Effect of a single session of aerobic walking exercise on arterial pressure in community-living elderly individuals

Several studies have demonstrated that one exercise session (ES) on a cycloergometer or ergometric treadmill causes a reduction in blood pressure (BP). However, there are few similar studies on walking, which is the exercise modality most available to the elderly. We investigated the immediate and 24-h effects of walking on BP in independent, community-living elderly individuals. Volunteers participated in a single ES and resting control session (CS). Before and after each session, BP was measured by auscultatory and oscillometric methods. After each session, 24-h ambulatory blood pressure monitoring was conducted. An accelerometer was installed 48 h before the sessions and left in place for 5 days. The mean volunteer age was 67.7 +/- 3.5 years; 11 were hypertensive patients under treatment, and 12 were normotensive. In the total sample, there were immediate 14mm Hg and 12 mm Hg reductions in systolic BP (SBP) after the ES according to the auscultatory and oscillometric methods, respectively. Diastolic BP (DBP) was reduced by 4 mm Hg after the ES according to both methods. SBP during wakefulness and sleep and DBP during wakefulness were lower after the ES than after the CS (P<0.01), when wakefulness and sleep were determined individually (variable-time pattern) using data from the activity monitors and provided by the volunteers. The variable-time pattern was more effective in detecting reductions in BP than the fixed-time pattern. Hypertension Research (2012) 35, 457-462; doi: 10.1038/hr.2011.227; published online 9 February 2012

The role of reactive oxygen species in the modulation of the contraction induced by angiotensin II in carotid artery from diabetic rat

The modulation played by reactive oxygen species on the angiotensin II-induced contraction in type I-diabetic rat carotid was investigated. Concentration-response curves for angiotensin II were obtained in endothelium-intact or endothelium-denuded carotid from control or streptozotocin-induced diabetic rats, pre-treated with tiron (superoxide scavenger), PEG-catalase (hydrogen peroxide scavenger), dimethylthiourea (hydroxyl scavenger), apocynin [NAD(P) H oxidase inhibitor], SC560 (cyclooxygenase-1 inhibitor), SC236 (cyclooxygenase-2 inhibitor) or Y-27632 (Rho-kinase inhibitor). Reactive oxygen species were measured by flow cytometry in dihydroethidium (DHE)-loaded endothelial cells. Cyclooxygenase and AT1-receptor expression was assessed by immunohistochemistry. Diabetes increased the angiotensin II-induced contraction but reduced the agonist potency in rat carotid. Endothelium removal, tiron or apocynin restored the angiotensin II-induced contraction in diabetic rat carotid to control levels. PEG-catalase, DMTU or SC560 reduced the angiotensin II-induced contraction in diabetic rat carotid at the same extent. SC236 restored the angiotensin II potency in diabetic rat carotid. Y-27632 reduced the angiotensin II-induced contraction in endothelium-intact or -denuded diabetic rat carotid. Diabetes increased the DHE-fluorescence of carotid endothelial cells. Apocynin reduced the DHE-fluorescence of endothelial cells from diabetic rat carotid to control levels. Diabetes increased the muscular cyclooxygenase-2 expression but reduced the muscular AT1-receptor expression in rat carotid. In summary, hydroxyl radical, hydrogen peroxide and superoxide anion-derived from endothelial NAD(P) H oxidase mediate the hyperreactivity to angiotensin II in type I-diabetic rat carotid, involving the participation of cyclooxygenase-1 and Rho-kinase. Moreover, increased muscular cyclooxygenase-2 expression in type I-diabetic rat carotid seems to be related to the local reduced AT1-receptor expression and the reduced angiotensin II potency. (C) 2011 Elsevier B. V. All rights reserved.

Influência da suplementação de creatina sobre a massa óssea de ratos espontaneamente hipertensos

INTRODUÇÃO: Recentes evidências indicam que a suplementação de creatina (Cr) é capaz de aumentar a densidade mineral óssea (DMO) no fêmur de ratos saudáveis em crescimento. Entretanto, há poucos estudos que testam a efetividade da suplementação desse nutriente em condições de perda óssea. OBJETIVO: Investigar o efeito da suplementação de Cr na DMO e no conteúdo mineral ósseo (CMO) de ratos espontaneamente hipertensos (SHR), um modelo experimental de baixa massa óssea. MATERIAIS E MÉTODOS: Dezesseis ratos SHR machos com 8 meses de idade foram randomizados em dois grupos experimentais pareados pelo peso corporal, a saber: 1) Pl: SHR tratados com placebo (água destilada; n = 8); e 2) Cr: SHR tratados com Cr (n = 8). Após nove semanas de suplementação os animais foram eutanasiados e o fêmur e a coluna vertebral (L1-L4) foram analisados por densitometria óssea (Dual Energy X-Ray Absorptiometry). RESULTADOS: Não houve diferença significativa na DMO (Pl = 0,249 ± 0,003 g/cm² vs. Cr = 0,249 ± 0,004 g/cm²; P = 0,95) e no CMO (Pl = 0,509 ± 0,150 g vs. Cr = 0,509 ± 0,017 g; P = 0,99) da coluna vertebral e na DMO (Pl = 0,210 ± 0,004 g/cm² vs. Cr = 0,206 ± 0,004 g/cm2;P = 0,49) e no CMO (Pl = 0,407 ± 0,021 g vs. Cr = 0,385 ± 0,021 g; P = 0,46) do fêmur total entre os grupos experimentais. CONCLUSÃO: Neste estudo, usando um modelo experimental de baixa massa óssea, a suplementação de Cr não afetou a massa óssea.

O treinamento físico aeróbio corrige a rarefação capilar e as alterações nas proporções dos tipos de fibra muscular esquelética em ratos espontaneamente hipertensos

O treinamento físico (TF) aeróbio tem sido utilizado como um importante tratamento não farmacológico na hipertensão arterial (HA), uma vez que ele reduz a pressão arterial. Estudos mostram que as anormalidades do músculo esquelético na HA estão associados à rarefação capilar, um aumento na porcentagem de fibras de contração rápida (tipo II), com predominância do metabolismo glicolítico e um aumento da fadiga muscular. Entretanto, pouco se conhece sobre os efeitos do TF sobre estes parâmetros na HA. Nós hipotetizamos que o TF corrija a rarefação capilar potencialmente contribuindo para a restauração da proporção dos tipos de fibras musculares. Ratos espontaneamente hipertensos (SHR, n=14) e Wistar Kyoto (WKY, n=14) com 12 semanas de vida e divididos em 4 grupos: SHR, SHR treinado (SHR-T), WKY e WKY treinado (WKY-T) foram estudados. Como esperado, 10 semanas de TF foi efetivo em reduzir a pressão arterial em SHR-T. Além disso, avaliamos os principais marcadores de TF. A bradicardia de repouso, o aumento da tolerância a realização de esforço, do consumo de oxigênio de pico e da atividade da enzima citrato sintase muscular nos grupos de animais treinados (WKY-T e SHR-T) mostram que a condição aeróbia foi alcançada com este TF. O TF também corrigiu a rarefação capilar no músculo sóleo em SHR-T. Em paralelo, foi observada uma redução na porcentagem de fibras do tipo IIA e IIX, ao passo que aumentou a porcentagem de fibras do tipo I induzidas pelo TF na HA. Estes resultados sugerem que o TF previne as alterações na composição dos tipos de fibras no músculo sóleo em SHR, uma vez que a angiogênese e o aumento da atividade da enzima citrato sintase são umas das mais importantes adaptações ao TF aeróbio, atuando na manutenção do metabolismo oxidativo e do perfil de fibras do músculo.

Mesenchymal stem cells (MSC) prevented the progression of renovascular hypertension, improved renal function and architecture

Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×10(5) cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.

Changes in renal glucose transporters in an animal model of metabolic syndrome

Considering the similarity between structural, hemodynamic, and functional changes of obesity-related renal disease and diabetic nephropathy, we hypothesized that renal glucose transporter changes occur in obesity as in diabetes. The aim of the work was to evaluate GLUT1 and GLUT2 in kidneys of an animal model of metabolic syndrome. Neonate spontaneously hypertensive rats (SHR), n=15/group, were treated with monosodium glutamate (5 mg/g) (MetS) for 9 days and compared with saline-treated Wistar-Kyoto (C) and SHR (H) rats. Lee index, systolic arterial pressure (SAP), glycemia, insulin resistance, triglycerides, and HDL cholesterol were evaluated at 3 and 6 months. Medullar GLUT1 and cortical GLUT2 were analyzed by Western blot. MetS vs. C and H rats had the highest Lee index (p<0.001) and insulin resistance (3-months C: 4.3±0.7, H: 3.9±0.9, MetS: 2.7±0.6; 6-months C: 4.2±0.6, H: 3.8±0.5, MetS: 2.4±0.6% • min−1, p<0.001), similar glycemia, and the lowest HDL-cholesterol at 6-months (p<0.001). In the MetS and H rats, SAP was higher vs. C at 3-months (p<0.001) and 6-months (C: 151±15, H: 190±11, MetS: 185±13 mm Hg, p<0.001) of age. GLUT1 was ̴ 13× lower (p<0.001) at 3-months, reestablishing its content at 6-months in MetS group, while GLUT2 was 2× higher (p<0.001) in this group at 6-months of age. Renal GLUT1 and GLUT2 are modulated in kidney of rats with metabolic syndrome, where obesity, insulin resistance and hypertension coexist, despite normoglycemia. Like in diabetes, cortical GLUT2 overexpression may contribute to the development of kidney disease

Effect of simvastatin in the autonomic system is dependent on the increased gain/sensitivity of the baroreceptors

A number of mechanisms have been proposed to explain the pleiotropic effect of statin therapy to reduce sympathetic outflow in cardiovascular disease. We tested the hypothesis that statin treatment could improve baroreflex gain-sensitivity triggered by morphological adaptations in the mechanoreceptor site, thus reducing sympathetic activity, regardless of arterial pressure (AP) level reduction. Male spontaneously hypertensive rats (SHR) were divided into control (SHR, n = 8) and SHR-simvastatin (5 mg/kg/day, for 7 days) (SHR-S, n = 8). After treatment, AP, baroreflex sensitivity (BRS) in response to AP-induced changes, aortic depressor nerve activity, and spectral analyses of pulse interval (PI) and AP variabilities were performed. Internal and external carotids were prepared for morphoquantitative evaluation. Although AP was similar between groups, sympathetic modulation, represented by the low frequency band of PI (SHR: 6.84 ± 3.19 vs. SHR-S: 2.41 ± 0.96 msec2) and from systolic AP variability (SHR: 3.95 ± 0.36 vs. SHR-S: 2.86 ± 0.18 mmHg2), were reduced in treated animals. In parallel, simvastatin induced an increase of 26% and 21% in the number of elastic lamellae as well as a decrease of 9% and 25% in the carotid thickness in both, external and internal carotid, respectively. Moreover, improved baroreceptor function (SHR: 0.78 ± 0.03 vs. SHR-S: 1.06 ± 0.04% mv/mmHg) was observed in addition to a 115% increase in aortic depressor nerve activity in SHR-S rats. Therefore, our data suggest that the reduction of sympathetic outflow in hypertension by simvastatin treatment may be triggered by structural changes in the carotid arteries and increased BRS in response to an improvement of the baroreceptors discharge and consequently of the afferent pathway of the baroreflex arch.

Die eNOS als ein therapeutisches Zielmolekül kardiovaskulärer Erkrankungen

Die endotheliale NO-Synthase (eNOS) erfüllt – solange sie funktionell ist – vasoprotektive und anti-atherosklerotische Funktionen im kardiovaskulären System. So stellt die eNOS ein therapeutisches Zielmolekül kardiovaskulärer Erkrankungen dar. Unter pathophysiologischen Bedingungen wurden Hinweise auf eine „eNOS-Entkopplung“, d.h. die NOS-katalysierte Produktion von reaktiven Sauerstoff-Spezies, gefunden. Wir haben in den letzten Jahren Substanzen identifiziert, die die eNOS-Expression steigern, aber auch gleichzeitig die eNOS-Entkopplung revertieren können. Midostaurin z.B. korrigierte einerseits die eNOS-Entkopplung durch Unterdrückung der Expression der vaskulären NADPH-Oxidasen und erhöhte andererseits die eNOS-Expression im Gefäß-Endothel. Kombination dieser beiden Wirkungen führte zur Relaxation der Widerstandsgefäße in atherosklerotischen Mäusen und zur Blutdrucksenkung in spontan-hypertensiven Ratten. So scheint es eine praktikable Strategie für kardiovaskuläre Erkrankungen zu sein, die eNOS-Expression zu steigern und gleichzeitig die eNOS-Entkopplung zu verhindern bzw. eine bereits bestehende eNOS-Entkopplung zu revertieren.

TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology

The transient receptor potential channel (TRP) family comprises at least 28 genes in the human genome. These channels are widely expressed in many different tissues, including those of the cardiovascular system. The transient receptor potential channel melastatin 4 (TRPM4) is a Ca(2+)-activated non-specific cationic channel, which is impermeable to Ca(2+). TRPM4 is expressed in many cells of the cardiovascular system, such as cardiac cells of the conduction pathway and arterial and venous smooth muscle cells. This review article summarizes the recently described roles of TRPM4 in normal physiology and in various disease states. Genetic variants in the human gene TRPM4 have been linked to several cardiac conduction disorders. TRPM4 has also been proposed to play a crucial role in secondary hemorrhage following spinal cord injuries. Spontaneously hypertensive rats with cardiac hypertrophy were shown to over-express the cardiac TRPM4 channel. Recent studies suggest that TRPM4 plays an important role in cardiovascular physiology and disease, even if most of the molecular and cellular mechanisms have yet to be elucidated. We conclude this review article with a brief overview of the compounds that have been shown to either inhibit or activate TRPM4 under experimental conditions. Based on recent findings, the TRPM4 channel can be proposed as a future target for the pharmacological treatment of cardiovascular disorders, such as hypertension and cardiac arrhythmias.

Neuropeptide Y restores non-receptor-mediated vasoconstrictive action in superior mesenteric arteries in portal hypertension

BACKGROUND & AIMS Vascular hyporeactivity to vasoconstrictors contributes to splanchnic arterial vasodilatation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY), a sympathetic cotransmitter, has been shown to improve adrenergic vascular contractility in portal hypertensive rats and markedly attenuate hyperdynamic circulation. To further characterize the NPY-effects in portal hypertension, we investigated its role for non-receptor-mediated vasoconstriction in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham-operated rats. METHODS Ex vivo SMA perfusion of PVL and sham rats was used to analyse the effects of NPY on pressure response to non-receptor-mediated vasoconstriction. Dose-response curves to KCl (30-300 mM) were used to bypass G protein-coupled receptor mechanisms. Potential involvement of the cyclooxygenase-pathway was tested by non-selective cyclooxygenase-inhibition using indomethacin. RESULTS KCl-induced vascular contractility but not vascular sensitivity was significantly attenuated in PVL rats as compared with sham rats. Administration of NPY resulted in an augmentation of KCl-evoked vascular sensitivity being not different between study groups. However, KCl-induced vascular contractility was markedly more enhanced in PVL rats, thus, vascular response was no more significantly different between PVL and sham rats after addition of NPY. Administration of indomethacin abolished the NPY-induced enhancement of vasoconstriction. CONCLUSIONS Receptor-independent vascular contractility is impaired in mesenteric arteries in portal hypertension. NPY improves non-receptor mediated mesenteric vasoconstriction more effective in portal hypertension than in healthy conditions correcting splanchnic vascular hyporesponsiveness. This beneficial vasoactive action of NPY adds to its well known more pronounced effects on adrenergic vasoconstriction in portal hypertension making it a promising therapeutic agent in portal hypertension.

Caracterización y cuantificación de células progenitoras endoteliales de ratas espontáneamente hipertensas alimentadas con fructosa

Objetivo: Examinar cómo se ve afecta la participación de las células progenitoras endoteliales (CPE) por la resistencia a la insulina (IR) asociada a un modelo experimental de síndrome metabólico (SM), generado por la administración crónica de fructosa a ratas espontáneamente hipertensas. Material y métodos: Ratas WKY y SHR, macho, distribuidas en 4 grupos (n=8 c/u): WKY: controles; FFR: WKY recibiendo fructosa en agua de bebida al 10 % (v/v) durante 6 semanas; SHR; FFHR: SHR recibiendo fructosa en agua de bebida al 10 % (v/v) durante 6 semanas. Al finalizar el protocolo se determinó: presión arterial sistólica, variables bioquímicas, índice HOMA, cuantificación por citometría de flujo de los niveles de CPE en sangre periférica y en médula ósea, inmunofluorescencia en cultivo celular, para identificar los marcadores CD34 y VEGFR-2, recuento de colonias de CPE y actividad de NAD(P)H-oxidasa en tejido aórtico. Resultados: Se confirmó el modelo experimental en base a las variables metabólicas analizadas. Se observó una disminución en los niveles de CPE; en sangre periférica y médula ósea, la que se hace más importante en los grupos de animales tratados con fructosa. En estos también hay menor número de colonias de CPE desarrolladas en cultivo celular y presentan un aumento en los niveles de estrés oxidativo, estimado por la actividad de NAD(P)H oxidasa. Conclusión: el SM causado por la administración crónica de fructosa en FFHR ha demostrado generar una disminución en los niveles de CPE, así como en su capacidad funcional. Los mecanismos intracelulares que producen este fenómeno podrían estar desencadenados por el grado de IR que presenta este modelo experimental.

Aminopeptidase A inhibitors as potential central antihypertensive agents

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

Mécanismes moléculaires de l’hypertrophie vasculaire dans le modèle animal d’hypertension essentielle (SHR)

La voie de signalisation des phosphoinositides joue un rôle clé dans la régulation du tonus vasculaire. Plusieurs études rapportent une production endogène de l’angiotensin II (Ang II) et de l’endothéline-1 (ET-1) par les cellules musculaires lisses vasculaires (CMLVs) de rats spontanément hypertendus (spontaneously hypertensive rats : SHR). De plus, l’Ang II exogène induit son effet prohypertrophique sur les CMLVs selon un mécanisme dépendant de la protéine Gqα et de la PKCẟ. Cependant, le rôle de l’axe Gqα/PLCβ/PKCẟ dans l’hypertrophie des CMLVs provenant d’un modèle animal de l’hypertension artérielle n’est pas encore étudié. L’objectif principal de cette thèse est d’examiner le rôle de l’axe Gqα/PLCβ1 dans les mécanismes moléculaires de l’hypertrophie des CMLVs provenant d’un modèle animal d’hypertension artérielle essentielle (spontaneously hypertensive rats : SHR). Nos premiers résultats indiquent que contrairement aux CMLVs de SHR âgés de 12 semaines (absence d’hypertrophie cardiaque), les CMLVs de SHR âgés de 16 semaines (présence d’hypertrophie cardiaque) présentent une surexpression protéique endogène de Gqα et de PLCβ1 par rapport aux CMLVs de rats WKY appariés pour l’âge. L’inhibition du taux d’expression protéique de Gqα et de PLCβ1 par des siRNAs spécifiques diminue significativement le taux de synthèse protéique élevé dans les CMLVs de SHR. De plus, la surexpression endogène des Gqα et PLCβ1, l’hyperphosphorylation de la molécule ERK1/2 et le taux de synthèse protéique élevé dans les CMLVs de SHR de 16 semaines ont été atténués significativement par des antagonistes des récepteurs AT1 (losartan) et ETA (BQ123), mais pas par l’antagoniste du récepteur ETB (BQ788). L’inhibition pharmacologique des MAPKs par PD98059 diminue significativement la surexpression endogène de Gqα/PLCβ1 et le taux de synthèse protéique élevé dans les CMLVs de SHR. D’un côté, l’inhibition du stress oxydatif (par DPI, inhibiteur de la NAD(P)H oxidase, et NAC , molécule anti-oxydante), de la molécule c-Src (PP2) et des récepteurs de facteurs de croissance (AG1024 (inhibiteur de l’IGF1-R), AG1478 (inhibiteur de l’EGFR) et AG1295 (inhibiteur du PDGFR)) a permis d’atténuer significativement la surexpression endogène élevée de Gqα/PLCβ1 et l’hypertrophie des CMLVs de SHR. D’un autre côté, DPI, NAC et PP2 atténuent significativement l’hyperphosphorylation de la molécule c-Src, des RTKs (récepteurs à activité tyrosine kinase) et de la molécule ERK1/2. Dans une autre étude, nous avons aussi démontré que la PKCẟ montre une hyperphosphorylation en Tyr311 dans les CMLVs de SHR comparées aux CMLVs de WKY. La rottlerin, utilisée comme inhibiteur spécifique de la PKCẟ, inhibe significativement cette hyperphosphorylation en Tyr311 dépendamment de la concentration. L’inhibition de l’activité de la PKCẟ par la rottlerin a été aussi associée à une atténuation significative de la surexpression protéique endogène de Gqα/PLCβ1 et l’hypertrophie des CMLVs de SHR. De plus, l’inhibition pharmacologique de l’activité de la PKCẟ, en amont du stress oxydatif, a permis d’inhiber significativement l’activité de la NADPH, le taux de production élevée de l’ion superoxyde ainsi que l’hyperphosphorylation de la molécule ERK1/2, de la molécule c-Src et des RTKs. À notre surprise, nous avons aussi remarqué une surexpression protéique de l’EGFR et de l’IGF-1R dans les CMLVs de SHR à l’âge de 16 semaines. L’inhibition pharmacologique de l’activité de la PKCẟ, de la molécule c-Src et du stress oxydatif a permis d’inhiber significativement la surexpression protéique endogène de ces RTKs. De plus, l’inhibition de l’expression protéique de l’EGFR et de la molécule c-Src par des siRNA spécifiques atténue significativement le taux d’expression protéique élevé de Gqα et de PLCβ1 ainsi que le taux de synthèse protéique élevé dans les CMLVs de SHR. Des siRNAs spécifiques à la PKCẟ ont permis d’atténuer significativement le taux de synthèse protéique élevé dans les CMLVs de SHR et confirment le rôle important de la PKCẟ dans les mécanismes moléculaires de l’hypertrophie des CMLVs selon une voie dépendante du stress oxydatif. En conclusion, ces résultats suggèrent un rôle important de l’activation endogène de l’axe Gqα-PLCβ-PKCẟ dans le processus d’hypertrophie vasculaire selon un mécanisme impliquant une activation endogène des récepteurs AT1/ETa, de la molécule c-Src, du stress oxidatif, des RTKs et des MAPKs.

Antioxidant supplementation enhances erythrocyte antioxidant status and attenuates cyclosporine-induced vascular dysfunction

The aim of this study was to determine the effects of dietary antioxidant supplementation with a-tocopherol and a-lipoic acid on cyclosporine-induced alterations to erythrocyte and plasma redox balance, and cyclosporine-induced endothelial and smooth muscle dysfunction. Rats were randomly assigned to either control, antioxidant, cyclosporine or cyclosporine + antioxidant treatments. Cyclosporine A was administered for 10 days after an 8-week feeding period. Plasma was analyzed for alpha-tocopherol, total antioxidant capacity, malondialdehyde and creatinine. Erythrocytes were analyzed for glutathione, methemoglobin, superoxide dismutase, catalase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, alpha-tocopherol and malondialdehye. Vascular endothelial and smooth muscle function was determined in vitro. Antioxidant supplementation resulted in significant increases in erythrocyte a-tocopherol concentration and glutathione peroxidase activity in both of the antioxidant-supplemented groups. Cyclosporine administration caused significant decreases in glutathione concentration, methemoglobin concentration and superoxide dismutase activity. Antioxidant supplementation attenuated the cyclosporine-induced decrease in superoxide dismutase activity. Cyclosporine therapy impaired both endothelium-independent and -dependent relaxation of the thoracic aorta, and this was attenuated by antioxidant supplementation. In summary, dietary supplementation with alpha-tocopherol and alpha-lipoic acid attenuated the cyclosporine-induced decrease in erythrocyte superoxide dismutase activity and attenuated cyclosporine-induced vascular dysfunction.