Role of endothelium on the abnormal Angiotensin-mediated vascular functions in epileptic rats


Epidemiological studies have found that the risk for cardiovascular disease is increased in patients with epilepsy. The Renin Angiontensin System (RAS), an important player in vascular tone control, is also involved in many neurological disorders, including seizures and epilepsy. Although it has been reported that Angiotensin II (Ang II) release and Angiotensin receptors expression are altered in many cerebral areas in patients/animal models with neurological disorders, there are no data on the vascular function. We evaluated Ang I and Ang II-mediated vascular responses and to correlate their contractile responses to the pres- ence of endothelium and the protein levels of components of the RAS (AT1, AT2, Mas and ACE) in aorta isolated from genetically epileptic rats (WAR strain). The major finding was that the vascular contractile response induced by Ang I and Ang II is endothelium-dependent. Ang II induced contractions in aortas from Wistar rats either with intact endothelium (E+) (1.16 ± 0.04 g, n = 6) and endothelium-denuded (E-) (1.24 ± 0.04 g, n = 6). Maximum contractile response (ME) induced by Ang I was lower in Wistar E+ (0.45 ± 0.03 g, n = 6) compared with Wistar E- (1.13 ± 0.08 g, n = 6). Ang I and Ang II failed to induce contraction in WAR E+, whereas the ME induced by Ang I in WAR E- was lower (0.52 ± 0.04 g, n = 11) than in the Wistar. ME induced by Ang II in aortas from WAR was also lower (0.40 ± 0.03 g, n = 11) compared with Wistar. AT1 receptor expression in both E+ WAR and Wistar was lower than in both E- WAR and Wistar. AT2 and Mas receptor expression was higher in Wistar E- and E+ as compared to WAR E- and E+. ACE expression was higher in both E+ WAR and Wistar, but it was lower in both E- WAR and Wistar. Endothelium impairs the contractile response induced by Angiotensin in WAR, suggesting that endothelial relaxing factors play important role on the aorta contraction.

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Restini, C. , Reis, R. , Costa-Neto, C. , Garcia-Cairasco, N. , Cortes-de-Oliveira, J. and Bendhack, L. (2012) Role of endothelium on the abnormal Angiotensin-mediated vascular functions in epileptic rats. Journal of Biophysical Chemistry, 3, 174-182. doi: 10.4236/jbpc.2012.32019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Earnest, M.P., Thomas, G.E., Eden, R.A. and Hossack, K.F. (1992) The sudden unexplained death syndrome in epilepsy: Demographic, clinical, and postmortem features. Epilepsia, 33, 310-316. doi:10.1111/j.1528-1157.1992.tb02321.x
[2] Ficker, D.M., So, E.L., Shen, W.K., Annegers, JF, O’Brien, P.C., Cascino, G.D. and Belau, P.G. (1998) Populationbased study of the incidence of sudden unexplained death in epilepsy. Neurology, 51, 1270-1274.
[3] Bell, G.S. and Sander, J.W. (2006) Sudden unexpected death in epilepsy. Risk factors, possible mechanisms and prevention: A reappraisal. Acta Neurologica Taiwanica, 15, 72-83.
[4] Nei, M. and Hays, R. (2010) Sudden unexpected death in epilepsy. Current Neurology and Neuroscience Reports, 10, 319-326. doi:10.1007/s11910-010-0116-4
[5] Scorza, F.A., Arida, R.M., Terra, V.C. and Cavalheiro, E.A. (2010) What can be done to reduce the risk of SUDEP? Epilepsy Behavior, 18, 137-138. doi:10.1016/j.yebeh.2010.04.046
[6] Shorvon, S. and Tomson, T. (2011) Sudden unexpected death in epilepsy. Lancet, 378, 2028-2038. doi:10.1016/S0140-6736(11)60176-1
[7] Tchekalarova, J. and Georgiev, V. (2005) Angiotensin pep tides modulatory system: How is it implicated in the control of seizure susceptibility? Life Science, 76, 955-970. doi:10.1016/j.lfs.2004.10.012
[8] Arga?araz, G.A., Konno, A.C., Perosa, S.R., Santiago, J.F.C., Boim, M.A., Vidotti, D.B., Varella, P.P., Costa, L.G., Canzian, M., Porcionatto, M.A., Yacubian, E.M., Sakamoto, A.C., Carrete, H. Jr., Centeno, R.S., Amado, D., Cavalheiro, E.A., Silva J.A. Jr. and Mazzacoratti, M.G. (2008) The renin-Angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis. Epilepsia, 49, 1348-1357. doi:10.1111/j.1528-1167.2008.01581.x
[9] Peach, M.J. (1977) Renin-Angiotensin system: Biochemistry and mechanisms of action. Physiological Reviews, 57, 313-370.
[10] Ferrario, C.M., Jessup, J., Chappell, M.C., Averill, D.B., Brosnihan, K.B., Tallant E.A., Diz, D.I., and Gallagher, P.E. (2005) Effect of Angiotensin-converting enzyme inhibition and Angiotensin II receptor blockers on cardiac Angiotensin-converting enzyme 2, Circulation, 111, 2605-2610. doi:10.1161/CIRCULATIONAHA.104.510461
[11] Ferrario, C.M. and Strawn W.B. (2006) Role of the reninAngiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. The American Journal of Cardiology, 98, 121-128. doi:10.1016/j.amjcard.2006.01.059
[12] Mascareno, E., Galatioto, J., Rozenberg, I., Salciccioli, L., Kamran, H., Lazar, J.M., Liu, F., Pedrazzini, T. and Siddiqui, M.A. (2012) Cardiac lineage protein-1 (CLP-1) regulates cardiac remodeling via transcriptional modulation of diverse hypertrophic and fibrotic responses and Angiotensin II-transforming growth factor β (TGFβ1) signaling axis. Journal of Biological Chemistry, 287, 13084-13093. doi:10.1074/jbc.M111.288944
[13] Matsusaka, T. and Ichikawa, I. (1997) Biological functions of Angiotensin and its receptors. Annual Review of Physiology, 59, 395-412. doi:10.1146/annurev.physiol.59.1.395
[14] Santos, R.A.S., Campagnole-Santos, M.J. and Andrade, S. (2000) Angiotensin-(1-7): Na update. Regulatory Peptides, 91, 45-62. doi:10.1016/S0167-0115(00)00138-5
[15] Vickers, C., Hales, P., Kaushik, V., Dick, L., Gavin, J., Tang, J., Godbout, K., Parsons, T., Baronas, E., Hsieh, F., Acton, S., Patane, M., Nichols, A. and Tummino, P. (2002) Hydrolysis of biological peptides by human Angiotensinconverting enzyme related carboxypeptidase. Journal of Biological Chemistry, 277, 14838-14843. doi:10.1074/jbc.M200581200
[16] Oudit, G.Y., Crackower, M.A., Backx, P.H. and Penninger, J.M. (2003) The role of ACE2 in cardiovascular physiology. Trends in Cardiovascular Medicine, 13, 93-101. doi:10.1016/S1050-1738(02)00233-5
[17] Ferrario, C.M., Chappell, M.C., Tallant, E.A., Brosnihan, K.B. and Diz, D.I. (1997) Counterregulatory actions of Angiotensin-(1-7). Hypertension, 30, 535-541.
[18] Santos, R.A., Simoes e Silva, AC.,. Maric, C., Silva, D.M., Machado, R.P., de Buhr, I., Heringer-Walther, S., Pinheiro, S.V., Lopes, M.T., Bader, M., Mendes, E.P., Lemos, V.S., Campagnole-Santos, M.J., Schultheiss H.P., Speth, R. and Walther, T. (2003) Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences, 100, 8258-8263. doi:10.1073/pnas.1432869100
[19] De gasparo, M., Catt, C.J., Inagami, Wright, T.J.W. and Unger, T.H. (2000) International union of pharmacology. XXIII. The Angiotensin II receptors. Pharmacological Reviews, 52, 415-472.
[20] Ishii, K., Takekoshi, K., Shibuya, S., Kawakami, Y., Isobe, K. and Nakai, T. (2001) Angiotensin subtype-2 receptor (AT2) negatively regulates subtype-1 receptor (AT1) in signal transduction pathways in cultured porcine adrenal medullary chromaffin cells. Journal of Hypertension, 19, 1991-1999. doi:10.1097/00004872-200111000-00009
[21] Carey, R.M. (2005) Cardiovascular and renal regulation by the Angiotensin type 2 receptor: The AT2 receptor comes of age. Hypertension, 45, 840-844. doi:10.1161/01.HYP.0000159192.93968.8f
[22] Gendron, L., Payet, M.D. and Gallo-Payet, N. (2003). The Angiotensin type 2 receptor of Angiotensin II and neuronal differentiation: from observations to mechanisms. Journal of Molecular Endocrinology, 31, 359-372. doi:10.1677/jme.0.0310359
[23] Horiuchi, M., Akishita, M. and Dzau, V.J. (1999) Recent progress in Angiotensin II type 2 receptor research in the cardiovascular system. Hypertension, 33, 613-621.
[24] Stoll, M. and Unger, T. (2001) Angiotensin and its AT2 receptor: New insights into an old system. Regulatory Peptides, 99, 175-182. doi:10.1016/S0167-0115(01)00246-4
[25] Yan, C., Kim, D., Aizawa, T. and Berk, B.C. (2003) Functional interplay between Angiotensin II and nitric oxide: Cyclic GMP as a key mediator. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 26-36. doi:10.1161/01.ATV.0000046231.17365.9D
[26] Konishi, M. and Su, C. (1983) Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension, 5, 881-886.
[27] Wu, C.C., Chen, S.J. and Yen, M.H. (1993) Different responses to acetylcholine in the presence of nitric oxide inhibitor in rat aortae and mesenteric arteries. Clinical and Experimental Pharmacology and Physiology, 20, 405-412. doi:10.1111/j.1440-1681.1993.tb01717.x
[28] Osaka, T., Yamashita, H. and Koizumi, K. (1992) Inhibitory inputs to the subfornical organ from the AV3V: Involvement of GABA. Brain Research Bulletin, 29, 581-587. doi:10.1016/0361-9230(92)90126-I
[29] Dampney, R.A.L., Hirooka, Y., Potts, P.D. and Head G.A. (1996) Functions of Angiotensin peptides in the rostral ventrolateral medulla. Clinical and Experimental Pharmacology and Physiology, 3, S105-S111. doi:10.1111/j.1440-1681.1996.tb02822.x
[30] Head, G.A. (1996) Role of AT1 receptors in the central control of sympathetic vasomotor function. Clinical and Experimental Pharmacology and Physiology, 3, S93-S98. doi:10.1111/j.1440-1681.1996.tb02820.x
[31] Muratami, H. (1996) Brain Angiotensin and circulatory control. Clinical and Experimental Pharmacology and Physiology, 23, 458-464. doi:10.1111/j.1440-1681.1996.tb02761.x
[32] Unger, T., Becker, H., Petty, M., Demmert, G., Schneider, B., Ganten, D. and Langer, R.E. (1985) Differential effects of central Angiotensin II and substance P on sympathetic nerve activity in conscious rats. Implications for cardiovascular adaptation to behavioral responses. Circulation Research, 56, 563-575.
[33] Barnes, N.M., Cheng, C.H., Costall, B., Naylor, R.J., Williams, T.J. and Wischik, C.M. (1991) Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer’s disease. European Journal of Pharmacology, 200, 289-292.
[34] Tian, J., Shi, J., Bailey, K., Harris, J.M., Pritchard, A., Lambert, J.C., Chartier-Harlin, M.C., Pickering-Brown, S.M., Lendon, C.L. and Mann, D.M. (2004) A polymerphism in the Angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer’s disease. Neuroscience Letters, 354, 103-106.
[35] Grammatopoulos, T.N., Ahmadi, F., Jones, S.M., Fariss, M.W., Weyhenmeyer, J.A. and Zawada, W.M. (2005) Angiotensin II protects cultured midbrain dopaminergic neurons against rotenone-induced cell death. Brain Research, 1045, 64-71. doi:10.1016/j.brainres.2005.03.038
[36] Bird, E.D. (1980) Chemical pathology of Huntington’s disease. Annual Review of Pharmacology and Toxicology, 20, 533-551. doi:10.1146/
[37] Fisher, R.S. (1989) Animal models of epilepsy. Brain Research, 14, 254-278. doi:10.1016/0165-0173(89)90003-9
[38] Mishra, P.K., Kahle, E.H., Bettendorf, A.F., Dailey, J.W. and Jobe, P.C. (1993) Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR9s). Life Sciences, 52, 1435-1441. doi:10.1016/0024-3205(93)90067-D
[39] Doretto, M.C., Fonseca, C.G., L?bo, R.B., Terra, V.C., Oliveira, J.A.C. and Garcia-Cairasco, N. (2003) Quantitative study of the response to genetic selection of the Wistar Audiogenic Rat Strain (WAR). Behavior Genetics, 33, 33-41. doi:10.1023/A:1021099432759
[40] Garcia-Cairasco N. (1989) Neural and ethological relations in the evaluation of motor control changes. II. Experimental models. Arquivos de Neuro-Psiquiatria, 47, 172-181. doi:10.1590/S0004-282X1989000200008
[41] Terra, V.C. and Garcia-Cairasco, N. (1992) Neuroethological evaluation of audiogenic seizures and audiogeniclike seizures induced by microinjection of bicuculline into the inferior colliculus. II. Effects of nigral clobazam microinjections. Behavioural Brain Research, 52, 19-28. doi:10.1016/S0166-4328(05)80321-3
[42] Terra, V.C. and Garcia-Cairasco, N. (1994) NMDA-dependent audiogenic seizures are differentially regulated by inferior colliculus subnuclei. Behavioural Brain Research, 62, 29-39. doi:10.1016/0166-4328(94)90035-3
[43] Tsutsui, J., Terra, V.C., Oliveira, J.A. and Garcia-Cairasco, N. (1992) Neuroethological evaluation of audiogenic seizures and audiogenic-like seizures induced by microinjection of bicuculline into the inferior colliculus. I. Effects of midcollicular knife cuts. Behavioural Brain Research, 52, 7-17. doi:10.1016/S0166-4328(05)80320-1
[44] Garcia-Cairasco, N., Terra, V.C. and Doretto, M.C. (1993) Midbrain substrates of audiogenic seizures in rats. Behavioural Brain Research, 58, 57-67. doi:10.1016/0166-4328(93)90090-D
[45] Garcia-Cairasco, N., Wakamatsu, H., Oliveira, J.A., Gomes, E.L., Del Bel, E.A. and Mello LE. (1996) Neuroethological and morphological (Neo-Timm staining) correlates of limbic recruitment during the development of audiogenic kindling in seizure susceptible Wistar rats. Epilepsy Research, 26, 177-192. doi:10.1016/S0920-1211(96)00050-2
[46] Moraes, M.F., Del Vecchio, F., Terra, V.C. and GarciaCairasco, N. (2000) Time evolution of acoustic information processing in the mesencephalon of Wistar rats. Neuroscience Letters, 284, 13-16. doi:10.1016/S0304-3940(00)00978-2
[47] Romcy-Pereira, R.N. and Garcia-Cairasco, N. (2003) Hippocampal cell proliferation and epileptogenesis after audiogenic kindling are not accompanied by mossy fiber sprouting or Fluoro-Jade staining. Neuroscience, 119, 533-546. doi:10.1016/S0306-4522(03)00191-X
[48] Galvis-Alonso, O.Y., Cortes De Oliveira, J.A. and GarciaCairasco, N. (2004) Limbic epileptogenicity, cell loss and axonal reorganization induced by audiogenic and amygdala kindling in wistar audiogenic rats (WAR strain). Neuroscience, 125, 787-802. doi:10.1016/j.neuroscience.2004.01.042
[49] Doretto, M.C., Garcia-Cairasco, N., Pimenta, N.J., Souza, D.A. and Tatsuo MA. (1998) Dipyrone, a novel anticonvulsant agent? Insights from three experimental epilepsy models. NeuroReport, 9, 2415-2421. doi:10.1097/00001756-199807130-00048
[50] Ribeiro, A.M., dos Santos, W.F. and Garcia-Cairasco, N. (2000) Neuroethological analysis of the effects of spider venom from Scaptocosa raptoria (Lycosidae: Araneae) microinjected in the lateral ventricle of Wistar rats. Brain Research Bulletin, 52, 581-588. doi:10.1016/S0361-9230(00)00300-2
[51] Rossetti, F., Rodrigues, M.C., de Oliveira, J.A. and Garcia-Cairasco, N. (2006) EEG wavelet analyses of the striatum-substantia nigra pars reticulata-superior colliculus circuitry: audiogenic seizures and anticonvulsant drug administration in Wistar audiogenic rats (War strain). Epilepsy Research, 72, 192-208. doi:10.1016/j.eplepsyres.2006.08.001
[52] Pereira, M.G., Gitaí, D.L., Pa?ó-Larson, M.L., Pesquero, J.B., Garcia-Cairasco, N. and Costa-Neto CM. (2008) Modulation of B1 and B2 kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy. International Immunopharmacology, 8, 200-205. doi:10.1016/j.intimp.2007.07.028
[53] Allen, A.M., Zhuo, J., Mendelsohn, F.A. (2001) AT1-receptors in the central nervous system. Journal of the ReninAngiotensin-Aldosterone System, 2, S95-S101. doi:10.1177/14703203010020011701
[54] Wright, J.W. and Harding, J. (2004) The brain Angiotensin system and extracellular matrix molecules in neural plasticity, learning and memory. Progress in Neurobiology, 72, 263-293. doi:10.1016/j.pneurobio.2004.03.003
[55] Wright, J.W., Reichert, J.R., Davis, C.J. and Harding, J.W. (2002) Neuronal plasticity and the brain renin-Angiotensin system. Neuroscience & Biobehavioral Reviews, 26, 529-552. doi:10.1016/S0149-7634(02)00019-2
[56] Pan, H.L. (2004) Brain Angiotensin II and synaptic transmission. The Neuroscientist, 10, 422-431. doi:10.1177/1073858404264678
[57] Sundt, T.M., Sharborough, F.W., Piegras, D.G., Kearns, T.P., Messick, J.M. and O’Fallon, W.M. (1981) Correlation of cerebral flow and electroencephalographic changes during carotid endarterectomy. Mayo Clinic Proceedings, 56, 533-543.
[58] Lhatoo, S.D., Langan, Y. and Sander, J.W. (1999) Sudden unexpected death in epilepsy. Postgraduate Medical Journal, 75, 706-709.
[59] Scorza, F.A., Arida, R.M., Cavalheiro, E.A. and Silva, M.R. (2012) Because scientists are unable to explain the unexplained, screening for cardiovascular abnormalities is a good method to protect against sudden unexpected death in patients with epilepsy. Clinics (Sao Paulo), 67, 1-2. doi:10.6061/clinics/2012(01)01
[60] Sevcencu, C. and Struijk, J.J. (2010) Autonomic alterations and cardiac changes in epilepsy. Epilepsia, 51, 725-737.
[61] Boulanger, C.M., Caputo, L. and Levy B.I. (1995) Endothelial AT,-mediated release of nitric oxide decreases angiotensin contraction in rat carotid artery. Hypertension, 26, 752-757.
[62] Caputo, L., Benessiano, J., Boulanger, C.M. and Levy, B. (1995) Angiotensin II increases cyclic guanosine monophosphate content via endothelia Angiotensin II AT~subtype receptors in the rat carotid artery. Arteriosclerosis, Thrombosis, and Vascular Biology, 15, 1646-1651. doi:10.1161/01.ATV.15.10.1646
[63] Gruetter, C.A., Ryan, C.A., Lemke, S.M., Bailly, D.A., Fox, M.K. and Schoepp, D.D. (1988) Endothelium-dependent modulation of Angiotensina lI-induced contraction in blood vessels. European Journal of Pharmacology, 146, 85-95. doi:10.1016/0014-2999(88)90489-X
[64] Zhang, J., Van Meel, C.A., Pfaffendorf, M., Zhang, J. and Van Zwiten, P.A. (1994) Endothelium-dependent, nitric oxide-mediated inhibition of Angiotensina II-induced contraction in rabbit aorta. European Journal of Pharmacology, 262, 247-253. doi:10.1016/0014-2999(94)90738-2
[65] Harada, S., Nakata, T., Oguni, A., Kido, H., Hatta, T., Fukuyama, R., Fushiki, S., Sasaki, S. and Takeda, K. (2002) Contrasting Effects of Angiotensin Type 1 and 2 Receptors on Nitric Oxide Release under Pressure. Hypertension Research, 25, 779-786. doi:10.1291/hypres.25.779
[66] Lemos, V.S., C?rtes, S.F., Silva, D.M.R., CampagnoleSantos, M.J. and Santos, R.A.S. (2002) Angiotensin-(1-7) is involved in the endothelium-dependent modulation of phenylephrine-induced contraction in the aorta of mRen-2 transgenic rats, British Journal of Pharmacology, 135, 1743-1748. doi:10.1038/sj.bjp.0704630
[67] Pueyo, M.E. and Michel, J.B. (1997) Angiotensin II receptors in endothelial cells. General Pharmacology, 29, 691-696. doi:10.1016/S0306-3623(97)00021-9
[68] Haberl, R., Anneser, F., Villringer, A. and Einhiupl, K.M. (1990) Angiotensin induces endothelium-dependent vasodilatation of rat cerebral arterioles. American Journal of Physiology, 258, 1840-1846.
[69] Abdalla, S., Lother, H., Abdel-Tawab, A.M. and Quitterer, U. (2001) The Angiotensina II AT2 receptor is an AT1 receptor antagonist. The Journal of Biological Chemistry, 276, 39721-29726. doi:10.1074/jbc.M105253200
[70] Tallant, E.A., Diz, D.I. and Ferrario, C.M. (1999) Stateof-the-Art lecture. Antiproliferative actions of Ang Iotensin-(1-7) in vascular smooth muscle. Hypertension, 34, 950-957.

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