Unmasking the potential of the angiotensin AT{2} receptor as a therapeutic target in hypertension in men and women: what we know and what we still need to find out

Major sex differences exist in the development and progression of hypertension and cardiovascular disease. Prior to menopause, women have lower arterial pressure and, furthermore, are protected from hypertension and cardiovascular disease relative to age-matched men. However, post-menopause this cardiovascular protection in women is lost. These sex differences have been linked to sexual dimorphism in the physiological mechanisms that regulate arterial pressure, including the renin-angiotensin system (RAS), which can also impact upon the male and female response to different therapeutic approaches. This suggests that anti-hypertensive regimens need to be tailored according to sex. Newly discovered components of the RAS have emerged in recent years, allowing us to look beyond the classical RAS for novel therapeutic targets for hypertension. In this context, it is now well established that the angiotensin type 2 receptor (AT(2) R) elicits depressor and natriuretic effects, and these effects are greater in females due to enhanced AT(2) R levels modulated by estrogen. In light of knowledge that AT(2) R expression is regulated by estrogen, and that the prevalence of hypertension and cardiovascular risk is greater in women post-menopause, AT(2) R agonist therapy may therefore represent an innovative therapeutic approach to treat hypertension. Consequently, understanding how ageing and changes in the sex hormone balance influences the RAS are vital if we are to evaluate the potential of the AT(2) R as a therapeutic target in women, and also, in men. (c) 2013 The Authors Clinical and Experimental Pharmacology and Physiology (c) 2013 Wiley Publishing Asia Pty Ltd.