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1.
Am J Physiol Heart Circ Physiol ; 317(1): H87-H96, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050559

RESUMO

Impairment of the myogenic response can affect capillary hydrostatic pressure and contribute to peripheral edema and exercise intolerance, which are markers of heart failure (HF). The aim of this study was to assess the effects of exercise training (ET) on myogenic response in skeletal muscle resistance arteries and peripheral edema in HF rats, focusing on the potential signaling pathways involved in these adjustments. Male Wistar rats were submitted to either coronary artery occlusion or a sham-operated surgery. After 4 wk, an exercise test was performed, and the rats were divided into the following groups: untrained normal control (UNC) and untrained HF (UHF) and exercise- trained (on treadmill, 50-60% of maximal capacity) NC (TNC) and exercise-trained HF (THF). Caudal tibial artery (CTA) myogenic response was impaired in UHF compared with UNC, and ET restored this response in THF to NC levels and increased it in TNC. Rho kinase (ROCK) inhibitor abolished CTA myogenic response in the untrained and blunted it in exercise-trained groups. CTA-stored calcium (Ca2+) mobilization was higher in exercise-trained rats compared with untrained rats. The paw volume was higher in UHF rats, and ET decreased this response compared with UNC. Myogenic constriction was positively correlated with maximal running distance and negatively correlated with paw volume. The results demonstrate, for the first time, that HF impairs the myogenic response in skeletal muscle arteries, which contributes to peripheral edema in this syndrome. ET restores the myogenic response in skeletal muscle arteries improving Ca2+ sensitization and handling. Additionally, this paradigm also improves peripheral edema and exercise intolerance. NEW & NOTEWORTHY The novel and main finding of the present study is that moderate intensity exercise training restores the impaired myogenic response of skeletal muscle resistance arteries, exercise intolerance and peripheral edema in rats with heart failure. These results also show for the first time to our knowledge that exercise training improving calcium sensitization through the ROCK pathway and enhancing intracellular calcium handling could contribute to restoration of flow autoregulation to skeletal muscle in heart failure.

2.
Int J Cardiol Heart Vasc ; 21: 22-28, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30258978

RESUMO

Background: Atrial fibrillation (AF) frequently coexists with congestive heart failure (CHF). The increased susceptibility to AF in CHF has been attributed to a variety of structural and electrophysiological changes in the atria, particularly dilation and interstitial fibrosis. We evaluated atrial remodeling and AF vulnerability in a rat model of CHF induced by left ventricle (LV) radiofrequency (RF) ablation. Methods: Wistar rats were divided into 3 groups: RF-induced CHF (Ab, n = 36), CHF animals treated with spironolactone (AbSpi, n = 20) and sham controls (Sham, n = 29). After 12 weeks, animals underwent echocardiographic and electrophysiological evaluation and were sacrificed for histological (atrial fibrosis) and Western blotting (TGF-ß1, collagen I/III, connexin 43 and CaV1.2) analysis. Results: Mild LV dysfunction and marked atrial enlargement were noted in both ablated groups. AF inducibility (episodes ≥2 s) increased in the Ab group compared to sham animals (31/36, 86%; vs. 15/29, 52%; p = 0.005), but did not differ from the AbSpi group (16/20, 80%; p = NS). Sustained AF (>30 s) was also more frequent in the Ab group compared to shams (56% vs. 28%; p = 0.04). Spironolactone reduced atrial fibrosis (p < 0.01) as well as TGF-ß1 (p < 0.01) and collagen I/III (p < 0.01) expression but did not affect connexin 43 and CaV1.2 expression. Conclusions: Rats with RF-induced CHF exhibit pronounced atrial structural remodeling and enhanced AF vulnerability. This model may be useful for studying AF substrate in CHF.

3.
Am J Physiol Heart Circ Physiol ; 314(4): H878-H887, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351461

RESUMO

Exercise training (ET) has emerged as a nonpharmacological therapy for cardiovascular diseases because of its helpful milieu for improving vascular function. The aim of the present study was to assess whether ET reverses the alterations in vascular reactivity observed in heart failure (HF)-related coronary arteries and to elucidate the molecular mechanisms involved in these adjustments. Male Wistar rats were subjected to either coronary artery ligation or sham operation. Four weeks after the surgery, rats were divided into two groups: untrained HF (UHF) and exercise-trained HF (THF). ET was conducted on a treadmill for 8 wk. An untrained SO group was included in the study as a normal control. ET restored the impaired acetylcholine (ACh)- and sodium nitroprusside-induced relaxation in coronary arteries to levels of the control. Oxidative stress and reduced nitric oxide (NO) production were observed in UHF, whereas ET restored both parameters to the levels of the control. Expression levels of endothelial NO synthase (eNOS) and soluble guanylyl cyclase subunits were increased in coronary arteries of UHF rats but reduced in THF rats. Tetrahydrobiopterin restored ACh-induced NO production in the UHF group, indicating that eNOS was uncoupled. ET increased the eNOS dimer-to-monomer ratio and expression of GTP cyclohydrolase 1, thus increasing NO bioavailability. Taken together, these findings demonstrate that ET reverses the dysfunction of the NO/soluble guanylyl cyclase pathway present in coronary arteries of HF rats. These effects of ET are associated with increased GTP cyclohydrolase 1 expression, restoration of NO bioavailability, and reduced oxidative stress through eNOS coupling. NEW & NOTEWORTHY The present study provides a molecular basis for the exercise-induced improvement in coronary arteries function in heart failure. Increasing the expression of GTP cyclohydrolase 1, the rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin, exercise training couples endothelial nitric oxide synthase, reduces oxidative stress, and increases nitric oxide bioavailability and sensitivity in coronary arteries of heart failure rats.


Assuntos
Vasos Coronários/enzimologia , Terapia por Exercício , Insuficiência Cardíaca/terapia , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação , Animais , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Tolerância ao Exercício , GTP Cicloidrolase/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos Wistar , Transdução de Sinais , Guanilil Ciclase Solúvel/metabolismo
4.
Front Physiol ; 7: 295, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462277

RESUMO

Divergent phenotypes between the perivascular adipose tissue (PVAT) surrounding the abdominal and the thoracic aorta might be implicated in regional aortic differences, such as susceptibility to atherosclerosis. Although PVAT of the thoracic aorta exhibits anti-contractile function, the role of PVAT in the regulation of the vascular tone of the abdominal aorta is not well defined. In the present study, we compared the anti-contractile function, nitric oxide (NO) availability, and reactive oxygen species (ROS) formation in PVAT and vessel walls of abdominal and thoracic aorta. Abdominal and thoracic aortic tissue from male Wistar rats were used to perform functional and molecular experiments. PVAT reduced the contraction evoked by phenylephrine in the absence and presence of endothelium in the thoracic aorta, whereas this anti-contractile effect was not observed in the abdominal aorta. Abdominal PVAT exhibited a reduction in endothelial NO synthase (eNOS) expression compared with thoracic PVAT, without differences in eNOS expression in the vessel walls. In agreement with this result, NO production evaluated in situ using 4,5-diaminofluorescein was less pronounced in abdominal compared with thoracic aortic PVAT, whereas no significant difference was observed for endothelial NO production. Moreover, NOS inhibition with L-NAME enhanced the phenylephrine-induced contraction in endothelial-denuded rings with PVAT from thoracic but not abdominal aorta. ROS formation and lipid peroxidation products evaluated through the quantification of hydroethidine fluorescence and 4-hydroxynonenal adducts, respectively, were similar between PVAT and vessel walls from the abdominal and thoracic aorta. Extracellular superoxide dismutase (SOD) expression was similar between the vessel walls and PVAT of the abdominal and thoracic aorta. However, Mn-SOD levels were reduced, while CuZn-SOD levels were increased in abdominal PVAT compared with thoracic aortic PVAT. In conclusion, our results demonstrate that the anti-contractile function of PVAT is lost in the abdominal portion of the aorta through a reduction in eNOS-derived NO production compared with the thoracic aorta. Although relative SOD isoforms are different along the aorta, ROS formation, and lipid peroxidation seem to be similar. These findings highlight the specific regional roles of PVAT depots in the control of vascular function that can drive differences in susceptibility to vascular injury.

5.
Hypertension ; 68(3): 726-35, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27432866

RESUMO

Sustained stimulation of ß-adrenoceptors (ß-ARs) and activation of renin-angiotensin-aldosterone system are common features of cardiovascular diseases with rising sympathetic activation, including essential hypertension, myocardial infarction, and heart failure. In this study, we investigated the role of AT1 receptor and mineralocorticoid receptor (MR) in the vascular alterations caused by ß-AR overstimulation. ß-AR overstimulation with associated cardiac hypertrophy and increased vasoconstrictor response to phenylephrine in aorta were modeled in rats by 7-day isoproterenol treatment. The increased vasoconstrictor response to phenylephrine in this model was blunted by the MR antagonist spironolactone, but not by the AT1 receptor antagonist losartan, despite the blunting of cardiac hypertrophy with both drugs. Spironolactone, but not losartan, restored NO bioavailability in association with lower endothelial nitric oxide synthase-derived superoxide production, increased endothelial nitric oxide synthase dimerization, and aortic HSP90 upregulation. MR genomic and nongenomic functions were activated in aortas from isoproterenol-treated rats. Isoproterenol did not modify plasma levels of MR ligands aldosterone and corticosterone but rather increased perivascular adipose tissue-derived corticosterone in association with increased expression of 11ß-hydroxysteroid dehydrogenase type 1. The anticontractile effect of aortic perivascular adipose tissue was impaired by ß-AR overstimulation and restored by MR blockade. These results suggest that activation of vascular MR signaling contributes to the vascular dysfunction induced by ß-AR overstimulation associated with endothelial nitric oxide synthase uncoupling. These findings reveal an additional explanation for the protective effects of MR antagonists in cardiovascular disorders with sympathetic activation.


Assuntos
Cardiomegalia/tratamento farmacológico , Losartan/administração & dosagem , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Mineralocorticoides/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/administração & dosagem , Tecido Adiposo/metabolismo , Análise de Variância , Animais , Cardiomegalia/induzido quimicamente , Modelos Animais de Doenças , Isoproterenol/farmacologia , Masculino , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/efeitos dos fármacos , Papel (figurativo) , Vasoconstrição/efeitos dos fármacos
6.
Hypertension ; 66(4): 767-75, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26238446

RESUMO

Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a ß-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension.


Assuntos
Galectina 3/antagonistas & inibidores , Hiperaldosteronismo/complicações , Hipertensão/complicações , Miocardite/prevenção & controle , Espironolactona/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/etiologia , Fibrose/patologia , Galectina 3/biossíntese , Humanos , Hiperaldosteronismo/tratamento farmacológico , Hiperaldosteronismo/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocardite/etiologia , Miocardite/patologia , Ratos , Ratos Endogâmicos WKY , Ratos Wistar
7.
J Mol Cell Cardiol ; 86: 110-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26225841

RESUMO

AIM: The endothelium, mainly via nitric oxide (NO) release, adjusts the coronary flow. Cardiac function is closely linked to blood flow; thus, we tested the hypothesis that NO modulation in coronary arteries could be differentially adjusted after myocardial infarction (MI) in the presence or absence of heart failure (HF). METHODS AND RESULTS: Four weeks after coronary occlusion, the infarcted rats were subdivided into rats without (MI) or with HF signs according to haemodynamic parameters. The septal coronary arteries were subsequently used to perform functional and molecular experiments. Acetylcholine (ACh)-induced relaxation was decreased in the coronary arteries following HF, whereas it was enhanced in the arteries of the MI compared with those of SHAM-operated (SO) rats. The relaxation induced by the NO donor was similar among the groups. NO production, which was evaluated by 4,5-diaminofluorescein diacetate, was reduced in the coronary arteries of the HF group and increased in the arteries with MI after ACh-induced stimulation. HF coronary arteries exhibited oxidative stress, which was evaluated via ethidium bromide-positive nuclei, whereas it was decreased in MI. To evaluate the mechanisms involved in the enhanced ACh-induced relaxation in the arteries following MI, certain septal coronary arteries were pre-incubated with L-NAME (a nonselective NO synthase (NOS) inhibitor), 7-NI (a selective neuronal NOS (nNOS) inhibitor) or LY294002 (a PI3-kinase inhibitor). L-NAME and LY294002 reduced ACh-induced relaxation in the MI and SO rats; however, these effects were greater in the MI arteries. 7-NI reduced only the ACh-relaxation in MI. In addition, the eNOS, nNOS, Akt, and superoxide dismutase isoform protein expressions were greater in the coronary arteries of the MI than in those of the SO groups. CONCLUSION: Our data suggested that endothelial function was closely related to cardiac function after coronary occlusion. The coronary arteries from the HF rats exhibited reduced NO bioavailability, whereas the MI rats exhibited increased NO bioavailability because of increased eNOS/nNOS/PI3-kinase/Akt pathway and a reduction in ROS generation. These results suggest that enhanced NO modulation can prevent the onset of HF.


Assuntos
Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Acetilcolina/administração & dosagem , Animais , Disponibilidade Biológica , Oclusão Coronária , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , NG-Nitroarginina Metil Éster/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ratos , Vasodilatadores/administração & dosagem
8.
Front Chem ; 3: 24, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25870854

RESUMO

NADPH oxidases derived reactive oxygen species (ROS) play an important role in vascular function and remodeling in hypertension through redox signaling processes. Previous studies demonstrated that protein disulfide isomerase (PDI) regulates Nox1 expression and ROS generation in cultured vascular smooth muscle cells. However, the role of PDI in conductance and resistance arteries during hypertension development remains unknown. The aim of the present study was to investigate PDI expression and NADPH oxidase dependent ROS generation during hypertension development. Mesenteric resistance arteries (MRA) and thoracic aorta were isolated from 6, 8, and 12 week-old spontaneously hypertensive (SHR) and Wistar rats. ROS production (dihydroethidium fluorescence), PDI (WB, imunofluorescence), Nox1 and NOX4 (RT-PCR) expression were evaluated. Results show a progressive increase in ROS generation in MRA and aorta from 8 to 12 week-old SHR. This effect was associated with a concomitant increase in PDI and Nox1 expression only in MRA. Therefore, suggesting a positive correlation between PDI and Nox1 expression during the development of hypertension in MRA. In order to investigate if this effect was due to an increase in arterial blood pressure, pre hypertensive SHR were treated with losartan (20 mg/kg/day for 30 days), an AT1 receptor antagonist. Losartan decreased blood pressure and ROS generation in both vascular beds. However, only in SHR MRA losartan treatment lowered PDI and Nox1 expression to control levels. In MRA PDI inhibition (bacitracin, 0.5 mM) decreased Ang II redox signaling (p-ERK 1/2). Altogether, our results suggest that PDI plays a role in triggering oxidative stress and vascular dysfunction in resistance but not in conductance arteries, increasing Nox1 expression and activity. Therefore, PDI could be a new player in oxidative stress and functional alterations in resistance arteries during the establishment of hypertension.

9.
PLoS One ; 10(4): e0125388, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25923465

RESUMO

OBJECTIVE: Previous studies have shown that estrogen deficiency, arising in postmenopause, promotes endothelial dysfunction. This study evaluated the effects of aerobic exercise training on endothelial dependent vasodilation of aorta in ovariectomized rats, specifically investigating the role of nitric oxide (NO) and reactive oxygen species (ROS). METHODS: Female Wistar rats ovariectomized (OVX - n=20) or with intact ovary (SHAM - n=20) remained sedentary (OVX and SHAM) or performed aerobic exercise training on a treadmill 5 times a week for a period of 8 weeks (OVX-TRA and SHAM-TRA). In the thoracic aorta the endothelium-dependent and -independent vasodilation was assessed by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Certain aortic rings were incubated with L-NAME to assess the NO modulation on the ACh-induced vasodilation. The fluorescence to dihydroethidium in aortic slices and plasma nitrite/nitrate concentrations were measured to evaluate ROS and NO bioavailability, respectively. RESULTS: ACh-induced vasodilation was reduced in OVX rats as compared SHAM (Rmax: SHAM: 86±3.3 vs. OVX: 57±3.0%, p<0.01). Training prevented this response in OVX-TRA (Rmax: OVX-TRA: 88±2.0%, p<0.01), while did not change it in SHAM-TRA (Rmax: SHAM-TRA: 80±2.2%, p<0.01). The L-NAME incubation abolished the differences in ACh-induced relaxation among groups. SNP-induced vasodilation was not different among groups. OVX reduced nitrite/nitrate plasma concentrations and increased ROS in aortic slices, training as effective to restore these parameters to the SHAM levels. CONCLUSIONS: Exercise training, even in estrogen deficiency conditions, is able to improve endothelial dependent vasodilation in rat aorta via enhanced NO bioavailability and reduced ROS levels.


Assuntos
Endotélio Vascular/metabolismo , Exercício , Menopausa/fisiologia , Óxido Nítrico/metabolismo , Condicionamento Físico Animal , Animais , Disponibilidade Biológica , Endotélio Vascular/patologia , Feminino , Humanos , Menopausa/metabolismo , Ovariectomia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/fisiologia
10.
Br J Pharmacol ; 172(14): 3484-94, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25832173

RESUMO

BACKGROUND AND PURPOSE: Eugenol, a vanilloid molecule found in some dietary plants, relaxes vasculature in part via an endothelium-dependent process; however, the mechanisms involved are unclear. Here, we investigated the endothelial cell-mediated mechanism by which eugenol modulates rat mesenteric artery contractility and systemic BP. EXPERIMENTAL APPROACH: The isometric tension of rat mesenteric arteries (size 200-300 µm) was measured using wire myography; non-selective cation currents (ICat ) were recorded in endothelial cells using patch clamp electrophysiology. Mean arterial pressure (MAP) and heart rate (HR) were determined in anaesthetized rats. KEY RESULTS: Eugenol relaxed endothelium-intact arteries in a concentration-dependent manner and this effect was attenuated by endothelium denudation. L-NAME, a NOS inhibitor, a combination of TRAM-34 and apamin, selective blockers of intermediate and small conductance Ca(2+) -activated K(+) channels, respectively, and HC-067047, a TRPV4 channel inhibitor, but not indomethacin, a COX inhibitor, reduced eugenol-induced relaxation in endothelium-intact arteries. Eugenol activated HC-067047-sensitive ICat in mesenteric artery endothelial cells. Short interfering RNA (siRNA)-mediated TRPV4 knockdown abolished eugenol-induced ICat activation. An i.v. injection of eugenol caused an immediate, transient reduction in both MAP and HR, which was followed by prolonged, sustained hypotension in anaesthetized rats. This sustained hypotension was blocked by HC-067047. CONCLUSIONS AND IMPLICATIONS: Eugenol activates TRPV4 channels in mesenteric artery endothelial cells, leading to vasorelaxation, and reduces systemic BP in vivo. Eugenol may be therapeutically useful as an antihypertensive agent and is a viable molecular candidate from which to develop second-generation TRPV4 channel activators that reduce BP.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Eugenol/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Relação Estrutura-Atividade
11.
Life Sci ; 125: 49-56, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25640757

RESUMO

AIMS: The aim of this study was to investigate whether ß-adrenoceptor (ß-AR) overstimulation induced by in vivo treatment with isoproterenol (ISO) alters vascular reactivity and nitric oxide (NO) production and signaling in pulmonary arteries. MAIN METHODS: Vehicle or ISO (0.3mgkg(-1)day(-1)) was administered daily to male Wistar rats. After 7days, the jugular vein was cannulated to assess right ventricular (RV) systolic pressure (SP) and end diastolic pressure (EDP). The extralobar pulmonary arteries were isolated to evaluate the relaxation responses, protein expression (Western blot), NO production (diaminofluorescein-2 fluorescence), and cyclic guanosine 3',5'-monophosphate (cGMP) levels (enzyme immunoassay kit). KEY FINDINGS: ISO treatment induced RV hypertrophy; however, no differences in RV-SP and EDP were observed. The pulmonary arteries from the ISO-treated group showed enhanced relaxation to acetylcholine that was abolished by the NO synthase (NOS) inhibitor N(ω)-nitro-l-arginine methyl ester (l-NAME); whereas relaxation elicited by sodium nitroprusside, ISO, metaproterenol, mirabegron, or KCl was not affected by ISO treatment. ISO-treated rats displayed enhanced endothelial NOS (eNOS) and vasodilator-stimulated phosphoprotein (VASP) expression in the pulmonary arteries, while phosphodiesterase-5 protein expression decreased. ISO treatment increased NO and cGMP levels and did not induce eNOS uncoupling. SIGNIFICANCE: The present data indicate that ß-AR overactivation enhances the endothelium-dependent relaxation of pulmonary arteries. This effect was linked to an increase in eNOS-derived NO production, cGMP formation and VASP content and to a decrease in phosphodiesterase-5 expression. Therefore, elevated NO bioactivity through cGMP/VASP signaling could represent a protective mechanism of ß-AR overactivation on pulmonary circulation.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Isoproterenol/farmacologia , Óxido Nítrico/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Moléculas de Adesão Celular/metabolismo , Endotélio Vascular/fisiologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfoproteínas/metabolismo , Artéria Pulmonar/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
12.
Am J Physiol Heart Circ Physiol ; 307(11): H1655-66, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25305179

RESUMO

Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.


Assuntos
Terapia por Exercício , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Reflexo/fisiologia , Adulto , Idoso , Doença Crônica , Ciclo-Oxigenase 2/fisiologia , Teste de Esforço , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor CB1 de Canabinoide/biossíntese , Transdução de Sinais/fisiologia , Volume Sistólico/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Canais de Cátion TRPV/biossíntese
13.
Exp Physiol ; 99(10): 1427-38, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25037566

RESUMO

Knockout mice lacking both α2A- and α2C-adrenergic receptors (α2A/α2C-ARKO) provide a model for understanding the mechanisms underlying the deleterious effects of sympathetic hyperactivity on the cardiovascular system. Thus, in the present study we investigated the vascular reactivity of large and small arteries of α2A/α2C-ARKO mice. Aorta and mesenteric small arteries (MSAs) from 7-month-old male α2A/α2C-ARKO mice and congenic C57BL6/J mice (wild-type, WT) were studied. In the aorta, noradrenaline- and serotonin-induced contraction was similar between groups, but in MSAs there was an increase in agonist-induced contraction in α2A/α2C-ARKO compared with WT. The l-NAME effect was reduced in MSAs of α2A/α2C-ARKO mice compared with WT mice, as was basal NO evaluated by a 4,5-diaminofluorescein diacetate probe. Increased total endothelial nitric oxide synthase (eNOS) protein expression was observed in MSAs from α2A/α2C-ARKO mice, while the dimer/monomer ratio of eNOS was decreased. Mesenteric small arteries from α2A/α2C-ARKO mice showed an increase in ethidium bromide-positive nuclei, indicating oxidative stress, which was attenuated by incubation with l-NAME. The sympathetic hyperactivity present in α2A/α2C-ARKO mice alters vascular reactivity only in certain types of arteries. Moreover, after chronic sympathetic hyperactivity, uncoupling eNOS may be a significant source of superoxide anion and reduced NO bioavailability in small vessels, increasing the contractile tone.


Assuntos
Endotélio Vascular/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Camundongos , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Receptores Adrenérgicos alfa 2/genética
14.
PLoS One ; 9(3): e91877, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24622771

RESUMO

OBJECTIVE: Sustained ß-adrenergic stimulation is a hallmark of sympathetic hyperactivity in cardiovascular diseases. It is associated with oxidative stress and altered vasoconstrictor tone. This study investigated the ß-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of ß-adrenoceptor overactivation. METHODS AND RESULTS: Mice lacking the ß1- or ß2-adrenoceptor subtype (ß1KO, ß2KO) and wild-type (WT) were treated with isoproterenol (ISO, 15 µg.g(-1) x day(-1), 7 days). ISO significantly enhanced the maximal vasoconstrictor response (Emax) of the aorta to phenylephrine in WT (+34%) and ß1KO mice (+35%) but not in ß2KO mice. The nitric oxide synthase (NOS) inhibitor L-NAME abolished the differences in phenylephrine response between the groups, suggesting that ISO impaired basal NO availability in the aorta of WT and ß1KO mice. Superoxide dismutase (SOD), pertussis toxin (PTx) or PD 98,059 (p-ERK 1/2 inhibitor) incubation reversed the hypercontractility of aortic rings from ISO-treated WT mice; aortic contraction of ISO-treated ß2KO mice was not altered. Immunoblotting revealed increased aortic expression of Giα-3 protein (+50%) and phosphorylated ERK1/2 (+90%) and decreased eNOS dimer/monomer ratio in ISO-treated WT mice. ISO enhanced the fluorescence response to dihydroethidium (+100%) in aortas from WT mice, indicating oxidative stress that was normalized by SOD, PTx and L-NAME. The ISO effects were abolished in ß2KO mice. CONCLUSIONS: The ß2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term ß2-AR activation might results in endothelial dysfunction.


Assuntos
Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Isoproterenol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/química , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Receptores Adrenérgicos beta 2/deficiência , Receptores Adrenérgicos beta 2/genética , Vasoconstrição/efeitos dos fármacos
15.
J Hypertens ; 32(3): 542-54, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24309491

RESUMO

AIMS: Endogenous ouabain is elevated in patients and experimental models of hypertension and is associated with elevated mortality. In this context, it is reasonable to assume that a new antihypertensive drug that inhibits the deleterious effects of endogenous ouabain may be a specific pharmacological tool for hypertension treatment. Here, we investigated the effects of rostafuroxin (ROSTA), an ouabain inhibitor, on SBP, endothelial dysfunction and oxidative stress in deoxycorticosterone acetate (DOCA)-salt rats. METHODS AND RESULTS: A hypertensive model was established in uninephrectomized Wistar rats using DOCA-salt. After SBP stabilization, DOCA-salt rats were divided into two groups: DOCA-salt (control) and DOCA-salt treatment with ROSTA (1 mg/kg per day gavage, 3 weeks). The SBP was measured using the tail-cuff method, and vascular function was assessed in mesenteric-resistance arteries (MRAs) using a wire myograph. Nitric oxide and reactive oxygen species production were investigated. Western blot was performed to quantify protein expression. Our results indicated that ROSTA treatment decreased SBP, improved acetylcholine-induced relaxation via enhanced nitric oxide synthesis and bioavailability, decreased superoxide anion generation from NAD(P)H oxidase and cyclooxygenase-2 and reduced cytoplasmic tyrosine kinase Src phosphorylation without changes in NaKATPase activity in MRA from DOCA-salt rats. CONCLUSION: This study reports the critical role of endogenous ouabain in volume-dependent hypertension. In MRA from DOCA-salt rats, the binding of endogenous ouabain to NaK-ATPase results in downstream c-SRC activation, oxidative stress and endothelial dysfunction. Endogenous ouabain is a putative target for the treatment of hypertension, and ROSTA may represent a novel therapeutic approach.


Assuntos
Androstanóis/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Ouabaína/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ciclo-Oxigenase 2/metabolismo , Acetato de Desoxicorticosterona/toxicidade , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/etiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , NADPH Oxidases/metabolismo , Ouabaína/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Cloreto de Sódio na Dieta/toxicidade , ATPase Trocadora de Sódio-Potássio/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases da Família src/metabolismo
16.
Int J Cardiol ; 168(4): 3829-36, 2013 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-23849970

RESUMO

BACKGROUND/OBJECTIVES: Therapy using bone marrow (BM) cells has been tested experimentally and clinically due to the potential ability to restore cardiac function by regenerating lost myocytes or increasing the survival of tissues at risk after myocardial infarction (MI). In this study we aimed to evaluate whether BM-derived mononuclear cell (MNC) implantation can positively influence the post-MI structural remodeling, contractility and Ca(2+)-handling proteins of the remote non-infarcted tissue in rats. METHODS AND RESULTS: After 48 h of MI induction, saline or BM-MNC were injected. Six weeks later, MI scars were slightly smaller and thicker, and cardiac dilatation was just partially prevented by cell therapy. However, the cardiac performance under hemodynamic stress was totally preserved in the BM-MNC treated group if compared to the untreated group, associated with normal contractility of remote myocardium as analyzed in vitro. The impaired post-rest potentiation of contractile force, associated with decreased protein expression of the sarcoplasmic reticulum Ca(2+)-ATPase and phosphorylated-phospholamban and overexpression of Na(+)/Ca(2+) exchanger, were prevented by BM-MNC, indicating preservation of the Ca(2+) handling. Finally, pathological changes on remodeled remote tissue such as myocyte hypertrophy, interstitial fibrosis and capillary rarefaction were also mitigated by cell therapy. CONCLUSIONS: BM-MNC therapy was able to prevent cardiac structural and molecular remodeling after MI, avoiding pathological changes on Ca(2+)-handling proteins and preserving contractile behavior of the viable myocardium, which could be the major contributor to the improvements of global cardiac performance after cell transplantation despite that scar tissue still exists.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Contração Miocárdica/fisiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Animais , Transplante de Medula Óssea/métodos , Feminino , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Endogâmicos Lew
17.
J Hypertens ; 31(5): 916-26, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23429663

RESUMO

OBJECTIVE: To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs). METHODS: De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied. Neuronal nitric oxide synthase (nNOS) expression and nitric oxide, superoxide anions (O(2.-)), noradrenaline and CGRP levels were also determined. RESULTS: Aerobic exercise training decreased vasoconstrictor response to EFS but increased noradrenaline response. Phentolamine decreased while N(ω)-nitro-(L)-arginine methyl ester ((L)-NAME) increased the response to EFS; the effect of both drugs was greater in trained animals. Training also decreased noradrenaline release and O(2.-) production and increased nNOS expression, nitric oxide release and the vasodilator response to DEA-NO. The O(2.-) scavenger tempol increased DEA-NO-induced vasodilation only in sedentary rats. The EFS-induced contraction was increased to a similar extent in both experimental groups by preincubation with CGRP (8-37). CGRP release and vasodilator response were not modified by training. CONCLUSION: Aerobic exercise training decreases contractile response to EFS in mesenteric artery from SHRs. This effect is the net result of decreased noradrenaline release, increased sensitivity to the vasoconstrictive effects of noradrenaline and increased neuronal nitric oxide release and bioavailability. These modifications might contribute to the beneficial effects of aerobic exercise training on blood pressure.


Assuntos
Hipertensão/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Condicionamento Físico Animal , Animais , Disponibilidade Biológica , Estimulação Elétrica , Masculino , Artérias Mesentéricas/inervação , Óxido Nítrico Sintase Tipo I/fisiologia , Ratos , Ratos Endogâmicos SHR , Vasoconstrição
18.
Arq. bras. cardiol ; 98(3): 243-251, mar. 2012. tab
Artigo em Português | LILACS | ID: lil-622515

RESUMO

FUNDAMENTO: A Contração Pós-Repouso (CPR) do músculo cardíaco fornece informações indiretas sobre a manipulação de cálcio intracelular. OBJETIVO: Nosso objetivo foi estudar o comportamento da CPR e seus mecanismos subjacentes em camundongos com infarto do miocárdio. MÉTODOS: Seis semanas após a oclusão coronariana, a contratilidade dos Músculos Papilares (MP) obtidos a partir de camundongos submetidos à cirurgia sham (C, n = 17), com infarto moderado (MMI, n = 10) e grande infarto (LMI, n = 14), foi avaliada após intervalos de repouso de 10 a 60 segundos antes e depois da incubação com cloreto de lítio (Li+) em substituição ao cloreto de sódio ou rianodina (Ry). A expressão proteica de SR Ca(2+)-ATPase (SERCA2), trocador Na+/Ca2+ (NCX), fosfolambam (PLB) e fosfo-Ser (16)-PLB foi analisada por Western blotting. RESULTADOS: Os camundongos MMI apresentaram potenciação de CPR reduzida em comparação aos camundongos C. Em oposição à potenciação normal para camundongos C, foram observadas degradações de força pós-repouso nos músculos de camundongos LMI. Além disso, a Ry bloqueou a degradação ou potenciação de PRC observada em camundongos LMI e C; o Li+ inibiu o NCX e converteu a degradação em potenciação de CPR em camundongos LMI. Embora os camundongos MMI e LMI tenham apresentado diminuição no SERCA2 (72 ± 7% e 47 ± 9% de camundongos controle, respectivamente) e expressão protéica de fosfo-Ser16-PLB (75 ± 5% e 46 ± 11%, respectivamente), a superexpressão do NCX (175 ± 20%) só foi observada nos músculos de camundongos LMI. CONCLUSÃO: Nossos resultados mostraram, pela primeira vez, que a remodelação miocárdica pós-IAM em camundongos pode mudar a potenciação regular para degradação pós-repouso, afetando as proteínas de manipulação de Ca(2+) em miócitos.


BACKGROUND: Post-rest contraction (PRC) of cardiac muscle provides indirect information about the intracellular calcium handling. OBJECTIVE: Our aim was to study the behavior of PRC, and its underlying mechanisms, in rats with myocardial infarction. METHODS: Six weeks after coronary occlusion, the contractility of papillary muscles (PM) obtained from sham-operated (C, n=17), moderate infarcted (MMI, n=10) and large infarcted (LMI, n=14) rats was evaluated, following rest intervals of 10 to 60 seconds before and after incubation with lithium chloride (Li+) substituting sodium chloride or ryanodine (Ry). Protein expression of SR Ca(2+)-ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLB) and phospho-Ser(16)-PLB were analyzed by Western blotting. RESULTS: MMI exhibited reduced PRC potentiation when compared to C. Opposing the normal potentiation for C, post-rest decays of force were observed in LMI muscles. In addition, Ry blocked PRC decay or potentiation observed in LMI and C; Li+ inhibited NCX and converted PRC decay to potentiation in LMI. Although MMI and LMI presented decreased SERCA2 (72±7% and 47±9% of Control, respectively) and phospho-Ser16-PLB (75±5% and 46±11%, respectively) protein expression, overexpression of NCX (175±20%) was only observed in LMI muscles. CONCLUSION: Our results showed, for the first time ever, that myocardial remodeling after MI in rats may change the regular potentiation to post-rest decay by affecting myocyte Ca(2+) handling proteins.


FUNDAMENTO: La Contracción pos pausa (CPP) del músculo cardíaco provee informaciones indirectas sobre la manejo del calcio intracelular. OBJETIVO: Nuestro objetivo fue estudiar el comportamiento de la CPP y sus mecanismos subyacentes en Ratas con infarto de miocardio. MÉTODOS: Seis semanas después de la oclusión coronaria, la contractilidad de los Músculos Papilares (MP) obtenidos a partir de Ratas sometidos a falsa cirurgia (C, n = 17), con infarto moderado (MMI, n = 10) y gran infarto (LMI, n = 14), fue evaluada después de pausas de estímulos de 10 a 60 segundos antes y después de la incubación con cloruro de litio (Li+) en substitución del cloruro de sodio o rianodina (Ry). La expresión proteica de SR Ca(2+)-ATPasa (SERCA2), intercambiador Na+/Ca2+ (NCX), fosfolamban (PLB) y fosfo-Ser (16)-PLB fue analizada por Western blotting. RESULTADOS: Los Ratas MMI presentaron potenciación de CPP reducida en comparación a los Ratas C. En oposición a la potenciación normal para Ratas C, fueron observadas decaimientos de fuerza post-reposo en los músculos de Ratas LMI. Además de eso, la Ry bloqueó la decaimiento o potenciación de PRC observada en Ratas LMI y C; el Li+ inhibió el NCX y convirtió la decaimiento en potenciación de CPP en Ratas LMI. Aunque los Ratas MMI y LMI hayan presentado disminución en el SERCA2 (72 ± 7% y 47 ± 9% de Ratas control, respectivamente) y expresión proteica de fosfo-Ser16-PLB (75 ± 5% y 46 ± 11%, respectivamente), la superexpresión del NCX (175 ± 20%) sólo fue observada en los músculos de Ratas LMI. CONCLUSIÓN: Nuestros resultados mostraron, por primera vez, que el remodelado miocárdico post-IAM en Ratas puede cambiar la potenciación regular para decaimiento post-reposo, afectando las proteínas de manejo del Ca(2+) en miocitos.


Assuntos
Animais , Ratos , Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Remodelação Ventricular/fisiologia , Modelos Animais de Doenças , Cloreto de Lítio/farmacologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/classificação , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Distribuição Aleatória , Ratos Wistar , Rianodina/farmacologia
19.
Arq Bras Cardiol ; 98(3): 243-51, 2012 Mar.
Artigo em Inglês, Português, Espanhol | MEDLINE | ID: mdl-22344675

RESUMO

BACKGROUND: Post-rest contraction (PRC) of cardiac muscle provides indirect information about the intracellular calcium handling. OBJECTIVE: Our aim was to study the behavior of PRC, and its underlying mechanisms, in rats with myocardial infarction. METHODS: Six weeks after coronary occlusion, the contractility of papillary muscles (PM) obtained from sham-operated (C, n=17), moderate infarcted (MMI, n=10) and large infarcted (LMI, n=14) rats was evaluated, following rest intervals of 10 to 60 seconds before and after incubation with lithium chloride (Li(+)) substituting sodium chloride or ryanodine (Ry). Protein expression of SR Ca(2+)-ATPase (SERCA2), Na(+)/Ca(2+) exchanger (NCX), phospholamban (PLB) and phospho-Ser(16)-PLB were analyzed by Western blotting. RESULTS: MMI exhibited reduced PRC potentiation when compared to C. Opposing the normal potentiation for C, post-rest decays of force were observed in LMI muscles. In addition, Ry blocked PRC decay or potentiation observed in LMI and C; Li(+) inhibited NCX and converted PRC decay to potentiation in LMI. Although MMI and LMI presented decreased SERCA2 (72±7% and 47±9% of Control, respectively) and phospho-Ser(16)-PLB (75±5% and 46±11%, respectively) protein expression, overexpression of NCX (175±20%) was only observed in LMI muscles. CONCLUSION: Our results showed, for the first time ever, that myocardial remodeling after MI in rats may change the regular potentiation to post-rest decay by affecting myocyte Ca(2+) handling proteins.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Cloreto de Lítio/farmacologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/classificação , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Rianodina/farmacologia
20.
J Hypertens ; 29(12): 2349-58, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22045123

RESUMO

OBJECTIVE: To evaluate the effect of low-intensity chronic exercise training (ExT) on blood pressure (BP), as well as the cardiac alterations associated with hypertension in aging hypertensive rats. METHODS: Male spontaneously hypertensive rats (SHR; 21 months old) and their normotensive control Wistar-Kyoto (WKY) rats were submitted to low-intensity training protocol for 13 weeks. BP, cardiac morphological and morphometric analysis, as well as gene expression of fibrotic and inflammatory factors were analyzed at the end of the training period. RESULTS: ExT reduced BP and heart rate in aged SHR. Left ventricle hypertrophy, collagen volume fraction and wall-to-lumen ratio of myocardium arterioles were also decreased in trained SHR. However, ExT was unable to reverse the either reduced capillary density or the cardiac myocyte hypertrophy observed in SHR as compared with WKY rats. Trained SHR showed higher metalloproteinase-2/tissue inhibitor metalloproteinase-2 (MMP-2/TIMP-2) ratio and lower levels of α-smooth muscle actin, but similar levels of connective tissue growth factor, transforming growth factor beta or IL-1 beta to that of nontrained SHR. CONCLUSION: Low to moderate-intensity chronic ExT reverses the cardiac alterations associated with hypertension: myocardial arteriole, left ventricle hypertrophy, collagen content and tachycardia. These changes could be consequence or cause of the reduction in BP observed in trained SHR. In addition, ExT does not worsen the underlying inflammatory burden associated with hypertension. Therefore, the data support a beneficial effect of ExT in aging SHR similar to that reported in young or middle-aged individuals, confirming that exercise is a healthy habit that induces cardiac improvements independently of age.


Assuntos
Envelhecimento/fisiologia , Coração/fisiopatologia , Hipertensão/fisiopatologia , Condicionamento Físico Animal , Actinas/metabolismo , Animais , Pressão Sanguínea/fisiologia , Colágeno/metabolismo , Vasos Coronários/patologia , Expressão Gênica , Frequência Cardíaca/fisiologia , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo
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