(Hypertension. 1995;25:314-319.)
© 1995 American Heart Association, Inc.
Articles |
Antisense Inhibition of Hypertension in the Spontaneously Hypertensive Rat
From the University of Florida, College of Medicine, Department of Physiology.
Correspondence to M.I. Phillips, University of Florida, College of Medicine, Department of Physiology, JHMHC Box 100274, Gainesville, FL 32610-0274.
Abstract Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to angiotensinogen mRNA was administered intracerebroventricularly in spontaneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hypertensive blood pressures to normotensive levels in spontaneously hypertensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered blood pressure. Injections of ASODN at the same dose that decreased hypertension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensinogen production was decreased in the brain stem and significantly decreased in the hypothalamus of the ASODN-treated rats (P<.05), supporting the concept of centrally mediated regulation of hypertension by an overactive brain angiotensin system. To determine the distribution of centrally administered oligodeoxynucleotides, fluorescein isothiocyanate–conjugated oligodeoxynucleotides were injected directly into the lateral ventricles. One hour later, oligodeoxynucleotides were distributed throughout the lateral and third ventricles, with tissue and cellular uptake observed in discrete cells at the injection site. This indicates that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and show that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the spontaneously hypertensive rat through a central mechanism.
Key Words: hypertension, essential • angiotensin II • angiotensinogen • RNA, messenger • DNA, antisense
This article has been cited by other articles:
 |
|
 |
|
  C. Sun, H. Li, Y. Gao, T. Matsuura, P. A. Upchurch, M. K. Raizada, and C. Sumners Lack of Macrophage Migration Inhibitory Factor Regulation Is Linked to the Increased Chronotropic Action of Angiotensin II in SHR Neurons Hypertension, March 1, 2007; 49(3): 528 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Sheriff, M. A. P. Fontes, S. Killinger, J. Horiuchi, and R. A. L. Dampney Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R733 - R740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, K. K. Griendling, A. Dikalova, G. K. Owens, and W. R. Taylor Vascular Hypertrophy in Angiotensin II-Induced Hypertension Is Mediated by Vascular Smooth Muscle Cell-Derived H2O2 Hypertension, October 1, 2005; 46(4): 732 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-Q. Zhu, L. Gao, Y. Li, K. P. Patel, I. H. Zucker, and W. Wang AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1828 - H1835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ito, M. Hiratsuka, K. Komatsu, K. Tsukamoto, K. Kanmatsuse, and A. F. Sved Ventrolateral Medulla AT1 Receptors Support Arterial Pressure in Dahl Salt-Sensitive Rats Hypertension, March 1, 2003; 41(3): 744 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ito, K. Komatsu, K. Tsukamoto, K. Kanmatsuse, and A. F. Sved Ventrolateral Medulla AT1 Receptors Support Blood Pressure in Hypertensive Rats Hypertension, October 1, 2002; 40(4): 552 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Inamdar, K. M. Eyster, and E. H. Schlenker Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Estrogen receptor-{alpha} antisense decreases brain estrogen receptor levels and affects ventilation in male and female rats J Appl Physiol, October 1, 2001; 91(4): 1886 - 1892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. De Wardener The Hypothalamus and Hypertension Physiol Rev, October 1, 2001; 81(4): 1599 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Pachori, M. J. Huentelman, S. C. Francis, C. H. Gelband, M. J. Katovich, and M. K. Raizada The Future of Hypertension Therapy: Sense, Antisense, or Nonsense? Hypertension, February 1, 2001; 37(2): 357 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kagiyama, A. Varela, M. I. Phillips, and S. M. Galli Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats Hypertension, February 1, 2001; 37(2): 371 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kimura, D. Mohuczy, X. Tang, and M. I. Phillips Attenuation of Hypertension and Heart Hypertrophy by Adeno-Associated Virus Delivering Angiotensinogen Antisense Hypertension, February 1, 2001; 37(2): 376 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Monti, M. Schinke, M. Bohm, D. Ganten, M. Bader, and G. Bricca Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN) Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2001; 280(1): R233 - R240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gardon, M. K Raizada, M. J Katovich, K. H Berecek, and C. H Gelband Gene therapy for hypertension and restenosis Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 211 - 216. [PDF]
|
|
|
|
 |
|
 N. Makino, M. Sugano, S. Ohtsuka, S. Sawada, and T. Hata Chronic antisense therapy for angiotensinogen on cardiac hypertrophy in spontaneously hypertensive rats Cardiovasc Res, December 1, 1999; 44(3): 543 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nakamura, A. Moriguchi, R. Morishita, K. Yamada, T. Nishii, N. Tomita, M. Ohishi, Y. Kaneda, J. Higaki, and T. Ogihara Activation of the Brain Angiotensin System by In Vivo Human Angiotensin-Converting Enzyme Gene Transfer in Rats Hypertension, August 1, 1999; 34(2): 302 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Y. Li, Y. C. Zhang, M. I. Philips, T. Sawamura, and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized Low-Density Lipoprotein (LOX-1) in Cultured Human Coronary Artery Endothelial Cells by Angiotensin II Type 1 Receptor Activation Circ. Res., May 14, 1999; 84(9): 1043 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Phillips Is Gene Therapy for Hypertension Possible? Hypertension, January 1, 1999; 33(1): 8 - 13. [Full Text] [PDF]
|
|
|
|
|
|
D. Mohuczy, C. H. Gelband, and M. I. Phillips Antisense Inhibition of AT1 Receptor in Vascular Smooth Muscle Cells Using Adeno-Associated Virus-Based Vector Hypertension, January 1, 1999; 33(1): 354 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Huang and F. H. H. Leenen Both Brain Angiotensin II and "Ouabain" Contribute to Sympathoexcitation and Hypertension in Dahl S Rats on High Salt Intake Hypertension, December 1, 1998; 32(6): 1028 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Yang, M. I. Phillips, Y. C. Zhang, B. Kimura, L. P. Shen, P. Mehta, and J. L. Mehta Critical Role of AT1 Receptor Expression After Ischemia/Reperfusion in Isolated Rat Hearts : Beneficial Effect of Antisense Oligodeoxynucleotides Directed at AT1 Receptor mRNA Circ. Res., September 7, 1998; 83(5): 552 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Yang, M. I. Phillips, D. Mohuczy, H. Meng, L. Shen, P. Mehta, and J. L. Mehta Increased Angiotensin II Type 1 Receptor Expression in Hypercholesterolemic Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1433 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Peng, B. Kimura, M. J. Fregly, and M. I. Phillips Reduction of Cold-Induced Hypertension by Antisense Oligodeoxynucleotides to Angiotensinogen mRNA and AT1-Receptor mRNA in Brain and Blood Hypertension, June 1, 1998; 31(6): 1317 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Yang, D. Li, M I. Phillips, P. Mehta, and J. L Mehta Myocardial angiotensin II receptor expression and ischemia-reperfusion injury Vascular Medicine, May 1, 1998; 3(2): 121 - 130. [Abstract] [PDF]
|
|
|
|
|
|
N. Makino, M. Sugano, S. Ohtsuka, and S. Sawada Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats Hypertension, May 1, 1998; 31(5): 1166 - 1170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lu, H. Yang, and M. K. Raizada Attenuation of ANG II actions by adenovirus delivery of AT1 receptor antisense in neurons and SMC Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H719 - H727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lu, M. K. Raizada, S. Iyer, P. Reaves, H. Yang, and M. J. Katovich Losartan Versus Gene Therapy : Chronic Control of High Blood Pressure in Spontaneously Hypertensive Rats Hypertension, September 1, 1997; 30(3): 363 - 370. [Abstract] [Full Text]
|
|
|
|
|
|
S. I. Garcia, P. I. Porto, A. L. Alvarez, V. N. Martinez, D. Shaurli, S. Finkielman, and C. J. Pirola Central Overexpression of the TRH Precursor Gene Induces Hypertension in Rats : Antisense Reversal Hypertension, September 1, 1997; 30(3): 759 - 766. [Abstract] [Full Text]
|
|
|
|
|
|
M. I. Phillips Antisense Inhibition and Adeno-Associated Viral Vector Delivery for Reducing Hypertension Hypertension, January 1, 1997; 29(1): 177 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Phillips, D. Mohuczy-Dominiak, M. Coffey, S. M. Galli, B. Kimura, P. Wu, and T. Zelles Prolonged Reduction of High Blood Pressure With an In Vivo, Nonpathogenic, Adeno-Associated Viral Vector Delivery of AT1-R mRNA Antisense Hypertension, January 1, 1997; 29(1): 374 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Madeddu, P. P. Parpaglia, N. Glorioso, L. Chao, and J. Chao Antisense Inhibition of the Brain Kallikrein-Kinin System Hypertension, December 1, 1996; 28(6): 980 - 987. [Abstract] [Full Text]
|
|
|
|
|
|
B. S. Huang and F. H.H. Leenen Brain "Ouabain" and Angiotensin II in Salt-Sensitive Hypertension in Spontaneously Hypertensive Rats Hypertension, December 1, 1996; 28(6): 1005 - 1012. [Abstract] [Full Text]
|
|
|
|
|
|
V. J. Dzau and M. Horiuchi In Vivo Gene Transfer and Gene Modulation in Hypertension Research Hypertension, December 1, 1996; 28(6): 1132 - 1137. [Abstract] [Full Text]
|
|
|
|
|
|
A. Tsukashima, T. Tsuchihashi, I. Abe, K. Nakamura, H. Uchimura, and M. Fujishima Angiotensin II Increases Norepinephrine Turnover in the Anteroventral Third Ventricle of Spontaneously Hypertensive Rats Hypertension, August 1, 1996; 28(2): 224 - 227. [Abstract] [Full Text]
|
|
|
|
|
|
D. Wielbo, A. Simon, M. I. Phillips, and S. Toffolo Inhibition of Hypertension by Peripheral Administration of Antisense Oligodeoxynucleotides Hypertension, July 1, 1996; 28(1): 147 - 151. [Abstract] [Full Text]
|
|
|
|
|
|
K. Tamura, S. Umemura, N. Nyui, T. Yamakawa, S. Yamaguchi, T. Ishigami, S.-i. Tanaka, K. Tanimoto, N. Takagi, H. Sekihara, et al. Tissue-Specific Regulation of Angiotensinogen Gene Expression in Spontaneously Hypertensive Rats Hypertension, June 1, 1996; 27(6): 1216 - 1223. [Abstract] [Full Text]
|
|
|
|
|
|
M. Schinke, M. Bohm, G. Bricca, D. Ganten, and M. Bader Permanent Inhibition of Angiotensinogen Synthesis by Antisense RNA Expression Hypertension, March 1, 1996; 27(3): 508 - 513. [Abstract] [Full Text]
|
|