This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nishimura, Y. Articles by Sandberg, K. Search for Related Content PubMed PubMed Citation Articles by Nishimura, Y. Articles by Sandberg, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Related Collections Cerebrovascular disease/stroke Primary prevention ACE/Angiotension receptors Acute Cerebral Infarction Brain Circulation and Metabolism

(Stroke. 2000;31:2478.)
© 2000 American Heart Association, Inc.

Original Contributions

Angiotensin II AT₁ Blockade Normalizes Cerebrovascular Autoregulation and Reduces Cerebral Ischemia in Spontaneously Hypertensive Rats

Yasuaki Nishimura, MD, PhD; Takeshi Ito, MD Juan M. Saavedra, MD

From the Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, Bethesda, Md.

Correspondence to Juan M. Saavedra, MD, Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, 10 Center Dr, Bldg 10, Room 2D-57, Bethesda, MD 20892. E-mail Saavedrj{at}irp.nimh.nih.gov

Background and Purpose—Angiotensin II, through stimulation of AT₁ receptors, not only controls blood pressure but also modulates cerebrovascular flow. We sought to determine whether selective AT₁ antagonists could be therapeutically advantageous in brain ischemia during chronic hypertension.

Methods—We pretreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls with the AT₁ antagonist candesartan (CV-11974), 0.5 mg/kg per day, for 3 to 14 days, via subcutaneously implanted osmotic minipumps. We analyzed cerebral blood flow by laser-Doppler flowmetry, cerebral stroke in SHR after occlusion of the middle cerebral artery with reperfusion, and brain AT₁ receptors by quantitative autoradiography.

Results—Candesartan treatment normalized blood pressure and the shift toward higher blood pressures at both the upper and lower limits of cerebrovascular autoregulation in SHR. Candesartan pretreatment of SHR for 14 days partially prevented the decrease in blood flow in the marginal zone of ischemia and significantly reduced the volume of total and cortical infarcts after either 1 or 2 hours of middle cerebral artery occlusion with reperfusion, relative to untreated SHR, respectively. This treatment also significantly reduced brain edema after 2 hours of middle cerebral artery occlusion with reperfusion. In SHR, candesartan markedly decreased AT₁ binding in areas inside (nucleus of the solitary tract) and outside (area postrema) the blood-brain barrier and in the middle cerebral artery.

Conclusions—Pretreatment with an AT₁ antagonist protected hypertensive rats from brain ischemia by normalizing the cerebral blood flow response, probably through AT₁ receptor blockade in cerebral vessels and in brain areas controlling cerebrovascular flow during stroke.

Editorial Comment

Kathryn Sandberg, Guest Editor

Center for Hypertension and Renal Disease Georgetown University Washington, DC

This article has been cited by other articles:

				W. Kozak, A. Kozak, M. H. Johnson, H. F. Elewa, and S. C. Fagan Vascular Protection with Candesartan after Experimental Acute Stroke in Hypertensive Rats: A Dose-Response Study J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 773 - 782. [Abstract] [Full Text] [PDF]

				B. K. Saxby, F. Harrington, K. A. Wesnes, I. G. McKeith, and G. A. Ford Candesartan and cognitive decline in older patients with hypertension: A substudy of the SCOPE trial Neurology, May 6, 2008; 70(19_Part_2): 1858 - 1866. [Abstract] [Full Text] [PDF]

				G. C. Newman, H. Bang, S. I. Hussain, and J. F. Toole Association of diabetes, homocysteine, and HDL with cognition and disability after stroke Neurology, November 27, 2007; 69(22): 2054 - 2062. [Abstract] [Full Text] [PDF]

				K.-H. Jung, K. Chu, S.-T. Lee, S.-J. Kim, E.-C. Song, E.-H. Kim, D.-K. Park, D.-I. Sinn, J.-M. Kim, M. Kim, et al. Blockade of AT1 Receptor Reduces Apoptosis, Inflammation, and Oxidative Stress in Normotensive Rats with Intracerebral Hemorrhage J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1051 - 1058. [Abstract] [Full Text] [PDF]

				F. H. Messerli Cerebroprotection by Hypertension in Ischemic Stroke: The Crumbling of a Hypothesis Circulation, June 12, 2007; 115(23): 2907 - 2908. [Full Text] [PDF]

				M. Ishikawa, E. Sekizuka, N. Yamaguchi, H. Nakadate, S. Terao, D. N. Granger, and H. Minamitani Angiotensin II type 1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2306 - H2315. [Abstract] [Full Text] [PDF]

				M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]

				J. Zhou, J. Pavel, M. Macova, Z.-X. Yu, H. Imboden, L. Ge, T. Nishioku, J. Dou, E. Delgiacco, and J. M. Saavedra AT1 Receptor Blockade Regulates the Local Angiotensin II System in Cerebral Microvessels From Spontaneously Hypertensive Rats Stroke, May 1, 2006; 37(5): 1271 - 1276. [Abstract] [Full Text] [PDF]

				J.-M. Vincent, Y. W. Kwan, S. Lung Chan, C. Perrin-Sarrado, J. Atkinson, and J.-M. Chillon Constrictor and Dilator Effects of Angiotensin II on Cerebral Arterioles Stroke, December 1, 2005; 36(12): 2691 - 2695. [Abstract] [Full Text] [PDF]

				J. P. Forder, D. H. Munzenmaier, and A. S. Greene Angiogenic protection from focal ischemia with angiotensin II type 1 receptor blockade in the rat Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1989 - H1996. [Abstract] [Full Text] [PDF]

				V. Papademetriou, C. Farsang, D. Elmfeldt, A. Hofman, H. Lithell, B. Olofsson, I. Skoog, P. Trenkwalder, A. Zanchetti, and for the SCOPE Study Group Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: The study on cognition and prognosis in the elderly (SCOPE) J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1175 - 1180. [Abstract] [Full Text] [PDF]

				M. Iwai, H.-W. Liu, R. Chen, A. Ide, S. Okamoto, R. Hata, M. Sakanaka, T. Shiuchi, and M. Horiuchi Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation Circulation, August 17, 2004; 110(7): 843 - 848. [Abstract] [Full Text] [PDF]

				S. I. Sokol, E. L. Portnay, J. P. Curtis, M. A. Nelson, P. R. Hebert, J. F. Setaro, and J. M. Foody Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke Neurology, July 27, 2004; 63(2): 208 - 213. [Abstract] [Full Text] [PDF]

				H. Ando, J. Zhou, M. Macova, H. Imboden, and J. M. Saavedra Angiotensin II AT1 Receptor Blockade Reverses Pathological Hypertrophy and Inflammation in Brain Microvessels of Spontaneously Hypertensive Rats Stroke, July 1, 2004; 35(7): 1726 - 1731. [Abstract] [Full Text] [PDF]

				I. Kusaka, G. Kusaka, C. Zhou, M. Ishikawa, A. Nanda, D. N. Granger, J. H. Zhang, and J. Tang Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2442 - H2451. [Abstract] [Full Text] [PDF]

				C. Delles, G. Michelson, J. Harazny, S. Oehmer, K. F. Hilgers, and R. E. Schmieder Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients Stroke, June 1, 2004; 35(6): 1289 - 1293. [Abstract] [Full Text] [PDF]

				E. Stenman and L. Edvinsson Cerebral Ischemia Enhances Vascular Angiotensin AT1 Receptor-Mediated Contraction in Rats Stroke, April 1, 2004; 35(4): 970 - 974. [Abstract] [Full Text] [PDF]

				C. Bregonzio, I. Armando, H. Ando, M. Jezova, G. Baiardi, and J. M. Saavedra Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury Am J Physiol Gastrointest Liver Physiol, July 7, 2003; 285(2): G414 - G423. [Abstract] [Full Text] [PDF]

				D. I. New, A. M. S. Chesser, R. C. Thuraisingham, and M. M. Yaqoob Cerebral artery responses to pressure and flow in uremic hypertensive and spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1212 - H1216. [Abstract] [Full Text] [PDF]

				E. Tronvik, L. J. Stovner, G. Helde, T. Sand, and G. Bovim Prophylactic Treatment of Migraine With an Angiotensin II Receptor Blocker: A Randomized Controlled Trial JAMA, January 1, 2003; 289(1): 65 - 69. [Abstract] [Full Text] [PDF]

				T. Ito, H. Yamakawa, C. Bregonzio, J. A. Terron, A. Falcon-Neri, and J. M. Saavedra Protection Against Ischemia and Improvement of Cerebral Blood Flow in Genetically Hypertensive Rats by Chronic Pretreatment With an Angiotensin II AT1 Antagonist Stroke, September 1, 2002; 33(9): 2297 - 2303. [Abstract] [Full Text] [PDF]

				H. L Elliott and G. T McInnes Special management needs of the elderly hypertensive patient Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1_suppl): S25 - S31. [PDF]

				T. WALTHER, L. OLAH, C. HARMS, B. MAUL, M. BADER, H. HORTNAGL, H.-P. SCHULTHEISS, and G. MIES Ischemic injury in experimental stroke depends on angiotensin II FASEB J, February 1, 2002; 16(2): 169 - 176. [Abstract] [Full Text] [PDF]

				T. Ito, Y. Nishimura, and J. Saavedra Pre-treatment with candesartan protects from cerebral ischaemia Journal of Renin-Angiotensin-Aldosterone System, September 1, 2001; 2(3): 174 - 179. [Abstract] [PDF]

				T. M Estrup, O. B Paulson, and S. Strandgaard No effect of angiotensin II AT2-receptor antagonist PD 123319 on cerebral blood flow autoregulation Journal of Renin-Angiotensin-Aldosterone System, September 1, 2001; 2(3): 188 - 192. [Abstract] [PDF]

				J. Culman, J. Baulmann, A. Blume, and T. Unger Review: The renin-angiotensin system in the brain: an update Journal of Renin-Angiotensin-Aldosterone System, June 1, 2001; 2(2): 96 - 102. [PDF]

				J. M Saavedra, T. Ito, and Y. Nishimura Review: The role of angiotensin II AT1-receptors in the regulation of the cerebral blood flow and brain ischaemia Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S102 - S109. [PDF]