Sex differences in the renal vascular response to angiotensin II involves the M as receptor

Aim The renin‐angiotensin system ( RAS ) depressor arm, particularly renal angiotensin type 2 receptor ( AT 2 R ) and M as receptor (mas R ) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that mas R activation increases renal blood flow ( RBF ) at rest and attenuates the reduction in RBF in response to angiotensin II (Ang II ) infusion in female rats. Furthermore, we postulated that combined activation of the AT 2 R and mas R would produce a greater response than mas R activation alone. Methods In anaesthetized male and female W istar rats, mean arterial pressure ( MAP ) and RBF responses during graded A ng II infusion (30–1000 ng kg −1  min −1 i.v.) were assessed following pre‐treatment with vehicle, the mas R antagonist A 779, or A 779 plus the AT 2 R antagonist PD 123319. Results Basal MAP was not altered by any pre‐treatment. Basal RBF decreased approx. 20% in female ( P  < 0.05), but not male rats in response to A 779. However, basal RBF was not altered by A 779 +  PD 123319. A ng II infusion reduced RBF in a dose‐related fashion ( P dose  < 0.0001) and mas R blockade did not alter the RBF response to A ng II infusion in male or female rats. However, A 779 +  PD 123319 attenuated the reduction in RBF response to A ng II in females ( P group  < 0.005), but not males. Conclusion The impact of the mas R on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT 2 R and mas R blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT 2 R and/or mas R stimulation can be advanced.