Abstract
Hypertension and related cardiovascular diseases are the leading causes of death in many countries. The etiology of human essential hypertension is largely unknown. It is highly likely that hypertension is a complex and multifactorial disease resulting from the interaction of multiple genetic and environmental factors. Animal models of hypertension have been proved to be useful to study the pathogenesis of, and to find a new therapy for, hypertension. The aim of this article is to briefly review the most widely used rodent models of experimental hypertension, including history and recent advances. These models are classified as genetically- induced, environmentally-induced, pharmacologically-induced, and renal-induced hypertension according to the way of induction; the typical representatives of each of these major types of experimental hypertension are spontaneous hypertension, cold-induced hypertension, DOCA-salt-induced hypertension, and renal-induced hypertension, respectively. The processes of induction of hypertension, possible pathogenesis, characteristics, advantages, and limitations of these animal models are reviewed. In addition, the clinical implications of the above experimental models of hypertension are addressed.
Similar content being viewed by others
Article PDF
References
Burt VL, Whelton P, Roccela EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population. Results from the third national health and nutrition examination survey, 1988–1991. Hypertension 1995; 25: 305–13.
National Heart, Lung, and Blood Institute . Age Page High blood pressure: a common but controllable disorder. Bethesda, MA, USA. Department of Health and Human Services and National Institute of Health. 1991.
Wu YK, Lu CQ, Gao RC, Yu JS, Liu GC . Nationwide hypertension screening in China during 1979-1980. Chin Med J 1982; 335: 101–5.
PRC National Blood Pressure Survey Cooperative Group . Prevalence and development trends of hypertension in China. Chin J Hypertens 1996; 3: 7–13.
Joffres MR, Hamet P, Rabkin SW, Gelskey D, Hogan K, Fodor G . Prevalence, control and awareness of high blood pressure among Canadian adults. Can Med Assoc J 1992; 146: 1997–2005.
Hamet P, Gong LS . Chinese contribution to trials on antihypertensive therapy. J Hypertens 1996; 14: S123–9.
Yagil Y, Yagil C . Genetic models of hypertension in experimental animals. Exp Nephrol 2001; 9: 1–9.
O'Dowd BF, Rapp JP . Heterogeneity of rennin alleles in outbred Dahl salt-sensitive (Brookhaven) rats. Hypertension 1991; 18: 9–11.
Deng Y, Rapp JP . Cosegregation of blood pressure with angiotensin converting enzyme and arterial natriuretic peptide receptor genes using Dahl salt sensitive rats. Nat Genet 1992; 1: 267–72.
Langheinrich M, Lee MA, Bohm M, Pinto YM, Ganten D, Paul M . The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. Am J Hypertens 1996; 9: 506–12.
Pravenec M, Zidek V, Landa V, Kostka V, Musilova A, Kazdova L, et al. Genetic analysis of cardiovascular risk factor clustering in spontaneous hypertension. Folia Biol Praha 2000; 46: 233–40.
Yang RH, Jin H, Wyss JM, Oparil S . Depressor effect of blocking angiotensin subtype 1 receptors in the anterior hypothalamus. Hypertension 1992; 19: 475–81.
Pinto YM, Paul M, Ganten D . Lessons from rat models of hypertension: from Goldblatt to genetic engineering. Cardiovasc Res 1975; 39: 77–88.
Mann JF, Phillips MI, Dietz R, Haebara H, Ganten D . Effects of central and peripheral angiotensin blockade in hypertensive rats. Am J Physiol 1978; 234: H629–37.
DePasquale MJ, Fossa AA, Holt WF, Mangiapane ML . Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats. Hypertension 1992; 19: 668–71.
Trippodo NC, Frohlich ED . Similarities of genetic (spontaneous) hypertension: man and rat. Circ Res 1981; 48: 309–19.
Arendshorst WJ, Beierwaltes D . Renal and nephron hemodynamics in spontaneously hypertensive rats. Am J Physiol 1979; 236: F246–51.
Yamori Y . Development of the spontaneously hypertensive rat (SHR) the stroke prone hypertensive SHR (SHRSP) and their various substrain models for hypertension-related cardiovascular diseases. In: Ganten D, de Jong W (volume editors) Birkenhager WH, Reid JT (series editors). Handbook of hypertension, v 16: Experimental and genetic models of hypertension. Amsterdam: Elsevier; 1994. p 23–31.
Coleman TG, Guyton AC, Young DB . The role of the kidney in essential hypertension. Clin Exp Pharmacol Physiol 1975; 2: 571–81.
Zimmerman RS, Frohlich ED . Stress and hypertension. J Hypertension 1990; 8: S103–7.
Smookler HH, Buckley JP . Relationships between brain catecholamine synthesis, pituitary adrenal function and the production of hypertension during prolonged exposure to environmental stress. Int I Neuropharmacol 1969; 8: 33–41.
Lin Q, Li P . The effects of chronic stress on blood pressure and heart rate in rats. Chin J Physiol Sci 1990; 6: 101–7.
Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA . Sympathetic neural mechanisms in white-coat hypertension. J Am Coll Cardiol 2002; 40: 126–32.
Coste SC, Brooks VL, McCarron DA, Hatton DC . Captopril and stress-induced hypertension in the borderline hypertensive rat. J Hypertens 1995; 13( 12 Pt 1): 1391–8.
Li P, Zhu DN, Kao KM, Lin Q, Sun SY . Role of acetylcholine, corticoids and opioids in the rostral ventrolateral medulla in stress-induced hypertensive rats. Biol Signals 1995; 4: 124–32.
Lin Q, Li P . Rostral medullary cholinergic mechanisms and chronic stress-induced hypertension. J Auton Nerv Syst 1990; 31: 211–8.
Hwang IS, Hwang WC, Wu JN . Effect of fructose-induced hypertension on the renin-angiotensin-aldosterone system and atrial natriuretic factor. Am J Hypertens 1989; 2: 424–7.
Iyer SN, Raizada MK, Katovich MJ . AT1 receptor density changes during development of hypertension in hyperinsulinemic rats. Clin Exper Hypertens 1996; 18: 793–810.
Wang DH, Wu W, Lookingland KJ . Degeneration of capsaicin-sensitive sensory nerves leads to increased salt sensitivity through enhancement of sympathoexcitatory response. Hypertension 2001; 37( 2 Part 2): 440–3.
Huang Y, Wang DH . Role of AT1 and AT2 receptor subtypes in salt-sensitive hypertension induced by sensory nerve degeneration. J Hypertens 2001; 19: 1841–6.
Fregly MJ, Kikta DC, Threatte RM, Torres JL, Barney CC . Development of hypertension in rats during chronic exposure to cold. J Appl Physiol 1989; 66: 741–9.
Sun Z, Fregly MJ, Cade R . Effect of renal denervation on elevation of blood pressure in cold-exposed rats. Can J Physiol Pharmacol 1995; 73: 72–8.
Sun Z, Cade R, Tatum C . Central imidazoline and angiotensin II receptors in cardiovascular responses to chronic cold exposure in rats. J Therm Biol 2001; 26: 513–8.
Sun Z, Cade R, Morales C . Role of central angiotensin II receptors in cold-induced hypertension. Am J Hypertens 2002; 15: 85–92.
Sun Z, Cade R, Katovich MJ, Fregly MJ . Body fluid distribution in rats with cold-induced hypertension. Physiol Behav 1999; 65: 879–84.
Sun Z, Cade R . Cold-induced hypertension and diuresis. J Thermal Biol 2000; 25: 105–9.
Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas AM, Schroll M . Stroke incidence, case fatality, and mortality in the WHO MONICA project: World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases. Stroke 1995; 26: 361–7.
Donaldson GC, Robinson D, Allaway SL . An analysis of arterial disease mortality and BUPA health screening data in men, in relation to outdoor temperature. Clin Sci Colch 1997; 92: 261–8.
Gyllerup S, Lanke J, Lindholm LH, Schersten B . Cold climate is an important factor in explaining regional differences in coronary mortality even if serum cholesterol and other established risk factors are taken into account. Scott Med J 1993; 38: 169–72.
Sheth T, Nair C, Muller J, Yusuf S . Increased winter mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol 1999; 33: 1916–9.
He BL . Epidemiological characteristic of stroke in 1985-1989, Beijing. Chin J Med 1993; 73: 104–8.
Marchant B, Ranjadayalan K, Stevenson R, Wilkinson P, Timmis AD . Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993; 69: 385–7.
Papanek PE, Wood CE, Fregly MJ . Role of the sympathetic nervous system in cold-induced hypertension in rats. J Appl Physiol 1991; 71: 300–6.
Flaim SF, Hsieh C . Effect of cold acclimatization on rabbit ca rot id artery: altered response to norepinephrine. Gen Pharmacol 1978; 9: 437–42.
Fregly MJ, Brummermann M . Effect of chronic exposure to cold on vascular responsiveness to phenylephrine and angiotensin II. Pharmacology 1993; 47: 237–43.
Shechtman O, Fregly MJ, van Bergen P, Papanek PE . Prevention of cold-induced increase in blood pressure of rats by captopril. Hypertension 1991; 17: 763–70.
Peng JF, Kimura B, Fregly MJ, Phillips MI . Reduction of cold-induced hypertension by antisense oligodeoxynucleotides to angiotensinogen mRNA and AT1-receptor mRNA in brain and blood. Hypertension 1998; 31: 1317–23.
Sun Z, Cade R, Zhang Z, Alouidor J, Van H . Angiotensinogen gene knockout delays and attenuates cold-induced hypertension. Hypertension 2003; 41: 322–7.
van Bergen P, Fregly MJ, Papanek PE . Effect of a reduction in sodium intake on cold-induced elevation of blood pressure in the rat. Proc Soc Exp Biol Med 1992; 200: 472–9.
Sellye H . Production of nephrosclerosis by overdosage with deoxycorticosterone acetate. Can Med Assoc J 1942; 47: 515–9.
Crofton JT, Share L, Shade RE . The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat. Hypertension 1978; 1: 31–8.
Intengan HD, Park JB, Schiffrin EL . Blood pressure and small arteries in DOCA-salt-treated genetically AVP-deficient rats. Role of endothelin. Hypertension 1999; 34 [ part2]: 907–13.
Mohring J, Mohring B, Petri M, Haack D . Vasopressor role of ADH in the pathogenesis of malignant DOC hypertension. Am J Physiol 1977; 232: F260–9.
Katholi RE, Naftilan AJ, Oparil S . Importance of renal sympathetic tone in the development of DOCA-salt hypertension in the rat. Hypertension 1980; 2: 266–73.
O'Hagan KP, Thomas GD, Zambraski EJ . Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension. Am J Hypertens 1990; 3: 62–4.
Wilson KM, Sumners C, Hathaway S, Fregly MJ . Mineralocorticoids modulate central angiotensin II receptors in rats. Brain Res 1986; 382: 87–96.
French JF, Anderson BA, Downs TR, Dage RC . Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase in rats with hypertension. J Cardiovasc Pharmacol 1995; 26: 107–13.
Wong PC, Price WA Jr, Chiu AT, Duncia JV, Carini DJ, Wexler RR . In vivo pharmacology of DuP 753. Am J Hypertens 1991; 4 ( 4 pt 2): S288–98.
Van den Berg DT, de Kloet ER, de Jong W . Central effect of mineralocorticoid antagonist RU-28318 on blood pressure of DOCA-salt hypertensive rats. Am J Physiol 1994; 267( 6 Pt 1): E927–33.
Matsumura Y, Hashimoto N, Taira S, Kuro T, Kitano R, Ohkita M, et al. Different contribution of endothelin-A and endothelin- B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats. Hypertension 1999; 33: 759–65.
Moreau P, Schifrin EL . Role of endothelins in animal models of hypertension: focus on cardiovascular protection. Can J Physiol Pharmacol 2003; 81: 511–21.
Schiffrin EL . Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens 2001; 14: S83–9.
van den Meiracker AH . Endothelins and venous tone in DOCA-salt hypertension. J Hypertens 2002; 20: 587–9.
Callera GE, Montezano AC, Touyz RM, Zorn TMT, Carvalho MHC, Fortes ZB, et al. ETA receptor mediates altered leukocytes- endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension 2004; 43: 872–9.
Li L, Chu Y, Fink GD, Engelhardt JF, Heistad DD, Chen A . Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension 2003; 42: 997–1003.
Manning RD Jr, Meng S, Tian N . Renal and vascular oxidative stress and salt-sensitivity of arterial pressure. Acta Physiol Scand 2003; 179: 243–50.
Goldblatt H, Lynch J, Hanzel RF . Studies on experimental hypertension. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934; 59: 347–79.
Zandberg P . Animal models in experimental hypertension: relevance to drug testing and discovery. In: van Zwieten PA, editor. Handbook of hypertension. Vol. 3: Pharmacology of antihypertensive drugs. New York: Elsevier Science Publishers; 1984. Chapter 2.
Leenen FHH, De Jong W . Plasma renin and sodium balance during development of moderate and severe renal hypertension in rats. Circ Res 1975; 36/37 ( Suppl 1): 179–84.
Liard JF, Cowley AW Jr, McCaa RE, McCaa CS, Guyton AC . Renin, aldosterone body fluid volumes and the baroreceptor reflex in the development and reversal of Goldblatt hypertension in conscious dogs. Circ Res 1974; 34: 549–60.
Sawamura T, Nakada T . Role of dopamine in the striatum, renin-angiotensin system and renal sympathetic nerve on the development of two-kidney, one clip Goldblatt hypertension. J Urol 1996; 155: 1108–11.
Bean BL, Brown JJ, Casals-Stenzel J, Fraser R, Lever AF, Millar JA, et al. The relation of arterial pressure and plasma angiotensin II concentration. A change produced by prolonged infusion of angiotensin II in conscious dog. Circ Res 1979; 44: 452–8.
Freeman RH, Davis JO, Watkins BE . Effects of continuous converting enzyme blockade on renovascular hypertension in the rat. Am J Physiol 1979; 236: F221–4.
Brown JJ, Fraser R, Lever AF . Mechanism in hypertension: a personal view. In: Genest J, Koiw E, Kuchel O, editors. Hypertension. New York: McGraw-Hill; 1977. Chapter 12.1.
Ten Berg RGM, Leenen FHH, De Jong W . Plasma renin activity and sodium, potassium and water excretion during reversal of hypertension in the one-clip, two kidney hypertensive rat. Clin Sci 1979; 57: 7–15.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by grant (No 0130387N) from the American Heart Association (National).
Rights and permissions
About this article
Cite this article
Sun, Zj., Zhang, Ze. Historic perspectives and recent advances in major animal models of Hypertension. Acta Pharmacol Sin 26, 295–301 (2005). https://doi.org/10.1111/j.1745-7254.2005.00054.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2005.00054.x
Keywords
This article is cited by
-
The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760
Biological Research (2023)
-
Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels
Cellular and Molecular Life Sciences (2022)
-
Repetitive Electroacupuncture Attenuates Cold-Induced Hypertension through Enkephalin in the Rostral Ventral Lateral Medulla
Scientific Reports (2016)
-
Rodent models of heart failure: an updated review
Heart Failure Reviews (2013)
-
AAV delivery of mineralocorticoid receptor shRNA prevents progression of cold-induced hypertension and attenuates renal damage
Gene Therapy (2006)