Unmasking the potential of the angiotensin AT2 receptor as a therapeutic target in hypertension in men and women: What we know and what we still need to find out

Clinical and Experimental Pharmacology and Physiology

Volumn 40, Issue 8, 2013, Pages 542-550

  Hilliard, Lucinda M ^a   Mirabito, Katrina M ^a   Denton, Kate M ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

Ageing; Angiotensin AT2 receptor; Cardio vascular disease; Hypertension; Menopause; Oestrogen; Renal function; Renin angiotensin system; Sex differences

Indexed keywords

1 (4 DIMETHYLAMINO 3 METHYLBENZYL) 5 DIPHENYLACETYL 4,5,6,7 TETRAHYDRO 1H IMIDAZO[4,5 C]PYRIDINE 6 CARBOXYLIC ACID; ANGIOTENSIN 1 RECEPTOR; ANGIOTENSIN 2 RECEPTOR; ANGIOTENSIN 2 RECEPTOR ANTAGONIST; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIHYPERTENSIVE AGENT; COMPOUND 21; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ESTROGEN; HORMONE; NICOTINOYLTYROSYL(N BENZYLOXYCARBONYLARGINYL)LYSYLHISTIDYLPROLYLISOLEUCINE; UNCLASSIFIED DRUG;

ANTIHYPERTENSIVE ACTIVITY; ARTERIAL PRESSURE; BLOOD PRESSURE REGULATION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR FUNCTION; CARDIOVASCULAR RISK; DRUG EFFECT; DRUG TARGETING; FEMALE; GLOMERULUS FILTRATION; GROUPS BY AGE; HORMONAL REGULATION; HORMONE SUBSTITUTION; HUMAN; HYPERTENSION; KIDNEY FUNCTION; MALE; MENOPAUSAL SYNDROME; MENOPAUSE; NATRIURESIS; NONHUMAN; OVARIECTOMY; POSTMENOPAUSE; PREMENOPAUSE; PREVALENCE; PROTEIN EXPRESSION; RENAL PROTECTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SEX DIFFERENCE;

EID: 84880974930     PISSN: 03051870     EISSN: 14401681     Source Type: Journal    
DOI: 10.1111/1440-1681.12067     Document Type: Review

References (83)

1. Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics-2013 update: A report from the american heart association. Circulation 2013; 127: e6-245.
2. Australian Institute of Health and Welfare (AIHW). Women and Heart Disease: Cardiovascular Profile of Women in Australia. Cardiovascular Disease Series No. 33. Catalogue no. CVD 49. AIHW, Canberra. 2010.
3. Wolf-Maier K, Cooper RS, Kramer H et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004; 43: 10-17.
4. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005; 365: 217-23.
5. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin-aldosterone system. Fundam. Clin. Pharmacol. 2010; 24: 687-98.
6. Pimenta E. Hypertension in women. Hypertens. Res. 2012; 35: 148-52.
7. Zucker I, Beery AK. Males still dominate animal studies. Nature 2010; 465: 690.
8. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol. Res. 2007; 55: 81-95.
9. Franconi F, Carru C, Spoletini I et al. A GENS-based approach to cardiovascular pharmacology: Impact on metabolism, pharmacokinetics and pharmacodynamics. Ther. Deliv. 2011; 2: 1437-53.
10. Oertelt-Prigione S, Regitz-Zagrosek V. Gender aspects in cardiovascular pharmacology. J. Cardiovasc. Transl. Res. 2009; 2: 258-66.
11. Stegbauer J, Coffman TM. New insights into angiotensin receptor actions: From blood pressure to aging. Curr. Opin. Nephrol. Hypertens. 2011; 20: 84-8.
12. 2 receptors: Cardiovascular hope or hype? Br. J. Pharmacol. 2003; 140: 809-24.
13. 2 receptors: Functional relevance in cardiovascular disease. Pharmacol. Ther. 2008; 120: 292-316.
14. Wenzel UO, Krebs C, Benndorf R. The angiotensin II type 2 receptor in renal disease. J. Renin Angiotensin Aldosterone Syst. 2010; 11: 37-41.
15. Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T. Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation 2001; 104: 346-51.
16. Kurisu S, Ozono R, Oshima T et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension 2003; 41: 99-107.
17. Hilliard LM, Sampson AK, Brown RD, Denton KM. The 'his and hers' of the renin-angiotensin system. Curr. Hypertens. Rep. 2013; 15: 71-9.
18. Sampson AK, Moritz KM, Jones ES, Flower RL, Widdop RE, Denton KM. Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats. Hypertension 2008; 52: 666-71.
19. Sampson AK, Hilliard LM, Moritz KM et al. The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012; 302: R159-65.
20. Brown RD, Hilliard LM, Head GA, Jones ES, Widdop RE, Denton KM. Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II. Hypertension 2012; 59: 129-35.
21. 2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. Cardiovasc. Res. 2004; 62: 587-93.
22. Hilliard LM, Nematbakhsh M, Kett MM et al. Gender differences in pressure-natriuresis and renal autoregulation: Role of the angiotensin type 2 receptor. Hypertension 2011; 57: 275-82.
23. Khraibi AA, Liang M, Berndt TJ. Role of gender on renal interstitial hydrostatic pressure and sodium excretion in rats. Am. J. Hypertens. 2001; 14: 893-6.
24. Reckelhoff JF, Zhang H, Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats. Hypertension 1998; 31: 435-9.
25. Turnbull F, Woodward M, Anna V. Effectiveness of blood pressure lowering. Evidence-based comparisons between men and women. Expert Rev. Cardiovasc. Ther. 2010; 8: 199-209.
26. Miller JA, Anacta LA, Cattran DC. Impact of gender on the renal response to angiotensin II. Kidney Int. 1999; 55: 278-85.
27. Miller JA, Cherney DZ, Duncan JA et al. Gender differences in the renal response to renin-angiotensin system blockade. J. Am. Soc. Nephrol. JASN 2006; 17: 2554-60.
28. Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure: A population study. Eur. J. Heart Fail. 2007; 9: 602-9.
29. Anton L, Brosnihan KB. Systemic and uteroplacental renin-angiotensin system in normal and pre-eclamptic pregnancies. Ther. Adv. Cardiovasc. Dis. 2008; 2: 349-62.
30. Takeda-Matsubara Y, Iwai M, Cui TX et al. Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change. Am. J. Hypertens. 2004; 17: 684-9.
31. Chen K, Merrill DC, Rose JC. The importance of angiotensin II subtype receptors for blood pressure control during mouse pregnancy. Reprod. Sci. 2007; 14: 694-704.
32. 2 receptors in uterine arteries from pregnant ewes. Eur. J. Pharmacol. 1999; 378: 195-202.
33. Hladunewich MA, Kingdom J, Odutayo A et al. Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia. J. Clin. Endocrinol. Metab. 2011; 96: 3517-24.
34. Garovic VD, Bailey KR, Boerwinkle E et al. Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J. Hypertens. 2010; 28: 826-33.
35. Anguiano-Robledo L, Reyes-Melchor PA, Bobadilla-Lugo RA, Perez-Alvarez VM, Lopez-Sanchez P. Renal angiotensin-II receptors expression changes in a model of preeclampsia. Hypertens. Pregnancy 2007; 26: 151-61.
36. Akbar SA, Khawaja NP, Brown PR, Tayyeb R, Bamfo J, Nicolaides KH. Angiotensin II type 1 and 2 receptors gene polymorphisms in pre-eclampsia and normal pregnancy in three different populations. Acta Obstet. Gynecol. Scand. 2009; 88: 606-11.
37. Phoon S, Howes LG. Forearm vasodilator response to angiotensin II in elderly women receiving candesartan. Role of AT(2)-receptors. J. Renin Angiotensin Aldosterone Syst. 2002; 3: 36-9.
38. McCarthy CA, Widdop RE, Denton KM, Jones ES. Update on the angiotensin AT(2) receptor. Curr. Hypertens. Rep. 2013; 15: 25-30.
39. 2 receptor agonists: Hypertension and beyond. Curr. Opin. Nephrol. Hypertens. 2012; 21: 142-6.
40. Foulquier S, Steckelings UM, Unger T. Impact of the AT(2) receptor agonist C21 on blood pressure and beyond. Curr. Hypertens. Rep. 2012; 14: 403-9.
41. 2 receptor agonist. J. Med. Chem. 2004; 47: 5995-6008.
42. 2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. Br. J. Pharmacol. 2010; 159: 709-16.
43. 2 receptor exerts beneficial effects in stroke-prone rats: Focus on renal damage. J. Hypertens. 2009; 27: 2444-51.
44. Matavelli LC, Huang J, Siragy HM. Angiotensin AT(2) receptor stimulation inhibits early renal inflammation in renovascular hypertension. Hypertension 2011; 57: 308-13.
45. ω-nitro-l-arginine-methyl ester-induced hypertension: The effect on pulse wave velocity and aortic remodeling. Hypertension 2012; 59: 485-92.
46. Rehman A, Leibowitz A, Yamamoto N, Rautureau Y, Paradis P, Schiffrin EL. Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension 2012; 59: 291-9.
47. Hilliard LM, Jones ES, Steckelings UM, Unger T, Widdop RE, Denton KM. Sex-specific influence of angiotensin type 2 receptor stimulation on renal function: A novel therapeutic target for hypertension. Hypertension 2012; 59: 409-14.
48. 1 receptor blockade in conscious SHR. Br. J. Pharmacol. 2004; 142: 821-30.
49. 1 receptor-mediated pressor and chronotropic effects. J. Clin. Invest. 1998; 101: 527-35.
50. Tsutsumi Y, Matsubara H, Masaki H et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J. Clin. Invest. 1999; 104: 925-35.
51. Cosentino F, Savoia C, De Paolis P et al. Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists. Am. J. Hypertens. 2005; 18: 493-9.
52. Savoia C, Tabet F, Yao G, Schiffrin EL, Touyz RM. Negative regulation of RhoA/Rho kinase by angiotensin II type 2 receptor in vascular smooth muscle cells: Role in angiotensin II-induced vasodilation in stroke-prone spontaneously hypertensive rats. J. Hypertens. 2005; 23: 1037-45.
53. Chobanian AV, Bakris GL, Black HR et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA 2003; 289: 2560-72.
54. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: Current outcomes and control in the community. JAMA 2005; 294: 466-72.
55. Lionakis N, Mendrinos D, Sanidas E, Favatas G, Georgopoulou M. Hypertension in the elderly. World J. Cardiol. 2012; 4: 135-47.
56. Armando I, Jezova M, Juorio AV et al. Estrogen upregulates renal angiotensin II AT(2) receptors. Am. J. Physiol. Renal. Physiol. 2002; 283: F934-43.
57. 2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats. Neuroendocrinology 2008; 88: 276-86.
58. 1 receptor blockade. J. Mol. Cell. Cardiol. 2004; 37: 1023-30.
59. Heymes C, Silvestre JS, Llorens-Cortes C et al. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology 1998; 139: 2579-87.
60. Basso N, Paglia N, Stella I et al. Protective effect of the inhibition of the renin-angiotensin system on aging. Regul. Pept. 2005; 128: 247-52.
61. Benigni A, Corna D, Zoja C et al. Disruption of the AngII type 1 receptor promotes longevity in mice. J. Clin. Invest. 2009; 119: 524-30.
62. Burrell LM, Johnston CI. Angiotensin II receptor antagonists. Potential in elderly patients with cardiovascular disease. Drugs Aging 1997; 10: 421-34.
63. Esposito C, Dal Canton A. Functional changes in the aging kidney. J. Nephrol. 2010; 23(Suppl. 15): S41-5.
64. Tank JE, Vora JP, Houghton DC, Anderson S. Altered renal vascular responses in the aging rat kidney. Am. J. Physiol. 1994; 266: F942-8.
65. Anderson S, Rennke HG, Zatz R. Glomerular adaptations with normal aging and with long-term converting enzyme inhibition in rats. Am. J. Physiol. 1994; 267: F35-43.
66. Zoja C, Remuzzi A, Corna D, Perico N, Bertani T, Remuzzi G. Renal protective effect of angiotensin-converting enzyme inhibition in aging rats. Am. J. Med. 1992; 92(Suppl. 2): S60-3.
67. Thompson MM, Oyama TT, Kelly FJ, Kennefick TM, Anderson S. Activity and responsiveness of the renin-angiotensin system in the aging rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2000; 279: R1787-94.
68. Touyz RM, Briones AM. Reactive oxygen species and vascular biology: Implications in human hypertension. Hypertens. Res. 2011; 34: 5-14.
69. 2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice. Hypertension 2003; 42: 600-4.
70. Pinaud F, Bocquet A, Dumont O et al. Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats. Hypertension 2007; 50: 96-102.
71. Bosnyak S, Widdop RE, Denton KM, Jones ES. Differential mechanisms of ang(1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. Int. J. Hypertens. 2012; 2012: 192567.
72. 2 receptors in hypertension and ageing. Clin. Exp. Pharmacol. Physiol. 2008; 35: 386-90.
73. 2 receptor: What exactly does it do? Hypertension 2004; 43: 1162-3.
74. Jones ES, Black MJ, Widdop RE. Influence of angiotensin II subtype 2 receptor (AT(2)R) antagonist, PD123319, on cardiovascular remodelling of aged spontaneously hypertensive rats during chronic angiotensin II subtype 1 receptor (AT(1)R) blockade. Int. J. Hypertens. 2012; 2012: 543062.
75. Fortepiani LA, Zhang H, Racusen L, Roberts LJ 2nd, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats. Hypertension 2003; 41: 640-5.
76. Jazbutyte V, Hu K, Kruchten P et al. Aging reduces the efficacy of estrogen substitution to attenuate cardiac hypertrophy in female spontaneously hypertensive rats. Hypertension 2006; 48: 579-86.
77. Chappell MC, Westwood BM, Yamaleyeva LM. Differential effects of sex steroids in young and aged female mRen2.Lewis rats. A model of estrogen and salt-sensitive hypertension. Gend. Med. 2008; 5 (Suppl. A): S65-75.
78. 2 receptor dysfunction in age-related gender difference in vascular remodeling. J. Am. Soc. Hypertens. 2011; 5: 76-84.
79. Yanes LL, Romero DG, Iliescu R, Zhang H, Davis D, Reckelhoff JF. Postmenopausal hypertension: Role of the renin-angiotensin system. Hypertension 2010; 56: 359-63.
80. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann. Intern. Med. 2000; 133: 933-41.
81. Rossouw JE, Prentice RL, Manson JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297: 1465-77.
82. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.
83. Schierbeck LL, Rejnmark L, Tofteng CL et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial. BMJ 2012; 345: e6409.