33 research outputs found
Deletion of kinin B2 receptor alters muscle metabolism and exercise performance
Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance
Avaliação de complexo enzimático e betaína natural em rações para frangos de corte criados em aviário comercial
Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function
Effects of losartan combined with exercise training in spontaneously hypertensive rats
Anatomic and physiological modifications in seedlings of Coffea arabica cultivar Siriema under drought conditions
Sistemas de alimentação para a recria de ovinos a pasto: avaliação do desempenho animal e características da forragem
Isoproterenol Induces Vascular Oxidative Stress And Endothelial Dysfunction Via A Giα-coupled β2-adrenoceptor Signaling Pathway
Objective: Sustained β-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 β-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of β-adrenoceptor overactivation. Methods and Results: Mice lacking the β1- or β2-adrenoceptor subtype (β1KO, β2KO) and wild-type (WT) were treated with isoproterenol (ISO, 15 μg.g-1.day-1, 7 days). ISO significantly enhanced the maximal vasoconstrictor response (Emax) of the aorta to phenylephrine in WT ( +34%) and β1KO mice (+35%) but not in β2KO 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 β1KO 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 β2KO 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 β2KO mice. Conclusions: The β2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term β2-AR activation might results in endothelial dysfunction. © 2014 Davel et al.93Parati, G., Esler, M., The human sympathetic nervous system: Its relevance in hypertension and heart failure (2012) Eur Heart J, 33, pp. 1058-1066Bristow, M.R., Gilbert, E.M., Abraham, W.T., Adams, K.F., Fowler, M.B., Hershberger, R.E., Kubo, S.H., Shusterman, N., Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure (1996) Circulation, 94 (11), pp. 2807-2816Carll, A.P., Willis, M.S., Lust, R.M., Costa, D.L., Farraj, A.K., Merits of non-invasive rat models of left ventricular heart failure (2011) Cardiovasc Toxicol, 11, pp. 91-112Banerjee, S.K., Sood, S., Dinda, A.K., Das, T.K., Maulik, S.K., Chronic oral administration of raw garlic protects against isoproterenol-induced myocardial necrosis in rat (2003) Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, 136 (4), pp. 377-386. , DOI 10.1016/j.cca.2003.10.011Murray, D.R., Mummidi, S., Valente, A.J., Yoshida, T., Somanna, N.K., β2 adrenergic activation induces the expression of IL-18 binding protein, a potent inhibitor of isoproterenol induced cardiomyocyte hypertrophy in vitro and myocardial hypertrophy in vivo (2012) J Mol Cell Cardiol, 52, pp. 206-218Murray, D.R., Prabhu, S.D., Chandrasekar, B., Chronic β-adrenergic stimulation induces myocardial proinflammatory cytokine expression (2000) Circulation, 101 (20), pp. 2338-2341Davel, A.P., Fukuda, L.E., Sá, L.L., Munhoz, C.D., Scavone, C., Effects of isoproterenol treatment for 7 days on inflammatory mediators in the rat aorta (2008) Am J Physiol Heart Circ Physiol, 295, pp. 211-219Davel, A.P.C., Kawamoto, E.M., Scavone, C., Vassallo, D.V., Rossoni, L.V., Changes in vascular reactivity following administration of isoproterenol for 1 week: A role for endothelial modulation (2006) British Journal of Pharmacology, 148 (5), pp. 629-639. , DOI 10.1038/sj.bjp.0706749, PII 0706749Kim, H.K., Park, W.S., Warda, M., Park, S.Y., Ko, E.A., Beta-adrenergic overstimulation impaired vascular contractility via actin-cytoskeleton disorganization in rabbit cerebral artery (2012) PLoS One, 7, pp. e43884Morisco, C., Zebrowski, D.C., Vatner, D.E., Vatner, S.F., Sadoshima, J., Beta-adrenergic cardiac hypertrophy is mediated primarily by the beta1-subtype in the rat heart (2001) Journal of Molecular and Cellular Cardiology, 33 (3), pp. 561-573. , DOI 10.1006/jmcc.2000.1332Patterson, A.J., Zhu, W., Chow, A., Agrawal, R., Kosek, J., Protecting the myocardium: A role for the β2-adrenergic receptor in the heart (2004) Crit Care Med, 32, pp. 1041-1048Srivastava, S., Chandrasekar, B., Gu, Y., Luo, J., Hamid, T., Hill, B.G., Prabhu, S.D., Downregulation of CuZn-superoxide dismutase contributes to b-adrenergic receptor-mediated oxidative stress in the heart (2007) Cardiovascular Research, 74 (3), pp. 445-455. , DOI 10.1016/j.cardiores.2007.02.016, PII S0008636307000673Ryall, J.G., Schertzer, J.D., Murphy, K.T., Allen, A.M., Lynch, G.S., Chronic β2- adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+- ATPase protein and activity (2008) Am J Physiol Heart Circ Physiol, 294, pp. H2587-H2595Au, D.H., Udris, E.M., Fan, V.S., Curtis, J.R., McDonell, M.B., Fihn, S.D., Risk of mortality and heart failure exacerbations associated with inhaled beta-adrenoceptor agonists among patients with known left ventricular systolic dysfunction (2003) Chest, 123 (6), pp. 1964-1969. , DOI 10.1378/chest.123.6.1964Xu, Q., Dalic, A., Fang, L., Kiriazis, H., Ritchie, R.H., Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure (2011) Br J Pharmacol, 162, pp. 1012-1028Flacco, N., Segura, V., Perez-Aso, M., Estrada, S., Seller, J.F., Different β-adrenoceptor subtypes coupling to cAMP or NO/cGMP pathways: Implications in the relaxant response of rat conductance and resistance vessels (2013) Br J Pharmacol, 169, pp. 413-425Chruscinski, A., Brede, M.E., Meinel, L., Lohse, M.J., Kobilka, B.K., Differential distribution of β-adrenergic receptor subtypes in blood vessels of knockout mice lacking β1- or β2- adrenergic receptors (2001) Mol Pharmacol, 60, pp. 955-962Daaka, Y., Luttrell, L.M., Lefkowitz, R.J., Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A (1997) Nature, 6, pp. 88-91Rohrer, D.K., Desai, K.H., Jasper, J.R., Stevens, M.E., Regula, D.P., Targeted disruption of the mouse β1-adrenergic receptor gene: Developmental and cardiovascular effects (1996) Proc Natl Acad Sci USA, 93, pp. 7375-7380Chruscinski, A.J., Rohrer, D.K., Schauble, E., Desai, K.H., Bernstein, D., Targeted disruption of the β2-adrenergic receptor gene (1999) J Biol Chem, 274, pp. 16694-16700Davel, A.P., Ceravolo, G.S., Wenceslau, C.F., Carvalho, M.H., Brum, P.C., Increased vascular contractility and oxidative stress in β2-adrenoceptor knockout mice: The role of NADPH oxidase (2012) J Vasc Res, 49, pp. 342-352Baloǧlu, E., Kiziltepe, O., Gürdal, H., The role of Gi proteins in reduced vasorelaxation response to beta-adrenoceptor agonists in rat aorta during maturation (2007) Eur J Pharmacol, 564, pp. 167-173Lembo, G., Iaccarino, G., Vecchione, C., Barbato, E., Morisco, C., Insulin enhances endothelial α2-adrenergic vasorelaxation by a pertussis toxin mechanism (1997) Hypertension, 30, pp. 1128-1134. , 1997Cai, S., Khoo, J., Mussa, S., Alp, N.J., Channon, K.M., Endothelial nitric oxide synthase dysfunction in diabetic mice: Importance of tetrahydrobiopterin in eNOS dimerisation (2005) Diabetologia, 48 (9), pp. 1933-1940. , DOI 10.1007/s00125-005-1857-5Lobato, N.S., Neves, K.B., Filgueira, F.P., Fortes, Z.B., Carvalho, M.H., The adipokine chemerin augments vascular reactivity to contractile stimuli via activation of the MEK-ERK1/2 pathway (2012) Life Sci, 91, pp. 600-606Fukuda, L.E., Davel, A.P., Verissimo-Filho, S., Lopes, L.R., Cachofeiro, V., Fenofibrate and pioglitazone do not ameliorate the altered vascular reactivity in aorta of isoproterenol-treated rats (2008) J Cardiovasc Pharmacol, 52, pp. 413-421Ogut, O., Brozovich, F.V., The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure (2008) J Cell Mol Med, 12, pp. 2158-2164Negrão, C.E., Hamilton, M.A., Fonarow, G.C., Hage, A., Moriguchi, J.D., Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure (2000) Am J Physiol Heart Circ Physiol, 278, pp. H168-H174Davel, A.P., Wenceslau, C.F., Akamine, E.H., Xavier, F.E., Couto, G.K., Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: An update (2011) Braz J Med Biol Res, 44, pp. 920-932Xu, J., Li, N., Dai, D.Z., Yu, F., Dai, Y., The endothelin receptor antagonist CPU0213 is more effective than aminoguanidine to attenuate isoproterenol-induced vascular abnormality by suppressing overexpression of NADPH oxidase, ETA, ETB, and MMP9 in the vasculature (2008) J Cardiovasc Pharmacol, 52, pp. 42-48Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A., Freeman, B.A., Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide (1990) Proc Natl Acad Sci USA, 87, pp. 1620-1624Mian, K.B., Martin, W., Differential sensitivity of basal and acetylcholine-stimulated activity of nitric oxide to destruction by superoxide anion in rat aorta (1995) Br J Pharmacol, 115, pp. 993-1000Ma, X.-I., Weyrich, A.S., Lefer, D.J., Lefer, A.M., Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium (1993) Circulation Research, 72 (2), pp. 403-412Ferro, A., Coash, M., Yamamoto, T., Rob, J., Ji, Y., Queen, L., Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt (2004) British Journal of Pharmacology, 143 (3), pp. 397-403. , DOI 10.1038/sj.bjp.0705933Pourageaud, F., Leblais, V., Bellance, N., Marthan, R., Muller, B., Role of β2- adrenoceptors (β-AR), but not β1-, β3-AR and endothelial nitric oxide, in beta- AR-mediated relaxation of rat intrapulmonary artery (2005) Naunyn Schmiedebergs Arch Pharmacol, 372, pp. 14-23Queen, L.R., Ji, Y., Xu, B., Young, L., Yao, K., Mechanisms underlying β2-adrenoceptor-mediated nitric oxide generation by human umbilical vein endothelial (2006) J Physiol, 576, pp. 585-594Xiao, R.P., Avdonin, P., Zhou, Y.Y., Cheng, H., Akhter, S.A., Coupling of β2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes (1999) Circ Res, 84, pp. 43-52Banquet, S., Delannoy, E., Agouni, A., Dessy, C., Lacomme, S., Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in β2-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery (2011) Cell Signal, 23, pp. 1136-1143Itoh, H., Toyama, R., Kozasa, T., Tsukamoto, T., Matsuoka, M., Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs (1988) J Biol Chem, 263, pp. 6656-6664Wong, Y.H., Conklin, B.R., Bourne, H.R., Gz-mediated hormonal inhibition of cyclic AMP accumulation (1992) Science, 255, pp. 339-342Li, Y., Anand-Srivastava, M.B., Inactivation of enhanced expression of Gi proteins by pertussis toxin attenuates the development of high blood pressure in spontaneously hypertensive rats (2002) Circulation Research, 91 (3), pp. 247-254. , DOI 10.1161/01.RES.0000029969.39875.4BSaha, S., Li, Y., Lappas, G., Anand-Srivastava, M.B., Activation of natriuretic peptide receptor-C attenuates the enhanced oxidative stress in vascular smooth muscle cells from spontaneously hypertensive rats: Implication of Gialpha protein (2008) J Mol Cell Cardiol, 44, pp. 336-344Anand-Srivastava, M.B., Enhanced expression of inhibitory guanine nucleotide regulatory protein in spontaneously hypertensive rats. Relationship to adenylate cyclase inhibition (1992) Biochem J, 288, pp. 79-85Ge, C., Garcia, R., Anand-Srivastava, M.B., Enhanced expression of Gialpha protein and adenylyl cyclase signaling in aortas from 1 kidney 1 clip hypertensive rats (2006) Canadian Journal of Physiology and Pharmacology, 84 (7), pp. 739-746. , DOI 10.1139/Y05-123Zemancíková, A., Török, J., Zicha, J., Kunes, J., Inactivation of G(i) proteins by pertussis toxin diminishes the effectiveness of adrenergic stimuli in conduit arteries from spontaneously hypertensive rats (2008) Physiol Res, 57, pp. 299-302Zou, M.-H., Shi, C., Cohen, R.A., Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite (2002) Journal of Clinical Investigation, 109 (6), pp. 817-826. , DOI 10.1172/JCI200214442Antoniades, C., Shirodaria, C., Leeson, P., Antonopoulos, A., Warrick, N., Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: Implications for endothelial function in human atherosclerosis (2009) Eur Heart J, 30, pp. 1142-1150Antoniades, C., Shirodaria, C., Warrick, N., Cai, S., De Bono, J., Lee, J., Leeson, P., Channon, K.M., 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: Effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling (2006) Circulation, 114 (11), pp. 1193-1201. , DOI 10.1161/CIRCULATIONAHA.106.612325, PII 0000301720060912000012Kim, N., Kim, H., Youm, J.B., Sun, P.W., Warda, M., Ko, J.-H., Han, J., Site specific differential activation of ras/raf/ERK signaling in rabbit isoproterenol-induced left ventricular hypertrophy (2006) Biochimica et Biophysica Acta - Molecular Cell Research, 1763 (10), pp. 1067-1075. , DOI 10.1016/j.bbamcr.2006.08.002, PII S0167488906002096Cheng, J., Wu, C.C., Gotlinger, K.H., Zhang, F., Falck, J.R., 20-Hydroxy- 5,8,11,14-eicosatetraenoic acid mediates endothelial dysfunction via IkappaB kinase-dependent endothelial nitric-oxide synthase uncoupling (2010) J Pharmacol Exp Ther, 332, pp. 57-65Bauersachs, J., Bouloumie, A., Fraccarollo, D., Hu, K., Busse, R., Ertl, G., Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: Role of enhanced vascular superoxide production (1999) Circulation, 100 (3), pp. 292-298Moens, A.L., Kietadisorn, R., Lin, J.Y., Kass, D., Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin (2011) J Mol Cell Cardiol, 5, pp. 559-563Kietadisorn, R., Juni, R.P., Moens, A.L., Tackling endothelial dysfunction by modulating NOS uncoupling: New insights into its pathogenesis and therapeutic possibilities (2012) Am J Physiol Endocrinol Metab, 302, pp. E481-E495Molenaar, P., Smolich, J.J., Russell, F.D., McMartin, L.R., Summers, R.J., Differential regulation of beta-1 and beta-2 adrenoceptors in guinea pig atrioventricular conducting system after chronic (-)-isoproterenol infusion (1990) Journal of Pharmacology and Experimental Therapeutics, 255 (1), pp. 393-400Soltysinska, E., Thiele, S., Olesen, S.P., Osadchii, O.E., Chronic sympathetic activation promotes downregulation of b-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction (2011) Pflugers Arch, 462, pp. 529-543Shenoy, S.K., Drake, M.T., Nelson, C.D., Houtz, D.A., Xiao, K., β-arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor (2006) J Biol Chem, 281, pp. 1261-1273Gava, A.L., Peotta, V.A., Cabral, A.M., Meyrelles, S.S., Vasquez, E.C., Decreased baroreflex sensitivity in isoproterenol-treated mice with cardiac hypertrophy (2004) Autonomic Neuroscience: Basic and Clinical, 114 (1-2), pp. 47-54. , DOI 10.1016/j.autneu.2004.07.003, PII S1566070204001614A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS) (1994) Circulation, 90, pp. 1765-1773. , CIBIS Investigators and CommitteesEffect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) (1999) Lancet, 353, pp. 2001-2007. , MERIT-HF Study GroupPacker, M., Bristow, M.R., Cohn, J.N., Colucci, W.S., Fowler, M.B., Gilbert, E.M., Shusterman, N.H., The effect of carvedilol on morbidity and mortality in patients with chronic heart failure (1996) New England Journal of Medicine, 334 (21), pp. 1349-1355. , DOI 10.1056/NEJM199605233342101Hothersall, J.D., Black, J., Caddick, S., Vinter, J.G., Tinker, A., The design, synthesis and pharmacological characterization of novel β2-adrenoceptor antagonists (2011) Br J Pharmacol, 164, pp. 317-33
Effect of exercise training and carvedilol treatment on cardiac function and structure in mice with sympathetic hyperactivity-induced heart failure
The present investigation was undertaken to study the effect of β-blockers and exercise training on cardiac structure and function, respectively, as well as overall functional capacity in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α2A/α2CArKO). α2A/α2CArKO and their wild-type controls were studied for 2 months, from 3 to 5 months of age. Mice were randomly assigned to control (N = 45), carvedilol-treated (N = 29) or exercise-trained (N = 33) groups. Eight weeks of carvedilol treatment (38 mg/kg per day by gavage) or exercise training (swimming sessions of 60 min, 5 days/week) were performed. Exercise capacity was estimated using a graded treadmill protocol and HR was measured by tail cuff. Fractional shortening was evaluated by echocardiography. Cardiac structure and gastrocnemius capillary density were evaluated by light microscopy. At 3 months of age, no significant difference in fractional shortening or exercise capacity was observed between wild-type and α2A/α2CArKO mice. At 5 months of age, all α2A/α2CArKO mice displayed exercise intolerance and baseline tachycardia associated with reduced fractional shortening and gastrocnemius capillary rarefaction. In addition, α2A/ α2CArKO mice presented cardiac myocyte hypertrophy and ventricular fibrosis. Exercise training and carvedilol similarly improved fractional shortening in α2A/α2CArKO mice. The effect of exercise training was mainly associated with improved exercise tolerance and increased gastrocnemius capillary density while β-blocker therapy reduced cardiac myocyte dimension and ventricular collagen to wild-type control levels. Taken together, these data provide direct evidence for the respective beneficial effects of exercise training and carvedilol in α2A/α2CArKO mice preventing cardiac dysfunction. The different mechanisms associated with beneficial effects of exercise training and carvedilol suggest future studies associating both therapies