Sex differences in acute ANG II-mediated hemodynamic responses in mice

Abstract

Male sex is associated with higher blood pressure and greater renal injury, perhaps related to greater sensitivity to ANG II. In anesthetized male and female C57BLK/6 mice, we assessed responses of mean arterial pressure (MAP) and renal vascular resistance (RVR; Transonic flow probe) to acute bolus injections of ANG II (0.3-3.0 microg/kg iv) and phenylephrine (PE; 30-300 microg/kg) during low-, normal-, and high-sodium diets. The role of reactive oxygen species was determined by coadministration of tempol. ANG II type 1 and type 2 (AT1 and AT2) receptor and endothelial nitric oxide synthase (NOS3) expression were determined in dissected kidney vessels. While no difference was found on the low-sodium (LS) diet, MAP and RVR responses to ANG II were greater in males during the normal-sodium (NS) and high-sodium (HS) diets (e.g., RVR response at ANG II 3.0 microg/kg during NS: +329 +/- 22 vs. +271 +/- 28 mmHg.ml(-1).min, P = 0.029, effect size = 0.75). Tempol had no effect on the sex-dependent responses on any of the diets. On the LS diet, AT1 and AT2 receptor expression was higher in males. No sex differences were found on the NS diet. On the HS diet, AT1 was higher, and NOS3 expression was lower in males. Acute responses to ANG II are greater in male mice during NS and HS diets, which is, in part, related to differences in AT1, AT2, and NOS3 expression in kidney vessels. Mouse models will be useful to study the role of sex differences in ANG II sensitivity for cardiovascular and renal disease.

Fig. 1.

Effect of acute graded infusions of ANG II (A–C) and phenylephrine (PE; D–F) on mean arterial pressure (MAP; A and D), renal blood flow (RBF; B and E) and renal vascular resistance (RVR; C and F) in male (■, n = 14) and female mice (□, n = 11) during a low-sodium diet (0.02%).

Fig. 2.

Effect of acute graded infusions of ANG II (A–C) and PE (D–F) on MAP (A and D), RBF (B and E) and RVR (C and F) in male (■, n = 13) and female mice (□, n = 15) during a normal sodium diet (0.29%).

Fig. 3.

Effect of acute graded infusions of ANG II (A–C) and PE (D–F) on MAP (A and D), RBF (B and E), and RVR (C and F) in male (■, n = 10) and female mice (□, n = 11) during a high-sodium diet (4%).

Fig. 4.

Effect of acute graded infusions of ANG II on RVR in the presence and absence of Tempol (5 mg·kg⁻¹·min⁻¹) in male (A, C, E) and female (B, D, F) mice on low- (A and B), normal- (C and D) and high- (E and F) sodium diets (low sodium: male n = 7, female n = 6; normal sodium: male n = 6, female n = 7; high sodium: male n = 5, female n = 6).

Fig. 5.

Expression of the AT1 receptor (A), AT2 receptor (B), and NOS3 (C), in kidney vessels from male and female mice on a low-sodium diet (all n = 5).

Fig. 6.

Expression of the AT1 receptor (A), AT2 receptor (B), and NOS3 (C) in kidney vessels from male and female mice on a normal sodium diet (all n = 5).

Fig. 7.

Expression of the AT1 receptor (A), AT2 receptor (B), and NOS3 (C) in kidney vessels from male and female mice on a high-sodium diet (all n = 5).