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. 1996 Jul 15;98(2):418–425. doi: 10.1172/JCI118807

Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure.

B I Levy 1, J Benessiano 1, D Henrion 1, L Caputo 1, C Heymes 1, M Duriez 1, P Poitevin 1, J L Samuel 1
PMCID: PMC507445  PMID: 8755652

Abstract

Angiotensin II (Ang II) is both a vasoactive and a potent growth-promoting factor for vascular smooth muscle cells. Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II. Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension. Normotensive rats received for 3 wk subcutaneous infusions of Ang II (120 ng/kg per min), or Ang II + PD 123319 (30 mg/kg per d), or Ang II + losartan (10 mg/kg per d) or PD 123319 alone, and were compared with control animals. In normotensive animals, chronic blockade of AT2 receptors did not affect the plasma level of angiotensin II and the vascular reactivity to angiotensin II mediated by the AT1 receptor. Chronic blockade of AT1I in rats receiving Ang II resulted in normal arterial pressure, but it induced significant aortic hypertrophy and fibrosis. Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors.

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Selected References

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  1. Albaladejo P., Bouaziz H., Duriez M., Gohlke P., Levy B. I., Safar M. E., Benetos A. Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats. Hypertension. 1994 Jan;23(1):74–82. doi: 10.1161/01.hyp.23.1.74. [DOI] [PubMed] [Google Scholar]
  2. Benessiano J., Levy B. I., Michel J. B. Instantaneous aortic blood flow measurement with range-gated Doppler flowmeter in anesthetized rat. J Pharmacol Methods. 1985 Sep;14(2):99–110. doi: 10.1016/0160-5402(85)90047-6. [DOI] [PubMed] [Google Scholar]
  3. Brilla C. G., Zhou G., Matsubara L., Weber K. T. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol. 1994 Jul;26(7):809–820. doi: 10.1006/jmcc.1994.1098. [DOI] [PubMed] [Google Scholar]
  4. Campbell D. J., Lawrence A. C., Towrie A., Kladis A., Valentijn A. J. Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension. 1991 Dec;18(6):763–773. doi: 10.1161/01.hyp.18.6.763. [DOI] [PubMed] [Google Scholar]
  5. Caputo L., Tedgui A., Lévy B. I. Control of carotid vasomotor tone by local renin-angiotensin system in normotensive and spontaneously hypertensive rats. Role of endothelium and flow. Circ Res. 1995 Aug;77(2):303–309. doi: 10.1161/01.res.77.2.303. [DOI] [PubMed] [Google Scholar]
  6. Chen L. I., Prakash O. M., Ré R. N. The interaction of insulin and angiotensin II on the regulation of human neuroblastoma cell growth. Mol Chem Neuropathol. 1993 Jan-Feb;18(1-2):189–196. doi: 10.1007/BF03160033. [DOI] [PubMed] [Google Scholar]
  7. Chiu A. T., Roscoe W. A., McCall D. E., Timmermans P. B. Angiotensin II-1 receptors mediate both vasoconstrictor and hypertrophic responses in rat aortic smooth muscle cells. Receptor. 1991;1(3):133–140. [PubMed] [Google Scholar]
  8. Geisterfer A. A., Peach M. J., Owens G. K. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988 Apr;62(4):749–756. doi: 10.1161/01.res.62.4.749. [DOI] [PubMed] [Google Scholar]
  9. Gibbons G. H., Pratt R. E., Dzau V. J. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest. 1992 Aug;90(2):456–461. doi: 10.1172/JCI115881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gill G. N., Ill C. R., Simonian M. H. Angiotensin stimulation of bovine adrenocortical cell growth. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5569–5573. doi: 10.1073/pnas.74.12.5569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Henrion D., Chillon J. M., Capdeville-Atkinson C., Vinceneux-Feugier M., Atkinson J. Chronic treatment with the angiotensin I converting enzyme inhibitor, perindopril, protects in vitro carbachol-induced vasorelaxation in a rat model of vascular calcium overload. Br J Pharmacol. 1991 Dec;104(4):966–972. doi: 10.1111/j.1476-5381.1991.tb12534.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jaiswal N., Tallant E. A., Diz D. I., Khosla M. C., Ferrario C. M. Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes. Hypertension. 1991 Jun;17(6 Pt 2):1115–1120. doi: 10.1161/01.hyp.17.6.1115. [DOI] [PubMed] [Google Scholar]
  13. Janiak P., Pillon A., Prost J. F., Vilaine J. P. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension. 1992 Dec;20(6):737–745. doi: 10.1161/01.hyp.20.6.737. [DOI] [PubMed] [Google Scholar]
  14. Katz A. M. Angiotensin II: hemodynamic regulator or growth factor? J Mol Cell Cardiol. 1990 Jul;22(7):739–747. doi: 10.1016/0022-2828(90)90086-h. [DOI] [PubMed] [Google Scholar]
  15. Koepke J. P., Bovy P. R., McMahon E. G., Olins G. M., Reitz D. B., Salles K. S., Schuh J. R., Trapani A. J., Blaine E. H. Central and peripheral actions of a nonpeptidic angiotensin II receptor antagonist. Hypertension. 1990 Jun;15(6 Pt 2):841–847. doi: 10.1161/01.hyp.15.6.841. [DOI] [PubMed] [Google Scholar]
  16. Kunert-Radek J., Stepień H., Komorowski J., Pawlikowski M. Stimulatory effect of angiotensin II on the proliferation of mouse spleen lymphocytes in vitro is mediated via both types of angiotensin II receptors. Biochem Biophys Res Commun. 1994 Feb 15;198(3):1034–1039. doi: 10.1006/bbrc.1994.1147. [DOI] [PubMed] [Google Scholar]
  17. Laurent S., Girerd X., Mourad J. J., Lacolley P., Beck L., Boutouyrie P., Mignot J. P., Safar M. Elastic modulus of the radial artery wall material is not increased in patients with essential hypertension. Arterioscler Thromb. 1994 Jul;14(7):1223–1231. doi: 10.1161/01.atv.14.7.1223. [DOI] [PubMed] [Google Scholar]
  18. Levy B. I., Duriez M., Phillipe M., Poitevin P., Michel J. B. Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats. Circulation. 1994 Dec;90(6):3024–3033. doi: 10.1161/01.cir.90.6.3024. [DOI] [PubMed] [Google Scholar]
  19. Levy B. I., Michel J. B., Salzmann J. L., Azizi M., Poitevin P., Safar M., Camilleri J. P. Effects of chronic inhibition of converting enzyme on mechanical and structural properties of arteries in rat renovascular hypertension. Circ Res. 1988 Jul;63(1):227–239. doi: 10.1161/01.res.63.1.227. [DOI] [PubMed] [Google Scholar]
  20. Macari D., Whitebread S., Cumin F., De Gasparo M., Levens N. Renal actions of the angiotensin AT2 receptor ligands CGP 42112 and PD 123319 after blockade of the renin-angiotensin system. Eur J Pharmacol. 1994 Jun 23;259(1):27–36. doi: 10.1016/0014-2999(94)90153-8. [DOI] [PubMed] [Google Scholar]
  21. Millan M. A., Carvallo P., Izumi S., Zemel S., Catt K. J., Aguilera G. Novel sites of expression of functional angiotensin II receptors in the late gestation fetus. Science. 1989 Jun 16;244(4910):1340–1342. doi: 10.1126/science.2734613. [DOI] [PubMed] [Google Scholar]
  22. Naftilan A. J., Pratt R. E., Eldridge C. S., Lin H. L., Dzau V. J. Angiotensin II induces c-fos expression in smooth muscle via transcriptional control. Hypertension. 1989 Jun;13(6 Pt 2):706–711. doi: 10.1161/01.hyp.13.6.706. [DOI] [PubMed] [Google Scholar]
  23. Nio Y., Matsubara H., Murasawa S., Kanasaki M., Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest. 1995 Jan;95(1):46–54. doi: 10.1172/JCI117675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Owens G. K. Differential effects of antihypertensive drug therapy on vascular smooth muscle cell hypertrophy, hyperploidy, and hyperplasia in the spontaneously hypertensive rat. Circ Res. 1985 Apr;56(4):525–536. doi: 10.1161/01.res.56.4.525. [DOI] [PubMed] [Google Scholar]
  25. Paquet J. L., Baudouin-Legros M., Brunelle G., Meyer P. Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens. 1990 Jun;8(6):565–572. doi: 10.1097/00004872-199006000-00010. [DOI] [PubMed] [Google Scholar]
  26. Pignoli P., Tremoli E., Poli A., Oreste P., Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986 Dec;74(6):1399–1406. doi: 10.1161/01.cir.74.6.1399. [DOI] [PubMed] [Google Scholar]
  27. Sans M., Moragas A. Mathematical morphologic analysis of the aortic medial structure. Biomechanical implications. Anal Quant Cytol Histol. 1993 Apr;15(2):93–100. [PubMed] [Google Scholar]
  28. Sechi L. A., Griffin C. A., Schambelan M. The cardiac renin-angiotensin system in STZ-induced diabetes. Diabetes. 1994 Oct;43(10):1180–1184. doi: 10.2337/diab.43.10.1180. [DOI] [PubMed] [Google Scholar]
  29. Smits G. J., Koepke J. P., Blaine E. H. Reversal of low dose angiotension hypertension by angiotensin receptor antagonists. Hypertension. 1991 Jul;18(1):17–21. doi: 10.1161/01.hyp.18.1.17. [DOI] [PubMed] [Google Scholar]
  30. Stoll M., Steckelings U. M., Paul M., Bottari S. P., Metzger R., Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995 Feb;95(2):651–657. doi: 10.1172/JCI117710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stouffer G. A., Owens G. K. Angiotensin II-induced mitogenesis of spontaneously hypertensive rat-derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor-beta. Circ Res. 1992 Apr;70(4):820–828. doi: 10.1161/01.res.70.4.820. [DOI] [PubMed] [Google Scholar]
  32. Tardy Y., Meister J. J., Perret F., Brunner H. R., Arditi M. Non-invasive estimate of the mechanical properties of peripheral arteries from ultrasonic and photoplethysmographic measurements. Clin Phys Physiol Meas. 1991 Feb;12(1):39–54. doi: 10.1088/0143-0815/12/1/003. [DOI] [PubMed] [Google Scholar]
  33. Tofovic S. P., Pong A. S., Jackson E. K. Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats. Hypertension. 1991 Dec;18(6):774–782. doi: 10.1161/01.hyp.18.6.774. [DOI] [PubMed] [Google Scholar]
  34. Tsutsumi K., Strömberg C., Viswanathan M., Saavedra J. M. Angiotensin-II receptor subtypes in fetal tissue of the rat: autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis. Endocrinology. 1991 Aug;129(2):1075–1082. doi: 10.1210/endo-129-2-1075. [DOI] [PubMed] [Google Scholar]
  35. Wong P. C., Hart S. D., Duncia J. V., Timmermans P. B. Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. Eur J Pharmacol. 1991 Sep 24;202(3):323–330. doi: 10.1016/0014-2999(91)90274-t. [DOI] [PubMed] [Google Scholar]
  36. Wong P. C., Hart S. D., Zaspel A. M., Chiu A. T., Ardecky R. J., Smith R. D., Timmermans P. B. Functional studies of nonpeptide angiotensin II receptor subtype-specific ligands: DuP 753 (AII-1) and PD123177 (AII-2). J Pharmacol Exp Ther. 1990 Nov;255(2):584–592. [PubMed] [Google Scholar]
  37. Wu J. N., Edwards D., Berecek K. H. Changes in renal angiotensin II receptors in spontaneously hypertensive rats by early treatment with the angiotensin-converting enzyme inhibitor captopril. Hypertension. 1994 Jun;23(6 Pt 2):819–822. doi: 10.1161/01.hyp.23.6.819. [DOI] [PubMed] [Google Scholar]
  38. Yamada T., Horiuchi M., Dzau V. J. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):156–160. doi: 10.1073/pnas.93.1.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. de Gasparo M., Husain A., Alexander W., Catt K. J., Chiu A. T., Drew M., Goodfriend T., Harding J. W., Inagami T., Timmermans P. B. Proposed update of angiotensin receptor nomenclature. Hypertension. 1995 May;25(5):924–927. doi: 10.1161/01.hyp.25.5.924. [DOI] [PubMed] [Google Scholar]

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