Hypertensive Models and Their Relevance to Pediatric Hypertension

  • Julie R. Ingelfinger
Reference work entry


Much of what we know about the physiology of blood pressure (BP) regulation and the pathogenesis and treatment of human hypertension has been derived from studies in other animal species. This chapter presents a variety of models of experimental hypertension with the intent of providing a background for the interested reader. Many models explore normal and abnormal physiology without genetic manipulation but rather with the use of surgery, infusion of medications, alterations in diet, and application of stressful conditions. In other models, inbreeding or genetic manipulation is used to produce increased (or decreased) BP. The many models available should be considered both for carrying out research and for evaluating published studies.


Experimental hypertension Animal models Transgenic Knockout Renovascular hypertension Consomic Congenic 


  1. Abassi ZA, Ellahham S, Winaver J, Hofman A (2001) The intrarenal endothelin system and hypertension. News Physiol Sci 16:52–56Google Scholar
  2. Barnes KL, Brosnihan KB, Gerrario CM (1977) Animal models, hypertension, and central nervous system mechanisms. Mayo Clin Proc 52(6):387–390PubMedGoogle Scholar
  3. Baylis C, Mitruka B, Deng A (1992) Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 90:278–281PubMedPubMedCentralGoogle Scholar
  4. Bechtold AG, Patel G, Hochhaus G, Scheuer DA (2009) Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress. Am J Physiol Regulatory 296(5):R1445–R1454Google Scholar
  5. Bianchi G, Fox U, Imbasciati E (1974) The development of a new strain of spontaneously hypertensive rats. Life Sci 14:339–347PubMedGoogle Scholar
  6. Billet S, Bardin S, Verp S, Baudrie V, Michaud A, Conchon S, Muffat-Joly M, Escoubet B, Souil E, Hamard G, Bernstein KE, Gasc JM, Elghozi JL, Corvol P, Clauser E (2007) Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fi brosis in mice. Clin Invest 117(7):1914–25PubMedPubMedCentralGoogle Scholar
  7. Blantz RC, Gabbai FB (1989) Glomerular haemodynamics in pathophysiologic conditions. Am J Hypertens 2(11 Pt 2):208S–2012PubMedGoogle Scholar
  8. Cao J, Sodhi K, Inoue K, Quilley J, Rezzani R, Rodella L, Vanella L, Germinario L, Stec DE, Abraham NG, Kappas A (2011) Lentiviral-human heme oxygenase targeting endothelium improved vascular function in angiotensin II animal model of hypertension. Hum Gene Ther 22(3):271–282PubMedGoogle Scholar
  9. Carroll RG, Lohmeier TE, Brown AJ (1987) Chronic angiotensin II infusion decreases renal norepinephrine overflow in the conscious dog. Hypertension 6:675–681Google Scholar
  10. Chapman CB, Gibbons TB (1950) The diet and hypertension: a review. Medicine (Baltimore) 29:29–60Google Scholar
  11. Chen D, Coffman TM (2012) The kidney and hypertension: lessons from mouse models. Can J Cardiol 28:305–310PubMedGoogle Scholar
  12. Cook JL, Re RN (2012) Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model. Am J Physiol Regul Integr Comp Physiol 302(5):R482–R493PubMedGoogle Scholar
  13. Cowley Jr AW, Liang M, Roman RJ, Greene AS, Jacob HJ (2004) Consomic rat model systems for physiological genomics. Acta Physiol Scand 181(4):585–92PubMedGoogle Scholar
  14. Cvetkovic B, Sigmund CD (2000) Understanding hypertension through genetic manipulation in mice. Kidney Int 57:863–874Google Scholar
  15. Dahl LK, Heine M, Tassinari L (1962) Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Nature 194:480–482Google Scholar
  16. Dahl LK, Knudsen KD, Heine MA, Leitl GJ (1968) Effects of chronic excess salt ingestion. Modification of experimental hypertension in the rat by variations in the diet. Circ Res 22:11–18PubMedGoogle Scholar
  17. Dornas WC, Silva ME (2011) Animal models for the study of arterial hypertension. J Biosci 36:731–737PubMedGoogle Scholar
  18. Ehrlich Y, Rosenthal T (1995) Effect of angiotensin-converting enzyme inhibitors on fructose induce hypertension and hyperinsulinaemia in rats. Clin Exp Pharmacol Physiol Suppl 22(1):S347–S349Google Scholar
  19. Ellison KE, Ingelfinger JR, Pivor M, Dzau VJ (1989) Androgen regulation of rat renal angiotensinogen messenger RNA expression. J Clin Invest 83:1941–1945PubMedPubMedCentralGoogle Scholar
  20. Felts JH (1977) Stephen Hales and the measurement of blood pressure. N C Med J 38(10):602–603PubMedGoogle Scholar
  21. Ferrario CM, Varagic J, Habibi J, Nagata S, Kato J, Chappell MC, Trask AJ, Kitamura K, Whaley Connell A, Sowers JR (2009) Differential regulation of angiotensin-(1–12) in plasma and cardiac tissue in response to bilateral nephrectomy. Am J Physiol Heart Circ 296:H1184–H1192Google Scholar
  22. Flister MJ, Prisco SZ, Sarkis AB, O’Meara CC, Hoffman M, Wendt-Andrae J, Moreno C, Lazar J, Jacob HJ (2012) Identifi cation of hypertension susceptibility loci on rat chromosome 12. Hypertension 60:942–948PubMedGoogle Scholar
  23. Fortepiani LA, Yanes L, Zhang H, Racusen LC, Reckelhoff JF (2003a) Role of androgens in mediating renal injury in aging SHR. Hypertension 42:952–955PubMedGoogle Scholar
  24. Fortepiani LA, Zhang H, Racusen L, Roberts LJ 2nd, Reckelhoff JF (2003b) Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats. Hypertension 41:640–645PubMedGoogle Scholar
  25. Fuji J, Kurihara H, Yamaguchi H, Terasawa F, Murata K, Matsushita S et al (1967) A persistent hypertension due to unilateral renal artery constriction in the rabbit. Jpn Circ J 31:1197–1200Google Scholar
  26. Goldblatt H, Lynch J, Hanzal RF, Summerville WW (1934) The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 59:347–379PubMedPubMedCentralGoogle Scholar
  27. Greene RW, Sapirstein LA (1952) Total body sodium, potassium and nitrogen in rats made hypertensive by subtotal nephrectomy. Am J Phys 169:343–349Google Scholar
  28. Guild S-J, McBryde FD, Malpas SC, Barrett CJ (2012) High dietary salt and angiotensin II chronically increase renal sympathetic nerve activity: a direct telemetric study. Hypertension 59:614–620PubMedGoogle Scholar
  29. Haddy FJ (2006) Role of dietary salt in hypertension. Life Sci 79:1585–1592PubMedGoogle Scholar
  30. Hales S (1733) Statical essays: containing haemastatics or, an account of some hydraulic and hydrostatical experiments made in the blood and blood-vessels of animals. Expts VII and XXII. W J Innys and T Woodward, London, p 33, 161–163Google Scholar
  31. Hayslett JP (1979) Functional adaptation to reduction in renal mass. Physiol Rev 59:137–164PubMedGoogle Scholar
  32. Heller J, Hellerova S, Dobesova Z, Kunês J, Zicha J (1993) The Prague hypertensive rat: a new model of genetic hypertension. Clin Exp Hypertens 15:807–818PubMedGoogle Scholar
  33. Henry JP, Liu Y-Y, Nadra WE, Qian CG, Mormede P, Lemaire V, Ely D, Hendley ED (1993) Psychosocial stress can induce chronic hypertension in normotensive strains of rats. Hypertension 21(5):714–723PubMedGoogle Scholar
  34. Hollenberg NK (2006) The influence of dietary sodium on blood pressure. J Am Coll Nutr 25(Suppl 3):240S–246SPubMedGoogle Scholar
  35. Hwang IS, Ho H, Hoffman BB, Reaven GM (1987) Fructose-induced insulin resistance and hypertension in rats. Hypertension 10(5):512–516PubMedPubMedCentralGoogle Scholar
  36. Inscho WE, Imig JD, Cook AK, Pollock DM (2005) ET (A) and ET (B) receptors differentially modulate afferent and efferent arteriolar responses to endothelin. Br J Pharmacol 146:1019–1026PubMedPubMedCentralGoogle Scholar
  37. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DE, Kang DH, Gersch MS, Benner S, Sanchez-Lozada LG (2007) Potential role sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 85:899–906Google Scholar
  38. Katholi RE, Naftolin AJ, Oparil S (1980) Importance of renal sympathetic tone in the development of DOCA-salt hypertension in the rat. Hypertension 2:266–273PubMedGoogle Scholar
  39. Kessler SP, Hashimoto S, Senanayake PS, Gaughan C, Sen GC, Schnermann J (2005) Nephron function in transgenic mice with selective vascular or tubular expression of Angiotensin-converting enzyme. J Am Soc Nephrol 16(12):3535–3542PubMedGoogle Scholar
  40. Kimura S, Mullins JJ, Bunnemann B, Metzger R, Hilgenfeldt U, Zimmermann F, Jacob H, Fuxe K, Ganten D, Kaling M (1992) High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J 11:821–827PubMedPubMedCentralGoogle Scholar
  41. Krieger EM (1967) Effect of sinoaortic denervation on cardiac output. Am J Phys 213:139–142Google Scholar
  42. Kuijpers MHM, Gruys E (1984) Spontaneous hypertension and hypertensive renal disease in the fawn-hooded rat. Br J Exp Pathol 65:181–190PubMedPubMedCentralGoogle Scholar
  43. Leenen FHH, de Jong W (1971) A solid silver clip for induction of predictable levels of renal hypertension in the rat. J Appl Physiol 31:142–144PubMedGoogle Scholar
  44. Lerman LO, Schwartz RS, Grande JP, Sheedy PF, Romero JC (1999) Noninvasive evaluation of a novel swine model of renal artery stenosis. J Am Soc Nephrol 10:1455–1465PubMedGoogle Scholar
  45. Lerman LO, Chade AR, Sica V, Napoli C (2005) Animal models of hypertension: an overview. J Lab Clin Med 146:160–183PubMedGoogle Scholar
  46. Markel AL (1992) Development of a new strain of rats with inherited stress-induced arterial hypertension. In: Sassard J (ed) Genetic hypertension, vol 218. Colloque INSERM, Paris, pp 405–407Google Scholar
  47. Markel AL (1995) Experimental model of inherited arterial hypertension conditioned by stress (in Russian). Izvestia Acad Nauk SSSR Seria Biol 3:466–469Google Scholar
  48. McCubbin JW, DeMoura RS, Page IH, Olmsted F (1965) Arterial hypertension elicited by subpressor amounts of angiotensin. Science 149:1394–1395PubMedGoogle Scholar
  49. Mohring J, Mohring B, Petri M, Haack D (1977) Vasopressor role of ADH in the pathogenesis of malignant DOC hypertension. Am J Physiol Renal Physiol 232:F260–F269Google Scholar
  50. Moon JY (2013) Recent update of renin-angiotensin-aldosterone system in the pathogenesis of hypertension. Electrolyte Blood Press 11(2):41–45PubMedPubMedCentralGoogle Scholar
  51. Mullins JJ, Peters J, Ganten DF (1990) Fulminant hypertension in renin in transgenic rats harbouring the mouse Ren-2 gene. Nature 344:541–544PubMedGoogle Scholar
  52. Münzel T, Daiber A, Steven S, Tran LP, Ullmann E, Kossmann S, Schmidt FP, Oelze M, Xia N, Li H, Pinto A, Wild P, Pies K, Schmidt ER, Rapp S, Kröller-Schön S (2017) Effects of noise on vascular function, oxidative stress, and inflammation: mechanistic insight from studies in mice. Eur Heart JGoogle Scholar
  53. Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–5PubMedGoogle Scholar
  54. Northcott CA, Glenn JP, Shade RE et al (2012) A custom rat and baboon hypertension gene array to compare experimental models. Exp Biol Med (Maywood) 237(1):99–110Google Scholar
  55. Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293PubMedGoogle Scholar
  56. Okamoto K, Yamamoto K, Morita N, Ohta Y, Chikugo T, Higashizawa T, Suzuki T (1986) Establishment and use of the M strain of stroke-prone spontaneously hypertensive rat. J Hypertens 4:S21–S23Google Scholar
  57. Page IH (1939) The production of persistent arterial hypertension by cellophane perinephritis. JAMA 113:2046–2048Google Scholar
  58. Panek RL, Ryan MJ, Weishaar RE, Taylor DG Jr (1991) Development of a high renin model of hypertension in the cynomolgus monkey. Clin Exp Hypertens A 13:1395–1414PubMedGoogle Scholar
  59. Pickering GW, Prinzmetal M (1937) Experimental hypertension of renal origin in the rabbit. Clin Sci 3:357–368Google Scholar
  60. Pinto YM, Paul M, Ganten D (1998) Lessons from rat models of hypertension: from Goldblatt to genetic engineering. Cardiovasc Res 39:77–88PubMedGoogle Scholar
  61. Pradervand S, Wang Q, Burnier M, Beermann F, Horisberger JD, Hummler E, Rossier BC (1999) A mouse model for Liddle’s syndrome. J Am Soc Nephrol 10:2527–2533PubMedGoogle Scholar
  62. Rapp JH (2000) Genetic analysis of inherited hypertension in the rat. Physiol Rev 80:135–172Google Scholar
  63. Reckelhoff JF, Granger JP (1999) Role of androgens in mediating hypertension and renal injury. Clin Exp Pharmacol Physiol 26:127–131PubMedGoogle Scholar
  64. Ribiero MO, Antunes E, De-Nucci G, Lovisolo SM, Zaatz R (1992) Chronic inhibition of nitric oxide synthesis: a new model of arterial hypertension. Hypertension 20:298–303Google Scholar
  65. Roberts CK, Vaziri NC, Wang XQ, Barnard RJ (2000) Enhanced NO inactivation and hypertension induced by a high-fat, refined-carbohydrate diet. Hypertension 36:432–439Google Scholar
  66. Roberts CK, Vaziri NC, Sindhu RK, Barnard RJ (2003) A high fat refined carbohydrate diet affects renal NO synthase protein expression and salt sensitivity. J Appl Physiol 94:941–946PubMedGoogle Scholar
  67. Romero JC, Fiksen-Olsen MJ, Schryver S (1981) Pathophysiology of hypertension: the use of experimental models to understand the clinical features of the hypertensive disease. In: Spittel JA Jr (ed) Clinical medicine, vol 7. Harper & Row, Philadelphia, pp 1–51Google Scholar
  68. Sarikonda KV, Watson RE, Opara OC, DiPette DJ (2009) Experimental animal models of hypertension. J Amer Soc Hypertension 3(3):158–165Google Scholar
  69. Sellye H (1942) Production of nephrosclerosis by overdosage with deoxycorticosterone acetate. Can Med Assoc J 47:515–519Google Scholar
  70. Shreenivas S, Oparil S (2007) The role of endothelin-1 in human hypertension. Clin Hemorheol Microcirc 37:157–178PubMedGoogle Scholar
  71. Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, et al. (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Sci 304:445–8PubMedGoogle Scholar
  72. Sigmund CD (1993) Expression of the human renin gene in transgenic mice throughout ontogeny. Pediatr Nephrol 7:639–645PubMedGoogle Scholar
  73. Smirk FH, Hall WH (1958) Inherited hypertension in rats. Nature 182:727–728PubMedGoogle Scholar
  74. Sriramula S, Cardinale JP, Lazartiques E, Francis J (2011) ACE2 overexpression the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovasc Res 92(3):401–408PubMedPubMedCentralGoogle Scholar
  75. Thompson MW, Merrill DC, Yang G, Robillard JE, Sigmund CD (1995) Transgenic animals in the study of blood pressure regulation and hypertension. Am J Physiol 269(5Pt 1):E793–E803PubMedGoogle Scholar
  76. Tigerstedt R, Bergman PG (1898) Niere und kreislaufn.d. (The kidneys and the circulation). Scand Arch Physiol 8:223–270 [Translated by Ruskin A (1956) In: Classics in arterial hypertension. Springfield, Charles C Thomas, p 273]Google Scholar
  77. Török J (2008) Participation of nitric oxide in different models of experimental hypertension. Physiol Res 57:813–825PubMedGoogle Scholar
  78. Tuong N, Daugherty M, Riddell J (2016) Acute Page kidney immediately following blunt trauma to a solitary pediatric kidney. Can Urol Assoc J 10(5–6):E192–E196PubMedPubMedCentralGoogle Scholar
  79. Vincent M, Bornet H, Berthezene F, Dupont J, Sassard J (1978) Thyroid function and blood pressure in two new strains of spontaneously hypertensive and normotensive rats. Clin Sci Mol Med 54:391–395PubMedGoogle Scholar
  80. Wiesel P, Mazzolai L, Nussberger J, Pedrazzini T (1997) Two-kidney, one clip and one-kidney, one clip hypertension in mice. Hypertension 29:1025–1030PubMedGoogle Scholar
  81. Yagil C, Hubner N, Kreutz R, Ganten D, Yagil Y (2003) Congenic strains confi rm the presence of saltsensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension. Physiol Genomics 12:85–95PubMedGoogle Scholar
  82. Yang G, Sigmund CD (1998) Regulatory elements required for human angiotensinogen expression in HepG2 cells are dispensable in transgenic mice. Hypertension 31:734–740PubMedGoogle Scholar
  83. Zamir N, Gutman Y, Ben-Ishay D (1978) Hypertension and brain catecholamine distribution in the Hebrew University Sabra, H and N rats. Clin Sci Mol Med 55(suppl 4):105s–107sGoogle Scholar
  84. Zhu Q, Hu J, Han WQ, Zhang F, Li PL, Wang Z, Li N (2014) Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats. Am J Hypertens 27(1):107–113PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Julie R. Ingelfinger
    • 1
  1. 1.Division of NephrologyMassGeneral for Children at Massachusetts General Hospital, Harvard Medical School, Department of PediatricsBostonUSA

Personalised recommendations