Why Can't a Woman Be More Like a Man?: Is the Angiotensin Type 2 Receptor to Blame or to Thank?
I n Pygmalion, Henry Higgins asked, "Why can't a woman be more like a man?" But when it comes to hypertension, Henry actually should have asked, "Why can't a man be more like a woman?" Women have lower blood pressure (BP) and a lower incidence of hypertension than aged-matched men through much of their lives. 1 We need to understand why, because a better understanding of what protects the female from this potentially devastating disease ultimately could lead to new therapeutic treatments for
... c treatments for both men and women. According to the American Heart Association, hypertension is a disease that afflicts Ͼ73 million people and kills Ͼ50 000 people per year in the United States alone. Uncontrolled hypertension leads to heart failure, myocardial infarction, stroke, and renal failure. Surprisingly, we still do not know the cause of essential hypertension, although it accounts for Ͼ90% of all cases of hypertension. In this issue of Hypertension, using a model of angiotensin II (Ang II)-induced hypertension, Sampson et al 1 suggest that the angiotensin type 2 receptor (AT 2 R) provides a major clue for solving the mystery of sex differences in hypertension. Ang II infusion is a widely used experimental model of hypertension, because inhibitors of Ang II synthesis and action have been very effective clinically to treat hypertension. In fact, most hypertensive patients respond to Ang II synthesis inhibitors and angiotensin type 1 receptor (AT 1 R) blockers, indicating that essential hypertension is primarily Ang II dependent. Thus, the mechanisms uncovered in this experimental model are likely to be clinically relevant. At high doses, Ang II (400 to 800 ng/kg per minute) can elicit a "rapid direct pressor" response in a matter of hours. At low doses, Ang II (100 to 200 ng/kg per minute) increases mean arterial pressure (MAP) gradually over a period of days resulting in a "slow pressor" response without a direct pressor effect. The majority of hypertension research to date has been conducted in male animals, as is typically found in biomedical research. Thus, we do not know to what extent the mechanisms uncovered in the male also apply to the female. What we do know is that there are significant differences in BP control between males and females. Women have lower BP and a lower incidence of hypertension than men up through their mid-50s. With increasing age, the incidence in women approaches and eventually surpasses that in men for reasons that have been ascribed to menopause and to the loss of hypertensive men in the aging population because of sex differences in cardiovascular mortality. 2 Although experimental studies of hypertension rarely include both sexes, the few reports that do suggest that sex differences in hypertension are a robust phenomenon that is observed in many experimental models of hypertension, including genetic models such as the spontaneously hypertensive rat and the Dahl and Sabra salt-sensitive rats, transgenic models, such as the mRen (2) .Lewis rat, and induced models, including aldosterone infusion, deoxycorticosterone acetate-salt, and cotreatment with fructose and insulin. 2 Sex differences are also observed in the Ang II infusion model of hypertension. The female C57/Bl6 mouse has lower MAP than the male after infusion of Ang II at a high dose (800 ng/kg per minute). 3 Furthermore, Ang II infusion at 700 ng/kg daily by SC injection for 10 days increases BP in the male Sprague-Dawley rat without having any BP effect in the female. 4 Sampson et al 1 support these previous findings by showing that a 2-week infusion of Ang II at 400 ng/kg per minute increased MAP by nearly 2-fold in the male Sprague-Dawley rat (⌬, 42 mm Hg) compared with the female (⌬, 24 mm Hg). No differences were found in basal BP, as was seen previously in both mice 3 and rats, 4 suggesting that sex differences in BP are detectable only under pathological conditions. Sampson et al 1 measured MAP after a very low Ang II dose (50 ng/kg per minute) and found a fascinating result. Although this low dose had no effect on MAP in the male, it significantly decreased MAP in the female, and this effect was prevented by coinfusing the animals with PD123319, an antagonist of the AT 2 R. These authors also found markedly higher AT 2 R mRNA expression in the female rat kidney (300-fold) and left ventricle of the heart (6-fold) compared with the male. This sex difference in AT 2 R expression resulted in significantly higher mRNA ratios of the AT 2 R to the angiotensin type 1 receptor subtypes (AT 1a R and AT 1b R) in the female heart and kidney compared with the male. This study suggests that the Ang II-induced vasodilatory effect observed in females is attributable to the AT 2 R, and, conversely, that the lack of effect in males may be a result of their lower levels of AT 2 R expression in these key target tissues. Thus, the vasodilator/vasoconstrictor balance is greater in the female compared with the male, partly because of the difference in the ratio between the AT 2 R and AT 1 R ( Figure, panel A) . This study extends the findings of a previous report, which suggested that sex differences exist in the vasodilator/