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In addition, C21 significantly increased renal vasodilatation in both sexes, and this response was greater in females, which may reduce glomerular pressure, prevent glomerular hyperfiltration and afford renoprotection. Accordingly, we suggest that there is still an unmet need to investigate the long-term and sex-specific antihypertensive effects of pharmacological AT2R stimulation to confirm whether AT2R stimulation should be considered as a novel antihypertensive therapy, particularly in women. Unmet need to investigate the anti-hypertensive effects of AT2R stimulation in females Furthermore, Alectinib it is commonly proposed that the inability of previous studies to identify any major effect of selective AT2R stimulation on arterial pressure is likely associated with the dominant pressor actions of AngII via the AT1R. That is, inhibition GPX4 of the AT1R is generally required to prevent endogenous AngII from exerting tonic AT1R-mediated vasoconstriction in order for AT2R-mediated vasodilatation to be manifest. Certainly, previous studies have shown that the AT2R agonists C21[42] and CGP42112[48] acutely reduce arterial pressure in male SHR during concomitant AT1R blockade. Furthermore, it has been shown previously in rodent models that overexpression of the AT2R in the heart[49] or vasculature[50] decreases sensitivity to AT1R-mediated pressor effects of AngII. Such findings have led to the proposition that combining an ARB with an AT2R agonist may provide complementary therapeutic benefit. Indeed, it is well accepted that selective AT1R blockade with an ARB increases endogenous AngII levels, resulting in unopposed AT2R stimulation, which, in turn, contributes to the arterial pressure-lowering effects of ARBs.[13] There is also now evidence that the depressor RAS arm is upregulated during AT1R blockade, including increased vascular AT2R expression.[51, 53] This cross-talk Osimertinib in vitro between the angiotensin receptors may further enhance the ability of these antihypertensive agents and provides a strong rationale for performing additional studies to investigate the long-term antihypertensive effects of this combination therapy and, moreover, whether these effects are sex dependent. When it comes to the identification of novel targets for the treatment of hypertension and associated disease, we cannot ignore the fact that the population most frequently in need of clinical treatment for hypertension and cardiovascular disease is the elderly.[53-55] After the age of 65�years, more than two-thirds of individuals have hypertension and this cohort also demonstrates the lowest rates of arterial pressure control.[53] Moreover, the prevalence and severity of hypertension increases more dramatically with increasing age in women, such that a higher percentage of women than men have hypertension after the age of 65?years.
