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1.
Life Sci ; 319: 121526, 2023 Apr 15.
Article in English | MEDLINE | ID: mdl-36828130

ABSTRACT

Perivascular adipose tissue (PVAT) exerts anticontractile effect, but under non-physiological conditions it may contribute to vascular dysfunction by releasing pro-inflammatory cytokines. Since PVAT is an important source of interleukin (IL)-6, we evaluated whether this cytokine would contribute to ethanol-induced vascular dysfunction. With this purpose, male C57BL/6 wild-type (WT) or IL-6-deficient mice (IL-6-/-) were treated with ethanol for 12 weeks. Increased blood pressure was evidenced after 4 and 6 weeks of treatment with ethanol in WT and IL-6-/- mice, respectively. In WT mice, ethanol increased plasma and PVAT levels of IL-6. Ethanol favoured pro-contractile phenotype of PVAT in mesenteric arteries from WT, but not IL-6-deficient mice. Functional studies showed that tiron [(a scavenger of superoxide (O2-)] reversed the pro-contractile effect of PVAT in mesenteric arteries from ethanol-treated mice. Ethanol increased the levels of O2- in PVAT from WT mice. Ethanol-induced increase in O2- generation was higher in arteries with PVAT from WT mice when compared to IL-6-deficient mice. Treatment with ethanol augmented myeloperoxidase activity in the mesenteric arterial bed (MAB; with or without PVAT) from WT, but not IL-6-deficient mice. In conclusion, IL-6 contributes to the pro-contractile effect of PVAT by a mechanism that involves increase in ROS generation. Additionally, IL-6 mediates intravascular recruitment of neutrophils in response to ethanol and plays a role in the early stages of ethanol-induced hypertension. Collectively, our findings provide novel evidence for a role of IL-6 in the vascular dysfunction induced by ethanol.


Subject(s)
Interleukin-6 , Obesity , Male , Mice , Animals , Interleukin-6/pharmacology , Mice, Inbred C57BL , Mesenteric Arteries , Phenotype , Ethanol/toxicity , Adipose Tissue
2.
Curr Hypertens Rev ; 18(2): 125-129, 2022.
Article in English | MEDLINE | ID: mdl-36508270

ABSTRACT

Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects. The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects. Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca2+. Regarding oxidative stress, O2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages. In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.


Subject(s)
Cannabidiol , Cannabinoids , Humans , Cannabidiol/adverse effects , Antioxidants/pharmacology , Antioxidants/therapeutic use , Hydrogen Peroxide/pharmacology , Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Oxidative Stress
3.
Cardiovasc Toxicol ; 21(3): 224-235, 2021 03.
Article in English | MEDLINE | ID: mdl-33067693

ABSTRACT

Changes in redox state are described in the early stages of ethanol-induced cardiac toxicity. Here, we evaluated whether nebivolol would abrogate ethanol-induced redox imbalance in the heart. Male Wistar rats were treated with a solution of ethanol (20% v/v) for 3 weeks. Treatment with nebivolol (10 mg/kg/day; p.o. gavage) prevented the increase of both superoxide (O2•-) and thiobarbituric acid reactive substances (TBARS) in the left ventricle of rats chronically treated with ethanol. Neither ethanol nor nebivolol affected the expression of Nox4, p47phox, or Rac-1. Nebivolol prevented ethanol-induced increase of Nox2 expression in the left ventricle. Superoxide dismutase (SOD) activity as well as the concentration of reduced glutathione (GSH) was not altered by ethanol or nebivolol. Augmented catalase activity was detected in the left ventricle of both ethanol- and nebivolol-treated rats. Treatment with nebivolol, but not ethanol increased eNOS expression in the left ventricle. No changes in the activity of matrix metalloproteinase (MMP)2 or in the expressions of MMP2, MMP9, and tissue inhibitor metalloproteinase (TIMP)1 were detected after treatment with ethanol or nebivolol. However, ethanol increased the expression of TIMP2, and this response was prevented by nebivolol. Our results provided novel insights into the mechanisms underlying the early stages of the cardiac injury induced by ethanol consumption. We demonstrated that Nox2/NADPH oxidase-derived ROS play a role in ethanol-induced lipoperoxidation and that this response was prevented by nebivolol. In addition, we provided evidence that MMPs are not activated in the early stages of ethanol-induced cardiac toxicity.


Subject(s)
Cardiomyopathy, Alcoholic/prevention & control , Heart Ventricles/drug effects , Lipid Peroxidation/drug effects , Myocytes, Cardiac/drug effects , NADPH Oxidase 2/metabolism , Nebivolol/pharmacology , Superoxides/metabolism , Animals , Cardiomyopathy, Alcoholic/enzymology , Cardiomyopathy, Alcoholic/etiology , Cardiomyopathy, Alcoholic/pathology , Catalase/metabolism , Disease Models, Animal , Ethanol , Heart Ventricles/enzymology , Heart Ventricles/pathology , Male , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Nitric Oxide Synthase Type III/metabolism , Rats, Wistar , Tissue Inhibitor of Metalloproteinase-2/metabolism , Up-Regulation
4.
Can J Physiol Pharmacol ; 99(7): 744-751, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33175570

ABSTRACT

We tested the hypothesis that ethanol consumption would aggravate the renal damage induced by cyclophosphamide (CYP). Male C57BL/6 J mice from control (n = 8) and CYP (n = 12) groups had free access to filtered water and standard rodent chow for 12 weeks. Then, 24 h before euthanasia mice received an intraperitoneal injection of saline or CYP (300 mg/kg). Mice from ethanol (n = 8) and CYP + ethanol (n = 12) groups had free access to increasing doses of ethanol for 12 weeks. Twenty-four hours before euthanasia, mice from ethanol and CYP + ethanol groups received an intraperitoneal injection of saline or CYP, respectively. Ethanol, CYP, or the association of both drugs augmented serum levels of creatinine and increased the levels of superoxide ([Formula: see text]) generation and thiobarbituric acid reactive substances in the renal cortex. Upregulation of Nox4 and increased activity of superoxide dismutase were detected in the renal cortex of mice treated with ethanol, CYP, or the combination of these drugs; however, these molecular alterations induced by CYP were not potentiated by ethanol consumption. Our findings revealed that chronic ethanol consumption had no potentiating effect on the nephrotoxic effects displayed by CYP. It is possible that the combination of these drugs showed no synergistic effect because they share the same molecular mechanisms of renal toxicity.


Subject(s)
Ethanol , Animals , Cyclophosphamide , Male , Mice , Superoxides
5.
Life Sci ; 242: 117239, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-31901444

ABSTRACT

AIMS: Reactive oxygen species (ROS) and pro-inflammatory cytokines play a critical role in organ damage induced by ethanol consumption. Interleukin (IL)-10 maintain tissue homeostasis through restriction of excessive inflammatory responses and inhibition of ROS generation. These responses limit unnecessary tissue damage in the cardiorenal system. We hypothesized that IL-10 would limit the deleterious effects induced by ethanol consumption in the cardiorenal system. MATERIALS AND METHODS: Male C57BL/6J wild-type (WT) or IL10-deficient mice (IL-10-/-) were treated with ethanol (20% v/v) for 6 weeks. KEY FINDINGS: IL-10 deficiency was associated with an increased mortality rate. Ethanol consumption decreased plasma levels of IL-10 in WT mice. Increased levels of IL-6 were detected in the aorta from IL-10-deficient mice, but not WT mice. No alterations in the levels of urea, creatinine, sodium, potassium or creatine kinase (CK)-MB were found after treatment with ethanol. Augmented concentration of thiobarbituric acid reactive substances (TBARS) was found in the left ventricle (LV) of IL-10-deficient mice, but not WT mice. Increased levels of superoxide anion (O2-) were found in the renal cortex of both WT and IL-10-deficient mice. Renal cortex from WT mice chronically treated with ethanol showed decreased levels of H2O2. No changes in the expression of Nox1, Nox4 or catalase were found in the renal cortex from ethanol-treated mice. SIGNIFICANCE: IL-10 limited the production of ROS and the synthesis of pro-inflammatory cytokines induced by ethanol in the cardiorenal system. These findings provided novel evidence that IL-10 counteracted the initial mechanisms whereby ethanol induces its cardiorenal damages.


Subject(s)
Ethanol/adverse effects , Heart/drug effects , Interleukin-10/metabolism , Kidney/drug effects , Acute Kidney Injury/chemically induced , Animals , Blotting, Western , Creatine Kinase, MB Form/blood , Creatinine/blood , Interleukin-10/blood , Interleukin-10/physiology , Male , Mice , Mice, Inbred C57BL , Potassium/blood , Sodium/blood , Urea/blood
6.
Curr Hypertens Rev ; 16(3): 163-165, 2020.
Article in English | MEDLINE | ID: mdl-31038067

ABSTRACT

Reactive Oxygen Species (ROS) are reactive derivatives of oxygen metabolism. The ROS generation can be mediated by distinctive enzymatic systems including NADPH oxidases. The components of this enzyme are expressed in endothelial and vascular smooth muscle cells, adventitial fibroblasts, and infiltrating monocytes/macrophages. Oxidative stress is a molecular dysregulation in ROS generation/elimination, which plays a key role in the development of vascular dysfunction in distinctive conditions including hypertension. It is characterized by vascular inflammation, a loss of NO bioavailability and endothelial dysfunction. Considering that oxidative stress is a key mediator of vascular dysfunction, antioxidant therapy with classic antioxidants seemed to be a promising alternative for the treatment of vascular diseases. In this sense, some commonly used drugs for the treatment of cardiovascular diseases such as Angiotensin Converting Enzyme (ACE) inhibitors or angiotensin receptor AT1 antagonists showed antioxidant effects that might have contributed, at least in part, to the beneficial effects of these drugs on the treatment of cardiovascular diseases. The effectiveness of these drugs shows that ROS are in fact important mediators of vascular dysfunction and that angiotensin II plays a critical role in such response.


Subject(s)
Hypertension , NADPH Oxidases , Angiotensin II , Humans , NADPH Oxidases/metabolism , Oxidative Stress , Reactive Oxygen Species
7.
Stress ; 23(3): 328-337, 2020 05.
Article in English | MEDLINE | ID: mdl-31583926

ABSTRACT

We evaluate whether acute restraint stress may affect the oxidative state of the cardiorenal system and the possible contribution of angiotensin II/AT1 receptors in such response. Male Wistar rats were restrained for 60 min within wire mesh chambers. Some rats were treated with losartan (selective AT1 receptor antagonist, 10 mg/kg, p.o., gavage) 30 min before being stressed. Biochemical analyses were conducted after the 60-min period of restraint. Treatment with losartan prevented the increase in mean arterial pressure (MAP), but not heart rate (HR) induced by acute stress. Phenylephrine-induced contraction of endothelium-intact aortas was not affected by acute stress. Losartan prevented the increase in both superoxide anion (O2•-) and hydrogen peroxide (H2O2) levels induced by acute stress in the aorta and renal cortex. Similarly, the augmented activity of superoxide dismutase (SOD) induced by acute stress in the aorta and renal cortex was prevented by losartan. Enhanced levels of O2•- and thiobarbituric acid reactive species (TBARS) were detected in the left ventricle (LV) of stressed rats, but losartan did not prevent these responses. Similarly, losartan did not inhibited stress-induced decrease in the concentration of nitrate/nitrite (NOx) and H2O2 in the left ventricle. Stress increased ROS generation and affected the enzymatic antioxidant system in the cardiorenal system. In addition to its well-known cardiovascular changes during acute stress, angiotensin II also induces ROS generation in the cardiorenal system in a tissue-specific manner. The increase in oxidative stress mediated by angiotensin II/AT1 receptors could be one mechanism by which acute stress predisposes to cardiorenal dysfunctions.


Subject(s)
Hydrogen Peroxide , Stress, Psychological , Angiotensin II , Animals , Blood Pressure , Male , Oxidative Stress , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1/metabolism
8.
Nitric Oxide ; 94: 19-26, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31610241

ABSTRACT

Hypertension is a risk factor for erectile dysfunction (ED) and both conditions are associated with oxidative stress. Given that nitrite is described to display antioxidant effects, we hypothesized that treatment with nitrite would exert antioxidant effects attenuating both reactive oxygen species (ROS) generation in the corpora cavernosa (CC) and ED induced by hypertension. Two kidney, one clip (2K1C) hypertension was induced in male Wistar rats. Treatment with sodium nitrite (15 mg/kg/day, p.o., gavage) was initiated two weeks after surgery to induce hypertension and maintained for four weeks. Nitrite abrogated both the decrease in intracavernosal pressure and endothelial dysfunction of the CC induced by hypertension. Treatment with nitrite decreased hypertension-induced ROS generation in the CC assessed in situ using the fluorescent dye dihidroethidium (DHE) and with the lucigenin assay. Western immunoblotting analysis revealed that nitrite prevented the increase in Nox1 expression in the CC from 2K1C rats. Decreased concentrations of hydrogen peroxide (H2O2) were found in the CC from hypertensive rats and treatment with nitrite prevented this response. Treatment with nitrite increased the fluorescence of DAF-2DA in the CC from sham-operated rats and restored nitric oxide (NO) levels in the CC from 2K1C rats. In summary, we found novel evidence that nitrite reversed the decrease in intracavernosal pressure induced by 2K1C hypertension. This response was partially attributed to the antioxidant effect of nitrite that blunted ROS generation and endothelial dysfunction in the CC. In addition, nitrite-derived NO may have promoted direct protective actions against hypertension-induced CC dysfunction.


Subject(s)
Erectile Dysfunction/drug therapy , Hypertension/drug therapy , Penis/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Animals , Antihypertensive Agents , Antioxidants , Erectile Dysfunction/metabolism , Hypertension/metabolism , Male , Nitrites , Penis/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism
9.
Can J Physiol Pharmacol ; 97(12): 1103-1114, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31340131

ABSTRACT

Oxidative stress is pointed out as a major mechanism by which ethanol induces functional and structural changes in distinctive tissues. We evaluated whether ethanol consumption would increase oxidative stress and cause micturition dysfunction. Male C57BL/6J mice were treated with 20% ethanol (v/v) for 10 weeks. Our findings showed that chronic ethanol consumption reduced micturition spots and urinary volume in conscious mice, whereas in anaesthetized animals cystometric analysis revealed reduced basal pressure and increased capacity, threshold pressure, and maximum voiding. Treatment with ethanol reduced the contraction induced by carbachol in isolated bladders. Chronic ethanol consumption increased the levels of oxidant molecules and thiobarbituric acid reactive species in the mouse bladder. Upregulation of Nox2 was detected in the bladder of ethanol-treated mice. Increased activity of both superoxide dismutase and catalase were detected in the mouse bladder after treatment with ethanol. Conversely, decreased levels of reduced glutathione were detected in the bladder of ethanol-treated mice. The present study first demonstrated that chronic ethanol consumption induced micturition dysfunction and that this response was accompanied by increased levels of oxidant molecules in the mousebladder. These findings suggest that ethanol consumption is a risk factor for vesical dysfunction.


Subject(s)
Alcohol Drinking/physiopathology , Oxidative Stress , Urinary Bladder/physiopathology , Urination , Alcohol Drinking/metabolism , Alcohol Drinking/pathology , Animals , Body Weight , Catalase/metabolism , Gene Expression Regulation, Enzymologic , Glutathione/metabolism , Male , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Organ Size , Oxidation-Reduction , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Time Factors , Urinary Bladder/pathology
10.
Curr Hypertens Rev ; 15(1): 22-31, 2019.
Article in English | MEDLINE | ID: mdl-30227820

ABSTRACT

BACKGROUND: Beta-adrenergic receptors are expressed in cardiomyocytes and activated by either noradrenaline released from sympathetic synapses or circulating catecholamines. Their corresponding receptors have three subtypes, namely, ß1, ß2 and ß3, which are members of the G protein-coupled receptors (GPCRs) family. Activation of ß1-adrenergic receptors causes various physiological reactions including cardiac contraction and renin secretion from juxtaglomerular cells of the kidney. Antagonists of ß-adrenergic receptors, known as ß-blockers, have been used effectively for over four decades and have beneficial effects in the treatment of cardiovascular diseases. There are three generations of ß-blockers according to their pharmacological properties. Firstgeneration ß-blockers are non-selective, blocking both ß1- and ß2-receptors; second-generation ß- blockers are more cardioselective in that they are more selective for ß1-receptors; and thirdgeneration ß-blockers are highly selective drugs for ß1-receptors. The latter also display vasodilator actions by blocking α1-adrenoreceptors and activating ß3-adrenergic receptors. In addition, thirdgeneration ß-blockers exhibit angiogenic, antioxidant, anti-proliferative, anti-hypertrophic and antiapoptotic activities among other effects that are still under investigation. CONCLUSION: The objective of this review is to describe the evolution observed during the development of the three distinctive generations, thereby highlighting the advantages of third-generation ß- blockers over the other two drug classes.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Cardiovascular Agents/therapeutic use , Heart Diseases/drug therapy , Myocytes, Cardiac/drug effects , Receptors, Adrenergic, beta/drug effects , Adrenergic beta-Antagonists/adverse effects , Adrenergic beta-Antagonists/classification , Animals , Cardiovascular Agents/adverse effects , Cardiovascular Agents/classification , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/physiopathology , Humans , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Receptors, Adrenergic, beta/classification , Receptors, Adrenergic, beta/metabolism , Signal Transduction/drug effects , Treatment Outcome
11.
Vascul Pharmacol ; 111: 44-53, 2018 12.
Article in English | MEDLINE | ID: mdl-30157459

ABSTRACT

AIM: We investigated the consequences of acute ethanol intake on the anti-contractile effect of perivascular adipose tissue (PVAT). METHODS: The effects of a single dose of ethanol (1 g/kg; p.o. gavage) on the vascular function were assessed within 30 min in male Wistar rats. RESULTS: Ethanol decreased the relaxation induced by acetylcholine and increased the contraction induced by phenylephrine in endothelium-intact, but not in endothelium-denuded aortas without PVAT. The vascular dysfunction induced by ethanol was not observed in aortic rings with PVAT. Nω-Nitro-l-arginine methyl ester (L-NAME), NG-nitro-l-arginine (L-NNA) and 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but not tiron or tempol, increased the contraction induced by phenylephrine in endothelium-intact aortas with PVAT from control and ethanol-treated rats. Catalase increased phenylephrine-induced contraction in aortas with PVAT from ethanol-treated rats, but not from control rats. Conversely, inhibition of catalase with aminotriazole decreased phenylephrine-induced contraction in aortas from ethanol-treated rats. Treatment with ethanol increased hydrogen peroxide (H2O2) levels and decreased catalase activity in aortas with PVAT. Ethanol increased superoxide anion (O2-) generation in aortas with or without PVAT. Superoxide dismutase (SOD) activity was not affected by ethanol intake. In situ quantification of H2O2 using 2'7'dichlorodihydrofluorescein diacetate (DCFH-DA) revealed increased levels of H2O2 in periaortic PVAT from ethanol-treated rats. However, in situ evaluation of nitric oxide (NO) in both aorta and PVAT showed no differences between groups. CONCLUSIONS: Our study provides novel evidence that the periaortic PVAT protects against the vascular dysfunction induced by acute ethanol intake through a mechanism that involves increased generation of H2O2.


Subject(s)
Adipose Tissue/drug effects , Aorta/drug effects , Endothelium, Vascular/drug effects , Ethanol/toxicity , Hydrogen Peroxide/metabolism , Vasoconstriction/drug effects , Vasodilation/drug effects , Adipose Tissue/metabolism , Adipose Tissue/physiopathology , Animals , Aorta/metabolism , Aorta/physiopathology , Catalase/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Ethanol/administration & dosage , Male , Rats, Wistar , Signal Transduction/drug effects , Superoxide Dismutase/metabolism , Superoxides/metabolism , Up-Regulation
12.
Atherosclerosis ; 274: 67-76, 2018 07.
Article in English | MEDLINE | ID: mdl-29753230

ABSTRACT

BACKGROUND AND AIMS: Chronic ethanol consumption is associated with hypertension and atherosclerosis. Vascular oxidative stress is described as an important mechanism whereby ethanol predisposes to atherosclerosis. We hypothesized that nebivolol would prevent ethanol-induced hypertension and vascular oxidative stress. METHODS: Male Wistar rats were treated with ethanol 20% (vol./vol.) or nebivolol (10 mg/kg/day, p. o., gavage), a selective ß1-adrenergic receptor antagonist. RESULTS: Ethanol-induced increase in blood pressure and in the circulating levels of adrenaline and noradrenaline was prevented by nebivolol. Similarly, nebivolol prevented ethanol-induced increase in plasma levels of renin, angiotensin I and II. Chronic ethanol consumption increased the aortic levels of superoxide anion (O2-), thiobarbituric acid reactive species (TBARS) as well as the expression of Nox1 and nitrotyrosine immunostaining in the rat aorta. Treatment with nebivolol prevented these responses. The decrease in aortic levels of nitrate/nitrite (NOx) induced by ethanol was prevented by the treatment with nebivolol. Finally, nebivolol attenuated ethanol-induced increase in phenylephrine- and noradrenaline-induced contraction of endothelium-intact and endothelium-denuded aortic rings. CONCLUSIONS: The novelty of our study is that nebivolol prevented ethanol-induced hypertension and vascular oxidative stress. Additionally, we showed that the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) are important endogenous mediators of the cardiovascular effects of ethanol.


Subject(s)
Adrenergic beta-1 Receptor Antagonists/pharmacology , Antihypertensive Agents/pharmacology , Aorta, Thoracic/drug effects , Arterial Pressure/drug effects , Ethanol , Hypertension/prevention & control , Nebivolol/pharmacology , Oxidative Stress/drug effects , Animals , Aorta, Thoracic/innervation , Aorta, Thoracic/metabolism , Biomarkers/metabolism , Catalase/metabolism , Disease Models, Animal , Epinephrine/blood , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Lipid Peroxidation/drug effects , Male , NADPH Oxidases/metabolism , Nitric Oxide/metabolism , Norepinephrine/blood , Rats, Wistar , Renin-Angiotensin System/drug effects , Superoxide Dismutase/metabolism , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiopathology , Tyrosine/analogs & derivatives , Tyrosine/metabolism
13.
J Am Soc Hypertens ; 12(7): 561-573, 2018 07.
Article in English | MEDLINE | ID: mdl-29680225

ABSTRACT

We evaluated the possible mechanisms underlying the oxidative stress induced by ethanol withdrawal. With this purpose, we verified the role of AT1 receptors in such response. Male Wistar rats were treated with ethanol 3%-9% (vol./vol.) for 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 hours after ethanol discontinuation. Increased plasma levels of angiotensin II were detected after ethanol withdrawal. Losartan (10 mg/kg; p.o. gavage), a selective AT1 receptor antagonist, impeded the increase in blood pressure induced by ethanol withdrawal. Increased lipoperoxidation and superoxide anion (O2-) levels were detected in aortas after ethanol withdrawal, and losartan prevented these responses. Decreased hydrogen peroxide and nitrate/nitrite concentration were detected in aortas after ethanol withdrawal, and losartan prevented these effects. Nitrotyrosine immunostaining in the rat aorta was increased after ethanol withdrawal, and AT1 blockade impeded this response. Increased expression of PKCδ and p47phox was detected after ethanol withdrawal, and treatment with losartan prevented these responses. Our study provides novel evidence that ethanol withdrawal increases vascular oxidative stress and blood pressure through AT1-dependent mechanisms. These findings highlight the importance of angiotensin II in ethanol withdrawal-induced increase in blood pressure and vascular oxidative damage.

14.
Eur J Pharmacol ; 825: 39-47, 2018 Apr 15.
Article in English | MEDLINE | ID: mdl-29438701

ABSTRACT

We hypothesized that long-term ethanol consumption would increase the mortality and aggravate the deleterious effects of sub-lethal cecal ligation and puncture (SL-CLP) in the vasculature by inducing the expression of inducible nitric oxide (NO) synthase (iNOS). Male C57BL/6J wild-type (WT) or iNOS-deficient mice (iNOS-/-) were treated with ethanol (20% v/v) for 12 weeks and then subjected to SL-CLP. Mice were killed 24 h post-operatively or followed six days for survival. Septic ethanol-treated mice showed a higher mortality than septic WT mice. However, septic iNOS-deficient mice treated with ethanol showed a decreased mortality rate when compared to ethanol-treated WT mice. Ethanol and SL-CLP augmented superoxide anion (O2-) generation in the mesenteric arterial bed (MAB) of both WT and iNOS-deficient mice. Treatment with ethanol and SL-CLP enhanced lipoperoxidation in the MAB of WT, but not iNOS-deficient mice. SL-CLP enhanced nitrate/nitrite (NOx) concentrations in the MAB of WT, but not iNOS-deficient mice. Both, ethanol and SL-CLP increased TNF-α and IL-6 levels in the MAB. Treatment with ethanol as well as SL-CLP up-regulated the expression of iNOS in the MAB of WT mice. The major finding of our study is that chronic ethanol consumption increases the mortality induced by SL-CLP and that iNOS plays a role in such response. Although ethanol led to vascular alterations, it did not aggravate the vascular injury induced by SL-CLP. Finally, iNOS mediated the increase in oxidative stress and pro-inflammatory cytokines induced by SL-CLP in the vasculature.


Subject(s)
Alcohol Drinking/metabolism , Alcohol Drinking/mortality , Ethanol/adverse effects , Nitric Oxide Synthase Type II/metabolism , Oxidative Stress/drug effects , Sepsis/metabolism , Sepsis/pathology , Animals , Cytokines/metabolism , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , Nitrates/metabolism , Nitrites/metabolism , Superoxides/metabolism , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects
15.
Atherosclerosis ; 270: 146-153, 2018 03.
Article in English | MEDLINE | ID: mdl-29425960

ABSTRACT

BACKGROUND AND AIMS: Increased activity of matrix metalloproteinase (MMP)-2 is observed in aortas of different models of hypertension, and its activation is directly mediated by oxidative stress. As quercetin is an important flavonoid with significant antioxidant effects, the hypothesis here is that quercetin will reduce increased MMP-2 activity by decreasing oxidative stress in aortas of hypertensive rats and then ameliorate hypertension-induced vascular remodeling. METHODS: Male two-kidney one-clip (2K1C) hypertensive Wistar rats and controls were treated with quercetin (10 mg/kg/day) or its vehicle for three weeks by gavage. Rats were then analyzed at five weeks of hypertension. Systolic blood pressure (SBP) was determined by tail-cuff plethysmography. Aortas were used to determine MMP activity by in situ zymography and reactive oxygen species (ROS) levels by dihydroethidium. Western blot was performed to detect focal adhesion kinase (FAK) and phosphorylated-FAK levels. RESULTS: SBP was increased in 2K1C rats and only a borderline reduction in SBP was observed after treating 2K1C rats with quercetin. Cross-sectional area and the number of vascular smooth muscle cells were significantly increased in aortas of hypertensive rats, and quercetin reduced them. Quercetin reduced ROS levels in aortas of 2K1C rats and the increased activity of gelatinases in situ. However, quercetin did not affect the levels of tissue inhibitor of MMP (TIMP)-2 and did not interfere with FAK and p-FAK levels in aortas of hypertensive rats. Furthermore, different concentrations of quercetin did not directly reduce the activity of human recombinant MMP-2 in vitro. CONCLUSIONS: Quercetin reduces hypertension-induced vascular remodeling, oxidative stress and MMP-2 activity in aortas.


Subject(s)
Antioxidants/pharmacology , Aorta/drug effects , Hypertension, Renovascular/drug therapy , Matrix Metalloproteinase 2/metabolism , Oxidative Stress/drug effects , Quercetin/pharmacology , Vascular Remodeling/drug effects , Animals , Aorta/enzymology , Aorta/pathology , Aorta/physiopathology , Disease Models, Animal , Focal Adhesion Kinase 1/metabolism , Hypertension, Renovascular/enzymology , Hypertension, Renovascular/pathology , Hypertension, Renovascular/physiopathology , Male , Phosphorylation , Rats, Wistar , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
16.
J Pineal Res ; 63(1)2017 Aug.
Article in English | MEDLINE | ID: mdl-28370218

ABSTRACT

The purpose of this study was to investigate the effects of melatonin on selected biomarkers of innate and humoral immune response as well as the antioxidant/oxidant status (superoxide dismutase-SOD and reduced glutathione levels (GSH) to understand whether age-related changes would influence the development of acute Trypanosoma cruzi (T. cruzi) infection. Young- (5 weeks) and middle-aged (18 months) Wistar rats were orally treated with melatonin (gavage) (05 mg/kg/day), 9 days after infection. A significant increase in both SOD activity and GSH levels was found in plasma from all middle-aged melatonin-treated animals. Melatonin triggered enhanced expression of major histocompatibility class II (MHC-II) antigens on antigen-presenting cell (APC) and peritoneal macrophages in all treated animals. High levels of CD4+ CD28-negative T cells (*P<.05) were detected in middle-aged control animals. Melatonin induced a significant reduction (***P<.001) in CD28-negative in CD4+ and CD8+ T cells in middle-aged control animals. Contrarily, the same group displayed upregulated CD4+ CD28+ T and CD8+ CD28+ T cells. Melatonin also triggered an upregulation of CD80 and CD86 expression in all young-treated groups. Significant percentages of B and spleen dendritic cells in middle-aged infected and treated animals were observed. Our data reveal new features of melatonin action in inhibiting membrane lipid peroxidation, through the reduction in 8-isoprostane, upregulating the antioxidant defenses and triggering an effective balance in the antioxidant/oxidant status during acute infection. The ability of melatonin to counteract the immune alterations induced by aging added further support to its use as a potential therapeutic target not only for T. cruzi infection but also for other immunocompromised states.


Subject(s)
Antioxidants/pharmacology , Chagas Disease , Melatonin/pharmacology , Oxidative Stress/drug effects , Aging , Animals , CD28 Antigens/metabolism , Chagas Disease/immunology , Chagas Disease/metabolism , Macrophages, Peritoneal/drug effects , Male , Oxidoreductases/metabolism , Rats , Rats, Wistar
17.
Eur J Pharmacol ; 804: 82-93, 2017 Jun 05.
Article in English | MEDLINE | ID: mdl-28315342

ABSTRACT

Ethanol consumption is associated with an increased risk of erectile dysfunction (ED), but the molecular mechanisms through which ethanol causes ED remain elusive. Reactive oxygen species are described as mediators of ethanol-induced cell toxicity/damage in distinctive tissues. The enzyme NADPH oxidase is the main source of reactive oxygen species in the endothelium and vascular smooth muscle cells and ethanol is described to increase NADPH oxidase activation and reactive oxygen species generation. This study evaluated the contribution of NADPH oxidase-derived reactive oxygen species to ethanol-induced ED, endothelial dysfunction and production of pro-inflammatory and redox-sensitive proteins in the rat cavernosal smooth muscle (CSM). Male Wistar rats were treated with ethanol (20% v/v) or ethanol plus apocynin (30mg/kg/day; p.o. gavage) for six weeks. Apocynin prevented both the decreased in acetylcholine-induced relaxation and intracavernosal pressure induced by ethanol. Ethanol increased superoxide anion (O2-) generation and catalase activity in CSM, and treatment with apocynin prevented these responses. Similarly, apocynin prevented the ethanol-induced decreased of nitrate/nitrite (NOx), hydrogen peroxide (H2O2) and SOD activity. Treatment with ethanol increased p47phox translocation to the membrane as well as the expression of Nox2, COX-1, catalase, iNOS, ICAM-1 and p65. Apocynin prevented the effects of ethanol on protein expression and p47phox translocation. Finally, treatment with ethanol increased both TNF-α production and neutrophil migration in CSM. The major new finding of this study is that NADPH oxidase-derived reactive oxygen species play a role on chronic ethanol consumption-induced ED and endothelial dysfunction in the rat CSM.


Subject(s)
Erectile Dysfunction/metabolism , Ethanol/pharmacology , Gene Expression Regulation/drug effects , Muscle, Smooth/drug effects , NADPH Oxidases/metabolism , Penis/metabolism , Reactive Oxygen Species/metabolism , Animals , Body Weight/drug effects , Cell Movement/drug effects , Erectile Dysfunction/chemically induced , Erectile Dysfunction/physiopathology , Male , Muscle, Smooth/metabolism , Muscle, Smooth/physiopathology , Neutrophils/cytology , Neutrophils/drug effects , Oxidative Stress/drug effects , Penile Erection/drug effects , Penis/drug effects , Penis/physiopathology , Phosphorylation/drug effects , Rats , Rats, Wistar
18.
Data Brief ; 11: 111-116, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28149929

ABSTRACT

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.

19.
Eur J Pharmacol ; 799: 33-40, 2017 Mar 15.
Article in English | MEDLINE | ID: mdl-28132913

ABSTRACT

We studied whether the ß1-adrenergic antagonist nebivolol would prevent ethanol-induced reactive oxygen species generation and lipoperoxidation in the rat renal cortex. Male Wistar rats were treated with ethanol (20% v/v) for 2 weeks. Nebivolol (10mg/kg/day; p.o. gavage) prevented both the increase in superoxide anion (O2-) generation and thiobarbituric acid reactive substances (TBARS) concentration induced by ethanol in the renal cortex. Ethanol decreased nitrate/nitrite (NOx) concentration in the renal cortex, and nebivolol prevented this response. Nebivolol did not affect the reduction of hydrogen peroxide (H2O2) concentration induced by ethanol. Nebivolol prevented the ethanol-induced increase of catalase (CAT) activity. Both SOD activity and the levels of reduced glutathione (GSH) were not affected by treatment with nebivolol or ethanol. Neither ethanol nor nebivolol affected the expression of Nox1, Nox4, eNOS, nNOS, CAT, Nox organizer 1 (Noxo1), c-Src, p47phox or superoxide dismutase (SOD) isoforms in the renal cortex. On the other hand, treatment with ethanol increased Nox2 expression, and nebivolol prevented this response. Finally, nebivolol reduced the expression of protein kinase (PK) Cδ and Rac1. The major finding of our study is that nebivolol prevented ethanol-induced reactive oxygen species generation and lipoperoxidation in the kidney by a mechanism that involves reduction on the expression of Nox2, a catalytic subunit of NADPH oxidase. Additionally, we demonstrated that nebivolol reduces NADPH oxidase-derived reactive oxygen species by decreasing the expression of PKCδ and Rac1, which are important activators of NADPH oxidase.


Subject(s)
Ethanol/toxicity , Gene Expression Regulation, Enzymologic/drug effects , Kidney Cortex/drug effects , Lipid Peroxidation/drug effects , NADPH Oxidases/metabolism , Nebivolol/pharmacology , Reactive Oxygen Species/metabolism , Animals , Creatinine/blood , Cytoprotection/drug effects , Enzyme Activation/drug effects , Hydrogen Peroxide/metabolism , Kidney Cortex/enzymology , Kidney Cortex/injuries , Kidney Cortex/metabolism , Male , Nitrogen Oxides/metabolism , Oxidative Stress/drug effects , Potassium/blood , Rats , Rats, Wistar , Sodium/blood , Superoxides/metabolism , Thiobarbituric Acid Reactive Substances/metabolism
20.
J Physiol Biochem ; 73(1): 5-16, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27722988

ABSTRACT

Chronic ethanol consumption is a risk factor for cardiovascular diseases. We studied whether NAD(P)H oxidase-derived reactive oxygen species (ROS) play a role in ethanol-induced hypertension, vascular dysfunction, and protein expression in resistance arteries. Male Wistar rats were treated with ethanol (20 % v/v) for 6 weeks. Ethanol treatment increased blood pressure and decreased acetylcholine-induced relaxation in the rat mesenteric arterial bed (MAB). These responses were attenuated by apocynin (30 mg/kg/day; p.o. gavage). Ethanol consumption increased superoxide anion (O2-) generation and decreased nitrate/nitrite (NO x ) concentration in the rat MAB and apocynin prevented these responses. Conversely, ethanol did not affect the concentration of hydrogen peroxide (H2O2) and reduced glutathione (GSH) or the activity of superoxide dismutase (SOD) and catalase (CAT) in the rat MAB. Ethanol increased interleukin (IL)-10 levels in the rat MAB but did not affect the levels of tumor necrosis factor (TNF)-α, IL-6, or IL-1ß. Ethanol increased the expression of Nox2 and the phosphorylation of SAPK/JNK, but reduced eNOS expression in the rat MAB. Apocynin prevented these responses. However, ethanol treatment did not affect the expression of Nox1, Nox4, p38MAPK, ERK1/2, or SAPK/JNK in the rat MAB. Ethanol increased plasma levels of TBARS, TNF-α, IL-6, IL-1ß, and IL-10, whereas it decreased NO x levels. The major finding of our study is that NAD(P)H oxidase-derived ROS play a role on ethanol-induced hypertension and endothelial dysfunction in resistance arteries. Moreover, ethanol consumption affects the expression and phosphorylation of proteins that regulate vascular function and NAD(P)H oxidase-derived ROS play a role in such responses.


Subject(s)
Disease Models, Animal , Endothelium, Vascular/metabolism , Hypertension/metabolism , Mesenteric Arteries/metabolism , NADPH Oxidases/metabolism , Reactive Oxygen Species/metabolism , Acetophenones/therapeutic use , Alcoholism/physiopathology , Animals , Cardiovascular Diseases/etiology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , Cytokines/blood , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , Enzyme Inhibitors/therapeutic use , Gene Expression Regulation, Enzymologic/drug effects , Hypertension/etiology , Hypertension/physiopathology , Hypertension/prevention & control , MAP Kinase Signaling System/drug effects , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mesenteric Arteries/drug effects , Mesenteric Arteries/immunology , Mesenteric Arteries/physiopathology , NADPH Oxidase 2 , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/genetics , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress/drug effects , Phosphorylation/drug effects , Random Allocation , Rats, Wistar , Reactive Oxygen Species/antagonists & inhibitors , Vascular Resistance/drug effects
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