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.
Giachini
Fernanda R
FR
Medical College of Georgia, Department of Physiology, 1120 Fifteenth St, CA-2095, Augusta, GA 30912-3000, USA. fgiachini@mcg.edu
Sullivan
Jennifer C
JC
Lima
Victor V
VV
Carneiro
Fernando S
FS
Fortes
Zuleica B
ZB
Pollock
David M
DM
Carvalho
Maria Helena C
MH
Webb
R Clinton
RC
Tostes
Rita C
RC
D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D001794:Blood Pressure; D015153:Blotting, Western; D003900:Desoxycorticosterone; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000097:blood; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009392:Nephrectomy / Q000379:methods; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D010991:Plethysmography; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D016753:Interleukin-10; D010656:Phenylephrine; D003900:Desoxycorticosterone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1