Extracellular Signal–Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in Desoxycorticosterone Acetate-Salt Hypertension Vascular Reactivity

Extracellular signal-regulated kinase (ERK)1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191+/-3 mm Hg) compared with female DOCA rats (172+/-7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22+/-3 mN; n=6) and small mesenteric arteries (13+/-2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16+/-3 and 10+/-2 mN, respectively; P<0.05) and female DOCA rats (15+/-1 and 11+/-1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 micromol/L) abrogated increased contraction to phenylephrine in aorta (14+/-2 mN) and small mesenteric arteries (10+/-2 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process.