The renin–angiotensin system (RAS) and oestrogen status are two of the most common risk factors implicated in the pathogenesis of hypertension, atherosclerosis and ischaemic heart disease [1–4]. Indeed, development and progression of hypertension, atherosclerosis, and ischaemic heart disease have been attributed to over-activation of the RAS [as reflected by increased expression and/or production of its major components, including renin, angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type 1 (AT1) receptors], as well as to deficiency of oestrogen after menopause [1–4]. Angiotensin II acts on AT1 receptors to induce vasoconstriction, stimulate cell growth and increase NADH/NADPH oxidase-derived superoxide anion in cardiovascular cells [1,5,6]. These actions of angiotensin II are pro-atherosclerotic and may be the leading causes of the endothelial dysfunction seen in hypertension, atherosclerosis and ischaemic heart disease [1,5,6]. By contrast, oestrogen was generally believed to be cardioprotective [3,7] until the controversial findings of the prospective Heart Oestrogen/Progestin Replacement Study (HERS) . There is also substantial evidence from human and animal studies that oestrogen may provide beneficial cardiovascular effects by modulating the RAS. Oestrogen has been shown to inhibit circulating renin and ACE, decrease circulating angiotensin II levels [9–12] and downregulate AT1 receptor expression in vascular smooth muscle cells, adrenal cortex and hypothalamus [13–16]. Conversely, oestrogen deficiency as a result of menopause or ovariectomy has the opposite effects on the RAS [13,17,18]. Hence, it is not surprising that the vasoconstrictor response to angiotensin II is attenuated by oestrogen [19,20], whereas oestrogen deficiency enhances the vasoconstrictor response to angiotensin II by upregulating AT1 receptors . For these reasons, oestrogen replacement therapy and blockade of the RAS with ACE inhibitors or AT1 receptor antagonists may be beneficial in restoring vascular endothelial dysfunction, lowering blood pressure and preventing the development of cardiovascular disease [1,2,6,7, 17,20].
Against this background, in this issue of the journal, Riveiro et al. report on their studies of whether oestrogen modulates the effects of AT1 receptor blockade on vascular endothelial function in ovariectomized and sham-ovariectomized spontaneously hypertensive rat (SHR) . Both groups were treated with the AT1 receptor antagonist irbesartan (50 mg/kg per day) for 30 weeks, and the vascular reactivity of aortic rings was compared at the end of the treatment period. In contrast to previous reports [17,19,20], they showed that endothelium-dependent vascular reactivity, as represented by responses to the nitric oxide synthase inhibitor l-NAME, phenylephrine and acetylcholine, was the same in irbesartan-treated ovariectomized and sham-ovariectomized SHR. The authors concluded that, in SHR, oestrogen does not play a role in the improvement of the vascular endothelial dysfunction observed after long-term AT1 receptor blockade. Although Riveiro et al. did not deal with the complex mechanisms underlying the lack of oestrogen modulation in the improved endothelial function produced by blocking the AT1 receptor with irbesartan, their findings clearly show that lack of oestrogen does not alter both endothelium-dependent and -independent relaxation in SHR after long-term treatment with irbesartan, regardless of oestrogen status . The results are generally in accordance with the HERS clinical trial, which found that hormone replacement therapy has no beneficial cardioprotective effects . However, the conclusion reached by Riveiro et al. that oestrogen has no beneficial cardiovascular effects should be viewed with caution, because ovariectomy removes the influences of all sexual steroids, and not just oestrogen. As the effects of oestrogen replacement were not studied in separate groups of ovariectomized animals, it is difficult to draw the conclusion that other sexual hormones produced by the ovaries do not modulate the vascular responses to AT1 receptor blockade. Moreover, the data are inconsistent with previous observations that oestrogen modulates the expression and/or production of major components of the RAS [9–15], as well as those published recently by Wassmann et al. who examined the role of oestrogen deficiency in endothelial dysfunction in ovariectomized SHR and found that it led to an enhanced vasoconstrictor response to angiotensin II associated with upregulation of vascular AT1 receptors and increased superoxide production in the vascular wall . Five weeks of treatment with the AT1 receptor blocker irbesartan or oestrogen replacement with 17β-oestradiol similarly prevented endothelial dysfunction and normalized vascular superoxide levels in ovariectomized SHR . These data suggest that angiotensin II and oestrogen may interact physiologically to maintain vascular endothelial function, and an imbalance of these interactions may play an important role in endothelial dysfunction during hypertension and cardiovascular disease.
The study by Riveiro et al. is not the only one to report a negative effect of oestrogen on vascular reactivity to angiotensin II or AT1 receptor blockade. For example, cardiovascular haemodynamic responses to angiotensin II are similar in female rats whether or not they undergo ovariectomy or oestrogen replacement . In premenopausal women, renal and peripheral haemodynamic responses to the AT1 receptor blocker losartan are also similar in the high and low oestrogen phases of the menstrual cycle . Thus, whether or not oestrogen is cardioprotective through interactions with angiotensin II remains controversial, and the causes underlying these conflicting results are more complex than previously thought. They may reflect differences in the animal models used (normotensive versus hypertensive), species (rats or mice versus humans), vessels studied (aorta versus other peripheral vessels), in-vitro versus ex-vivo conditions, and the length of ovariectomy and drug therapy (weeks versus months). One unique characteristic of the study by Riveiro et al. is that their experiments were performed 30 weeks after ovariectomy and/or irbesartan treatment, which may be relevant to clinical studies such as HERS . However, because the experiments were only performed on vessels harvested from animals 30 weeks after ovariectomy or irbesartan treatment, the data might overlook differences in the expression of vascular AT1 receptors and/or vascular reactivity to AT1 receptor blockade, which may be present during the early stages of ovariectomy in SHR [17–19]. Long-term administration of AT1 receptor antagonists is also associated with increased circulating levels of angiotensin II [24,25], which may act on unopposed angiotensin II type 2 receptors (AT2) . AT2 receptor activation via interactions with kinins and nitric oxide  may obscure differences in vascular reactivity to long-term irbesartan administration regardless of oestrogen status. Thus, the observation that oestrogen status fails to alter endothelium-dependent responses to angiotensin II or long-term AT1 receptor blockade should encourage, rather than deter, further exploration of interactions between oestrogen and angiotensin II and the mechanisms involved in the cardiovascular effects of oestrogen.
1. Dzau VJ. Theodore Cooper Lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047–1052.
2. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–153.
3. Cacciabaudo JM, August P. Female sex hormones and cardiovascular disease: implications for therapy. In: Laragh JH, Brenner BM (editors):Hypertension: pathophysiology
, and management
, 2nd edn. New York: Raven Press; 1995. pp. 2391–2406.
4. Simon G, Abraham G. Angiotensin II administration as an experimental model of hypertension. In: Laragh JH, Brenner BM (editors):Hypertension: pathophysiology
, and management
, 2nd edn. New York: Raven Press; 1995. pp. 1423–1435.
5. Griendling KK, Lassegue B, Alexander RW. Angiotensin receptors and their therapeutic implications. Annu Rev Pharmacol Toxicol 1996; 36: 281–306.
6. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994; 74: 1141–1148.
7. Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag the dogma. Circulation 2001; 104: 2256–2259.
8. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605–613.
9. Campbell DJ. Differential regulation of angiotensin peptides in plasma and kidney: effects of adrenalectomy and estrogen treatment. Clin Exp Hypertens 1997; 19: 687–698.
10. Gallagher PE, Li P, Lenhart JR, Chappell MC, Brosnihan KB. Estrogen regulation of angiotensin-converting enzyme mRNA. Hypertension 1999; 33: 323–328.
11. Brosnihan KB, Li P, Ganten D, Ferrario CM. Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS. Am J Physiol 1997; 273: R1908–R1915.
12. Brosnihan KB, Weddle D, Anthony MS, Heise C, Li P, Ferrario CM. Effects of chronic hormone replacement on the renin-angiotensin system in cynomolgus monkeys. J Hypertens 1997; 15: 719–726.
13. Nickenig G, Strehlow K, Wassmann S, Baumer AT, Albory K, Sauer H, Bohm M. Differential effects of estrogen and progesterone on AT1
receptor gene expression in vascular smooth muscle cells. Circulation 2000; 102: 1828–1833.
14. Roesch DM, Tian Y, Zheng W, Shi M, Verbalis JG, Sandberg K. Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats. Endocrinology 2000; 141: 4629–4636.
15. Kisley LR, Sakai RR, Fluharty SJ. Estrogen decreases hypothalamic angiotensin II AT1
receptor binding and mRNA in the female rat. Brain Res 1999; 844: 34–42.
16. Zhuo JL, Allen AM, Alcorn D, Aldred GP, MacGregor DP, Mendelsohn FAO. The distribution of angiotensin II receptors. In: Laragh JH, Brenner BM (editor):Hypertension: pathophysiology
, and management
, 2nd edn. New York: Raven Press; 1995. pp. 1739–1762.
17. Wassmann S, Baumer AT, Strehlow K, van Eickels M, Grohe C, Ahlbory K. et al
. Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats. Circulation 2001; 103: 435–441.
18. Nickenig G, Baumer AT, Grohe C, Kahlert S, Strehlow K, Rosenkranz S. et al
. Estrogen modulates AT1
receptor gene expression in vitro and in vivo. Circulation 1998; 97: 2197–2201.
19. Cheng DY, Gruetter CA. Chronic estrogen alters contractile responsiveness to angiotensin II and norepinephrine in female rat aorta. Eur J Pharmacol 1992; 215: 171–176.
20. Komesaroff PA, Fullerton M, Esler MD, Dart A, Jennings G, Sudhir K. Low-dose estrogen supplementation improves vascular function in hypogonadal men. Hypertension 2001; 38: 1011–1016.
21. Riveiro A, Mosquera A, Alonso M, Calvo C. Angiotensin II type 1 receptor blocker irbesartan ameliorates vascular function in spontaneously hypertensive rats regardless of estrogen status. J Hypertens 2002; 20: 1365–1372.
22. Tatchum-Talom R, Martel C, Marette A. Influence of estrogen on aortic stiffness and endothelial function in female rats. Am J Physiol Heart Circ Physiol 2002; 282: H491–H498.
23. Chidambaram M, Duncan JA, Lai VS, Cattran DC, Floras JS, Scholey JW, Miller JA. Variation in the renin angiotensin system throughout the normal menstrual cycle. J Am Soc Nephrol 2002; 13: 446–452.
24. Zhuo JL, Imig JD, Hammond TG, Orengo S, Benes E, Navar LG. Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT1
receptor. Hypertension 2002; 39: 116–121.
25. Campbell DJ. Endogenous angiotensin II levels and the mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor type 1 antagonists. Clin Exp Pharmacol Physiol Suppl 1996; 3: S125–S131.
26. Carey RM, Jin XH, Siragy HM. Role of the angiotensin AT2
receptor in blood pressure regulation and therapeutic implications. Am J Hypertens 2001; 14: 98S–102S.