release. However, tetraethylammonium (a nonselective K+ channels blocker) reduced acetylcholine-induced relaxation but this effect was lower in the preparations with cadmium, suggesting a decrease of K+ channels function in acetylcholine response after cadmium incubation. Apamin (a selective blocker of small Ca2+-activated K+ channels-SKCa), iberiotoxin (a selective blocker of large-conductance Ca2+-activated K+ channels-BKCa), and verapamil (a blocker of calcium channel) reduced the endothelium-dependent relaxation only in the absence of cadmium. Finally, cadmium decreases Na+/K+-ATPase activity. Our results provide evidence that the cadmium acute incubation unaffected the calcium-activated potassium channels (SKCa and BKCa) and voltage-calcium channels on the acetylcholine vasodilatation. In addition, acute cadmium incubation seems to reduce the Na+/K+-ATPase activity.

Aluminum Exposure at Human Dietary Levels for 60 Days Reaches a Threshold Sufficient to Promote Memory Impairment in Rats.

Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control-received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control-received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal.

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation.

1. The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg-1 day-1, s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2. Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of Nomega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 microM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3. Neither losartan (10 microM) nor indomethacin (10 microM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml-1) and L-arginine (5 mM), but neither catalase (300 U ml-1) nor apocynin (100 microM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4. In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO-mediated negative modulation even in the presence of high NO production and antioxidant defence.

Effects of high sodium intake diet on the vascular reactivity to phenylephrine on rat isolated caudal and renal vascular beds: Endothelial modulation.

High salt intake is involved in the genesis of hypertension and vascular changes in salt-sensitive patients. Although many mechanisms have been proposed, the underlying mechanisms of these alterations in healthy rats are not completely elucidated. The aim of this study was to investigate if male Wistar rats fed a high salt diet, NaCl 1.8% in drinking water for 4 weeks, develop changes in the pressor reactivity of isolated tail and renal vascular beds. Salt treatment increased mean arterial pressure (SALT = 124 +/- 2.2 vs. CT = 111 +/- 3.9 mmHg; p < 0.01) and urinary sodium excretion in the absence of changes in sodium plasma levels. Pressor reactivity was generated in isolated tail and kidney vascular beds as dose-response curves to phenylephrine (PHE = 0.01 to 300 microg). SALT increased the reactivity (E(max): SALT = 378 +/- 15.8 vs. CT = 282 +/- 10 mmHg; p < 0.01) without changing the sensitivity (pD(2)) to PHE in the tail vascular bed. However, these parameters did not change in the renal bed. In subsequent studies on the isolated caudal vascular bed, we found that endothelial damage, but not L-NAME (100 microM) or indomethacin (10 microM), abolished the increment in E(max) to PHE induced by SALT. On the other hand, losartan (100 microM) reduced E(max) in SALT to CT values. Additionally, local angiotensin-converting enzyme activity in segments from tail artery increased by 95%. In conclusion, 4 weeks of high salt diet increases blood pressure and induces specific territorial vascular changes in response to PHE. Results also suggest that the increment in E(max) in the tail vascular bed from SALT rats was endothelium-dependent and was mediated by the activation of the local renin-angiotensin system.

Ouabain-induced hypertension enhances left ventricular contractility in rats.

Chronic ouabain treatment produces hypertension acting on the central nervous system and at vascular levels. However, cardiac effects in this model of hypertension are still poorly understood. Hence, the effects of hypertension induced by chronic ouabain administration ( approximately 8 microg day(-1), s.c.) for 5 weeks on the cardiac function were studied in Wistar rats. Ouabain induces hypertension but not myocardial hypertrophy. Awake ouabain-treated rats present an increment of the left ventricular systolic pressure and of the maximum positive and negative dP/dt. Isolated papillary muscles from ouabain-treated rats present an increment in isometric force, and this effect was present even when inotropic interventions (external Ca(2+) increment and increased heart rate) were performed. However, the sarcoplasmic reticulum activity and the SERCA-2 protein expression did not change. On the other hand, the activity of myosin ATPase increased without changes in myosin heavy chain protein expression. In addition, the expression of alpha(1) and alpha(2) isoforms of Na(+), K(+)-ATPase also increased in the left ventricle from ouabain-hypertensive rats. The present results showed positive inotropic and lusitropic effects in hearts from awake ouabain-treated rats, which are associated with an increment of the isometric force development and of the activity of myosin ATPase and expression of catalytic subunits of the Na(+), K(+)-ATPase.

Blood Pressure Decreases Following Lead Treatment Cessation: Highest NO Bioavailability Involved.

Although lead is known to induce arterial hypertension and vascular damage, it is not clear if after cessation of lead treatment, the increase of blood pressure is sustained and the vascular function is different from untreated rats. Therefore, we aimed to evaluate the systolic blood pressure during and following lead-treatment discontinuance and the possible vascular alterations involved with it. Rats received lead acetate (100 mg/L) in the drinking water or distilled water for 14 days. After 14 days, lead acetate solution was substituted by water distilled for more 28 days, as control group. Systolic blood pressure (SBP) was measured weekly by tail plethysmography, and the vascular reactivity to phenylephrine in isolated aortic rings was evaluated at end of treatment time. The increase in SBP induced by lead was reversed after stopping exposure, and it was accompanied by a reduction on vasoconstrictor response to phenylephrine. L-NAME treatment increased the phenylephrine response in both groups, but its effect was greater in lead group. Our findings provide evidence that the increased modulation by NO on contractile response to phenylephrine could be a compensatory mechanism that might contribute to decrease blood pressure after lead treatment cessation.