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1.
Life Sci ; 343: 122488, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38428573

RESUMO

AIM: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes. MAIN METHODS: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05. STATISTICS: Two-way ANOVA (and Tukey's) or Student t-test. KEY FINDINGS: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased. SIGNIFICANCE: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress.


Assuntos
Acetilcolina , Antioxidantes , Ratos , Animais , Masculino , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Topiramato/farmacologia , Acetilcolina/metabolismo , Superóxidos/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Aorta Torácica/metabolismo , Fenilefrina/farmacologia , Óxido Nítrico/metabolismo
2.
Front Immunol ; 14: 949407, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37388729

RESUMO

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.


Assuntos
Artrite , Lipoxinas , Animais , Camundongos , NF-kappa B , Fator 2 Relacionado a NF-E2/genética , Lipoxinas/farmacologia , Líquido Sinovial , Inflamação , Canais de Cátion TRPV/genética
3.
Life Sci ; 288: 120189, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863798

RESUMO

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.


Assuntos
Aorta/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Topiramato/toxicidade , Doenças Vasculares/patologia , Animais , Anticonvulsivantes/toxicidade , Aorta/efeitos dos fármacos , Aorta/metabolismo , Feminino , Masculino , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Prostaglandina-Endoperóxido Sintases/genética , Ratos , Ratos Wistar , Fatores Sexuais , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/metabolismo
4.
J Cardiovasc Pharmacol ; 78(6): 858-866, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596621

RESUMO

ABSTRACT: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Doenças Cardiovasculares/induzido quimicamente , Lactação , Doenças Metabólicas/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Adiposidade/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Idade Gestacional , Hemodinâmica/efeitos dos fármacos , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/fisiopatologia , Gravidez , Ratos Wistar , Medição de Risco
5.
Reprod Fertil Dev ; 32(18): 1311-1325, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33308393

RESUMO

Paracetamol (PAR) is one of the most commonly used drugs by pregnant women because it is considered safe for the mother and fetus. However, PAR is transferred into breast milk and crosses the blood-placental barrier, being present in the progeny during important stages of development. Intrauterine exposure to PAR may decrease the anogenital distance and follicle reserve in female rodent offspring. Therefore, the aim of the present study was to evaluate whether maternal PAR treatment altered the reproductive behaviour of dams and the sexual development of female rat offspring. Pregnant Wistar rats were gavaged daily with 350mg kg-1 day-1 PAR or water during gestation (from Gestation Day (GD) 6 until delivery) or during gestation and lactation (from GD6 until weaning). Maternal PAR treatment had maternal effects (increased grooming behaviour), and resulted in impaired sexual behaviour, decreased follicle reserve and increased plasma oestradiol concentrations in female offspring.


Assuntos
Acetaminofen/farmacologia , Hormônios Esteroides Gonadais/metabolismo , Comportamento Materno/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Animais Recém-Nascidos , Ciclo Estral/sangue , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/sangue , Masculino , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos
6.
Arch Physiol Biochem ; 126(3): 276-281, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30270666

RESUMO

Objective: The aim was to evaluate if maternal treatment with metformin (MET) during pregnancy and lactation could be safe for metabolic and cardiovascular parameters of adult male and female offspring.Materials and methods: Wistar female rats were treated with MET (293 mg/kg/d) or tap water, by gavage during gestation (METG or CTRG) or gestation and lactation (METGL or CTRGL).Results: At 75 days of life, male and female MET offspring presented similar blood pressure when compared with their CTR. The heart rate of female METGL was higher than in the CTRGL. The insulin sensitivity, basal glycaemia, body weight, Lee index of obesity, plasmatic concentration of triglycerides, total cholesterol and fat acid of male and female MET were similar to CTR groups. Lower fat pad deposition was observed in female METG and METGL.Conclusion: MET exposure during gestational and lactation does not program cardiovascular and metabolic alterations in adult offspring life.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Lactação , Exposição Materna , Doenças Metabólicas/induzido quimicamente , Metformina/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Tecido Adiposo/metabolismo , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Peso Corporal , Feminino , Resistência à Insulina , Masculino , Metformina/administração & dosagem , Obesidade/metabolismo , Gravidez , Prenhez , Ratos , Ratos Wistar , Fatores de Tempo , Triglicerídeos/metabolismo
7.
Reprod Fertil Dev ; 31(5): 1002-1008, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30786956

RESUMO

Antidepressants are widely used around the world, primarily for the treatment of mood disorders, anxiety and pain syndromes. Women who use antidepressants often continue to use them during pregnancy. Selective serotonin reuptake inhibitors, including fluoxetine, are the main class of antidepressants prescribed to pregnant women. It is known that fluoxetine crosses the placental-blood barrier and is excreted in breast milk. Consequently, indirect exposure of the infant occurs. Knowing that fluoxetine alters the balance of neurotransmitters in the central nervous system, several studies have shown that maternal exposure to this drug leads to various adverse effects on the nervous, reproductive and cardiovascular systems of the offspring. The aim of the present study was to evaluate the effects of exposure to fluoxetine during gestation and lactation on parameters related to steroid hormones in prepubertal and pubertal male and female rats. The endpoints evaluated were date of puberty onset, plasma testosterone and oestrogen concentrations before and after puberty onset and corticosterone concentration before and after adrenocorticotrophin stimulus. None of the parameters was affected by fluoxetine exposure.


Assuntos
Corticosterona/sangue , Estrogênios/sangue , Fluoxetina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Testosterona/sangue , Animais , Feminino , Masculino , Exposição Materna , Placenta/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Útero/efeitos dos fármacos
8.
Front Physiol ; 9: 490, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867542

RESUMO

Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the association of testosterone to conventional hormonal therapy. Testosterone has been linked to development of cardiovascular diseases including hypertension and it also increases cytochrome P-450-induced 20-HETE synthesis which in turn results in vascular dysfunction. However, the effect of testosterone plus estrogen in the cardiovascular system is still very poorly studied. The aim of the present study is to evaluate the role of cytochrome P-450 pathway in a postmenopausal hypertensive female treated with testosterone plus estrogen. For that, hypertensive ovariectomized rats (OVX-SHR) were used as a model of postmenopausal hypertension and four groups were created: SHAM-operated (SHAM), ovariectomized SHR (OVX), OVX treated for 15 days with conjugated equine estrogens [(CEE) 9.6 µg/Kg/day/po] or CEE associated to testosterone [(CEE+T) 2.85 mg/kg/weekly/im]. Phenylephrine-induced contraction and generation of reactive oxygen species (ROS) were markedly increased in aortic rings from OVX-SHR compared to SHAM rats which were restored by CEE treatment. On the other hand, CEE+T abolished vascular effects by CEE and augmented both systolic and diastolic blood pressure of SHR. Treatment of aortic rings with the CYP/20-HETE synthesis inhibitor HET0016 (1 µM) reduced phenylephrine hyperreactivity and the augmented ROS generation in the CEE+T group. These results are paralleled by the increased CYP4F3 protein expression and activity in aortas of CEE+T. In conclusion, we showed that association of testosterone to estrogen therapy produces detrimental effects in cardiovascular system of ovariectomized hypertensive females via CYP4F3/20-HETE pathway. Therefore, our findings support the standpoint that the CYP/20-HETE pathway is an important therapeutic target for the prevention of cardiovascular disease in menopausal women in the presence of high levels of testosterone.

9.
Life Sci ; 207: 72-79, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29852188

RESUMO

The biguanide metformin (MET) has been used during pregnancy for treatment of polycystic ovary syndrome and gestational diabetes. MET crosses the placenta and maternal treatment can expose the progeny to this drug during important phases of body development. Direct vascular protective effects have been described with the treatment of metformin. Nevertheless, it is unclear whether intrauterine exposure to metformin is safe for the vascular system of offspring. Thus, the present study aimed to investigate the intrinsic effects of metformin exposure in utero in the offspring abdominal aorta reactivity, in the presence and absence of perivascular adipose tissue (PVAT) and endothelium. For this, Wistar rats were treated with metformin 293 mg/kg/day (MET) or water (CTR) by gavage during the gestational period. The abdominal aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in male adult offspring. It was observed that abdominal aorta relaxation was similar between MET and CTR groups in the presence or absence of PVAT. In addition, the contraction to phenylephrine was similar between MET and CTR groups in the presence and absence of PVAT and endothelium. Therefore, metformin exposure during pregnancy had no intrinsic effect on the offspring abdominal aorta PVAT and endothelial function, demonstrating it to be safe to the vascular system of the offspring.


Assuntos
Aorta Abdominal/fisiologia , Exposição Materna , Metformina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Aorta Abdominal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Masculino , Nitroprussiato/farmacologia , Gravidez , Prenhez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
10.
Vascul Pharmacol ; 108: 67-73, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29653281

RESUMO

The study aimed to evaluate if maternal exposure to fluoxetine (FLX) during pregnancy and lactation would result in altered aortic reactivity in adult offspring. We also sought to understand the role of endothelium derived relaxing factors in aortic response. Wistar rats (75­80 days old), whose progenitors had received FLX (5 mg/kg, FLX offspring) or tap water (control offspring) during pregnancy and lactation were anesthetized, after which the aorta was removed and cut into two rings, one with (Endo+) and the other without (Endo-) endothelium. Concentration-effect curves for acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (Phe) were performed. The vasodilation to ACh and SNP was similar between control and FLX groups in both male and female offspring. In male rats, the response to Phe was similar between the FLX and control groups on Endo+ and Endo- rings. The response to Phe was reduced on Endo+ rings from female FLX when compared with the control group. The endothelium removal, as well as L-NAME, indomethacin, and tranylcypromine incubation corrected the reduced Phe-induced contraction in the aorta from the female FLX group. On the other hand, catalase, NS-398, and L-NIL did not interfere with the vasoconstriction. The aortic level of nitric oxide (NO) was higher in the female FLX than the control group. Although endothelial NO synthase isoform and cyclooxygenase (COX)-1 expressions were similar between the groups, there was a notable increment in neuronal NO synthase expression in the aorta of FLX-exposed female rats, suggesting an important role of this enzyme in the higher levels of NO. Our results show that developmental exposure to FLX causes sex-specific alteration in aortic function through a mechanism involving endothelial factors, probably NO and COX-1 products.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Fluoxetina/farmacologia , Lactação , Músculo Liso Vascular/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Vasoconstrição/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Ciclo-Oxigenase 1/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Feminino , Idade Gestacional , Masculino , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Ratos Wistar , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
11.
Eur J Pharmacol ; 813: 147-152, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28822853

RESUMO

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressants to women during pregnancy. Maternal treatment with fluoxetine can expose fetuses and neonates to higher levels of serotonin that plays a role in stress response. Thus, the aim of the study was to evaluate whether maternal treatment with fluoxetine interferes with aorta reactivity of adult male offspring after acute restraint stress. Wistar rats were gavaged with fluoxetine (5mg/kg/day) or water (control) during pregnancy and lactation. The experiments were performed in adult male offspring, treated or not with reserpine (4mg/Kg, ip, 28h before the experimental protocol). Fluoxetine and control rats were submitted to a single restraint stress session (ST) for 1h. Curves to phenylephrine were performed in thoracic aorta with endothelium. Aortic nitric oxide (NOx) were evaluated by the Griess method. The aortic contraction induced by phenylephrine was similar between control and fluoxetine rats. The acute stress reduced contraction in aorta of control ST compared to control, and L-NAME equaled this response. In fluoxetine rats, ST did not change the aortic constriction. Reserpine treatment restored the vasoconstriction in control ST, but did not interfere with aortic contraction in control, fluoxetine or fluoxetine ST. The NOx concentration was higher in aortas from control ST than control rats, and reserpine reduced NOx levels of control ST. The NOx concentration was similar between fluoxetine and fluoxetine ST rats, treated or not with reserpine. In conclusion, maternal treatment with fluoxetine blunted acute restraint stress-induced NO system activation and aortic adaptation in adult offspring.


Assuntos
Aorta/fisiopatologia , Fluoxetina/farmacologia , Lactação , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/fisiopatologia , Útero/efeitos dos fármacos , Útero/fisiopatologia , Adaptação Fisiológica/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Feminino , Masculino , Óxido Nítrico/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Restrição Física/psicologia , Estresse Psicológico/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Vasoconstrição/efeitos dos fármacos
12.
J Cardiovasc Pharmacol ; 70(5): 300-304, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28731890

RESUMO

Metformin has been used for the treatment of some metabolic diseases during gestation and the beneficial effects of metformin to the vascular system have been described in diabetic and obese animal models. Nevertheless, the long-term consequences to the vascular system of offsprings maternally exposed to metformin have not yet been characterized. Therefore, we want to test the hypothesis that gestational and lactational exposure to metformin would be safe for the vascular reactivity of male adult offsprings. Wistar female rats were treated with metformin 293 mg·kg·d, by gavage, from gestational day (GD) 0 to GD 21 (METG) or GD 0 until postnatal day 21 (METGL). Control dams received water by gavage in the same periods (CTRG and CTRGL). In male offsprings (75 days), the aortic reactivity to phenylephrine, acetylcholine, and sodium nitroprusside in the presence or absence of endothelium were evaluated. The results demonstrated that aortic contraction and relaxation were similar between groups. These data showed that metformin exposure during pregnancy and lactation did not interfere with aortic reactivity, suggesting that metformin exposure during gestational and lactation are safe for the offsprings' vascular system.


Assuntos
Aorta Torácica/efeitos dos fármacos , Lactação/efeitos dos fármacos , Metformina/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Aorta Torácica/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Lactação/fisiologia , Masculino , Metformina/efeitos adversos , Nitroprussiato/efeitos adversos , Técnicas de Cultura de Órgãos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Vasoconstrição/fisiologia , Vasodilatação/fisiologia
13.
Life Sci ; 152: 165-70, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27021785

RESUMO

AIMS: Fluoxetine (FLX) is an antidepressant worldwide prescribed throughout life stages, including pregnancy and breastfeeding. Out of pregnancy, the combination of FLX with fish oil (FO) and folic acid (FA) is carried to enhance the therapeutic activity and reduce the side effects of the antidepressant. During pregnancy, FO and FA have been used to promote fetal development, and reduce, in mother, the risk of gestational and post-pregnancy depression. To evaluate if maternal exposure during pregnancy and lactation to FLX associated with FO or FA would prevent the antidepressant side effects in aorta reactivity and nitric oxide metabolites (NOx) plasmatic levels. We also sought to understand, in female offspring, the vascular effects of intrauterine and lactation exposure to FO and FA monotherapy. MAIN METHODS: Wistar rats were treated with water (control group), FLX (5mg/kg/day), FO (1.3g/kg/day), FA (3mg/kg/day), FLX+FO and FLX+FA, throughout pregnancy and lactation. On adulthood, in female offspring were evaluated the vascular reactivity to phenylephrine (Phe), the NOx and homocysteine (HCY) plasmatic levels. KEY FINDINGS: The developmental exposure to the associations of FO or FA with FLX did not correct the aortic hyporreactivity and increased NOx levels induced by intrauterine and lactation exposure to FLX. Also, isolated exposure to FO and FA did not interfere with Phe-induced aortic contraction and neither interferes with NOx and HCY plasmatic levels. SIGNIFICANCE: The developmental exposure to FO and FA was safe for vascular function of female offspring but did not prevent the vascular effects of FLX-exposure.


Assuntos
Antidepressivos de Segunda Geração/toxicidade , Vasos Sanguíneos/efeitos dos fármacos , Óleos de Peixe/uso terapêutico , Fluoxetina/toxicidade , Ácido Fólico/uso terapêutico , Exposição Materna/efeitos adversos , Animais , Feminino , Homocisteína/sangue , Lactação , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/sangue , Fenilefrina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Ratos , Ratos Wistar , Vasoconstritores/farmacologia
14.
PLoS One ; 9(11): e111117, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25369284

RESUMO

The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R) contributes to vascular hypertrophy in angiotensin II (ANG II)-induced hypertension, through a mechanism involving reactive oxygen species (ROS) generation and extracellular signal-regulated kinase (ERK1/2) activation. Male Wistar rats were infused with vehicle (control rats), 400 ng/Kg/min ANG II (ANG II rats) or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9)-Leu(8)-bradykinin (ANGII+DAL rats), via osmotic mini-pumps (14 days) or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats). After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg) 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE): 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1) and ERK1/2 phosphorylation (137 ± 20.7%) in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC) stimulated with low concentrations (0.1 nM) of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM), B1R antagonist (10 µM) and Tiron (superoxide anion scavenger, 10 mM). These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth. Our findings highlight an important cross-talk between the DABK and ANG II in the vascular system and contribute to a better understanding of the mechanisms involved in vascular remodeling in hypertension.


Assuntos
Hipertensão/patologia , Sistema Calicreína-Cinina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/toxicidade , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Aorta/metabolismo , Aorta/patologia , Pressão Sanguínea/efeitos dos fármacos , Antagonistas de Receptor B1 da Bradicinina/farmacologia , Células Cultivadas , Sinergismo Farmacológico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertrofia/metabolismo , Sistema Calicreína-Cinina/efeitos dos fármacos , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Superóxidos/metabolismo
15.
PLoS One ; 8(4): e61982, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23637941

RESUMO

Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium.


Assuntos
Hipertireoidismo/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais , Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertireoidismo/genética , Masculino , Modelos Biológicos , Miócitos de Músculo Liso/efeitos dos fármacos , Ratos , Receptor Tipo 2 de Angiotensina/genética , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Vasoconstrição/efeitos dos fármacos
16.
Steroids ; 78(3): 341-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23261957

RESUMO

OBJECTIVE: The increased risk of cardiovascular diseases in postmenopausal women has been linked to the decrease in plasma estrogen levels. Preparation of conjugate equine estrogens (CEE) is one of the most routinely used hormone therapy in postmenopausal women. However, studies on the vascular effects of CEE are still sparse and the mechanism of action is not completely elucidated. In this context, we have determined the effects of CEE in the vascular oxidative stress observed in ovariectomyzed (OVX) spontaneously hypertensive rats (SHR). Mechanisms by which CEE interferes with redox-sensitive pathways and endothelial function were also determined. RESULTS: Aortas from OVX rats exhibited increased generation of reactive oxygen species (ROS), NADPH oxidase activity and reduced catalase protein expression, compared to aortas from sham SHR. Endothelium-intact aortic rings from OVX were hyperreactive to NE when compared to Sham aortas. This hyperreactivity was corrected by superoxide dismutase (SOD), catalase, and endothelium removal. Treatment of OVX-SHR with CEE reduced vascular ROS generation, NADPH oxidase activity, enhanced SOD and catalase expression and also corrected the NE-hyperreactivity in aortic rings from OVX-SHR. CONCLUSION: Our study indicates a potential benefit of CEE therapy through a mechanism that involves reduction in oxidative stress, improving endothelial function in OVX hypertensive rats.


Assuntos
Aorta/efeitos dos fármacos , Estrogênios Conjugados (USP)/farmacologia , Hipertensão/tratamento farmacológico , Ovariectomia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Aorta/metabolismo , Catalase/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Cavalos , Humanos , Hipertensão/metabolismo , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Técnicas de Cultura de Tecidos
17.
Peptides ; 37(2): 216-24, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22868213

RESUMO

Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.


Assuntos
Bradicinina/farmacologia , Endotélio/metabolismo , Veia Porta/efeitos dos fármacos , Receptor B1 da Bradicinina/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Bradicinina/análogos & derivados , Relação Dose-Resposta a Droga , Masculino , Veia Porta/metabolismo , Ratos , Ratos Wistar , Receptor B1 da Bradicinina/biossíntese , Relação Estrutura-Atividade
18.
Cardiovasc Res ; 85(3): 560-70, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19734167

RESUMO

AIMS: Thyroid hormone (TH) rapidly relaxes vascular smooth muscle cells (VSMCs). However, the mechanisms involved in this effect remain unclear. We hypothesize that TH-induced rapid vascular relaxation is mediated by VSMC-derived nitric oxide (NO) production and is associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathway. METHODS AND RESULTS: NO levels were determined using a NO-specific fluorescent dye (DAF-2) and nitrite (NO2-) levels. Expression of NO synthase (NOS) isoforms and proteins of the PI3K/Akt pathway was determined by both western blotting and immunocytochemistry. Myosin light chain (MLC) phosphorylation levels were also investigated by western blotting. Exposure of cultured VSMCs from rat thoracic aortas to triiodothyronine (T3) resulted in a significant decrease of MLC phosphorylation levels. T3 also induced a rapid increase in Akt phosphorylation and increased NO production in a dose-dependent manner (0.001-1 microM). VSMCs stimulated with T3 for 30 min showed an increase in the expression of all three NOS isoforms and augmented NO production, effects that were prevented by inhibitors of PI3K. Vascular reactivity studies showed that vessels treated with T3 displayed a decreased response to phenylephrine, which was reversed by NOS inhibition. These data suggest that T3 treatment induces greater generation of NO both in aorta and VSMCs and that this phenomenon is endothelium independent. In addition, these findings show for the first time that the PI3K/Akt signalling pathway is involved in T3-induced NO production by VSMCs, which occurs with expressive participation of inducible and neuronal NOS. CONCLUSION: Our data strongly indicate that T3 causes NO-dependent rapid relaxation of VSMC and that this effect is mediated by the PI3K/Akt signalling pathway.


Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Óxido Nítrico/biossíntese , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Células Cultivadas , Endotélio Vascular/fisiologia , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Cadeias Leves de Miosina/metabolismo , Óxido Nítrico Sintase/fisiologia , Fenilefrina/farmacologia , Fosforilação , Ratos , Ratos Wistar , Vasoconstrição
19.
Hypertension ; 50(4): 756-61, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17664391

RESUMO

We investigated whether angiotensin II infusion modulates in vivo the kinin B1 receptor expression and the mechanisms involved in this process. We also evaluated the role of the B1 receptor activation in aorta. Wistar rats received 400 ng/kg per minute of angiotensin II or saline (control rats) infusion during 14 days through an osmotic minipump. To investigate the role of superoxide anion in B1 receptor expression, rats received a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor in the drinking water during 14 days (60 mg/L of apocynin) simultaneously with angiotensin II infusion. Angiotensin II induced B1 receptor expression in the aorta and increased significantly systolic blood pressure, superoxide anion, and the nuclear factor kappaB activity. Apocynin treatment did not alter the blood pressure levels of angiotensin II rats and reduced the B1 receptor expression, superoxide anion generation, and nuclear factor kappaB activity to similar levels of the control rats. Vascular reactivity studies in isolated aorta reveal that B1 receptor agonist promoted endothelium-dependent dilation and increased the NO generation in aorta of angiotensin II rats. NO synthase inhibitor and B1 receptor antagonist inhibited the vasodilation and NO generation, which were not affected by B2 receptor antagonist or indomethacin. These results provide evidence that angiotensin II induces B1 receptor expression in aorta by superoxide anion generation, via reduced nicotinamide-adenine dinucleotide phosphate oxidase, concomitant to nuclear factor kappaB activation. We have also shown that B1 receptor agonist causes endothelium-dependent vasodilation through NO production in aortic rings, suggesting that the B1 receptor expression could be related with the vascular tonus control of angiotensin II rats.


Assuntos
Angiotensina II/fisiologia , Aorta Torácica/metabolismo , Receptor B1 da Bradicinina/metabolismo , Acetofenonas/farmacologia , Angiotensina II/administração & dosagem , Animais , Aorta Torácica/fisiologia , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Bombas de Infusão Implantáveis , Masculino , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxidos/metabolismo
20.
Life Sci ; 80(8): 782-7, 2007 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-17161436

RESUMO

Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension and endothelial dysfunction in adulthood. We have evaluated the effect of the Renin Angiotensin System inhibition on the blood pressure and the mesenteric arteriolar reactivity of the intrauterine undernourished rats. Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. In this study only the male offspring was used. At 16 weeks of age, the rats were used for the study of blood pressure, microvascular reactivity studied in vivo-in situ to Angiotensin II (Ang II), Bradykinin (Bk) and Acetylcholine (Ach) before and after either losartan (10 mg/kg/15 days) or enalapril (15 mg/kg/21 days) treatment. We also evaluated the mesenteric and plasmatic Angiotensin Converting Enzyme (ACE), renal function, lipid plasmatic content, and insulin and glucose metabolism. Intrauterine undernutrition induced hypertension and increased response of mesenteric arterioles to Ang II and decreased vasodilation to Bk and Ach. The treatments with losartan or enalapril normalized the blood pressure levels and significantly improved the arteriolar responses to Bk, Ach and reduced the response to Ang II. No differences have been detected to ACE activity, renal function, lipid content and insulin and glucose metabolism. This study shows for the first time that Renin Angiotensin System inhibitors can normalize the cardiovascular alterations induced by intrauterine undernutrition.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Enalapril/uso terapêutico , Privação de Alimentos , Losartan/uso terapêutico , Desnutrição/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Glicemia/análise , Antagonismo de Drogas , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Insulina , Masculino , Mesentério/irrigação sanguínea , Gravidez , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
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