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(Hypertension. 2004;43:1080.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Reduced NOS3 Phosphorylation Mediates Reduced NO/cGMP Signaling in Mesenteric Arteries of Deoxycorticosterone Acetate-Salt Hypertensive Rats

Jennifer M. Sasser; Jennifer C. Sullivan; Ahmed A. Elmarakby; Bruce E. Kemp; David M. Pollock; Jennifer S. Pollock

From the Department of Pharmacology (J.M.S., J.C.S.,A.A.E.,D.M.P., J.S.P.), Vascular Biology Center (J.C.S., D.M.P., J.S.P.) and Department of Surgery (D.M.P.), Medical College of Georgia, Augusta; The St. Vincent’s Institute of Medical Research (B.E.K.) Fitzroy, Australia.

Correspondence to Jennifer S. Pollock, Medical College of Georgia, Vascular Biology Center, 1459 Laney Walker Blvd., Augusta, GA 30912. E-mail jpollock{at}mail.mcg.edu

Salt-sensitive hypertension is associated with impaired NO/cGMP signaling. We hypothesized that increased superoxide production by NADPH oxidase and altered endothelial NO synthase (NOS3) phosphorylation determine endothelial dysfunction in hypertension. Experiments tested if NO/cGMP signaling and NOS3 serine phosphorylation are decreased and NADPH oxidase activity is increased in mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt rats compared with arteries from placebo rats. Concentration response curves to phenylephrine were performed in mesenteric arteries in the presence and absence of N-nitro-L-arginine (LNA) and antioxidants to determine the influence of basal NO and superoxide production on vascular tone. LNA increased phenylephrine sensitivity in arteries from placebo, but not DOCA-salt rats, regardless of antioxidant treatment. To determine basal cGMP production, mesenteric arteries were incubated with 3-isobutyl-1-methylxanthine in the presence or absence of LNA, sodium nitroprusside (SNP), antioxidants, or tetrahydrobiopterin. NOS-dependent cGMP production was reduced in arteries from DOCA-salt rats compared with arteries from placebo rats and was not restored by acute treatment with antioxidants or tetrahydrobiopterin. SNP-induced cGMP production was similar between groups as was NADPH oxidase activity, measured by lucigenin chemiluminescence, in mesenteric arteries. Expression and phosphorylation of NOS3 were examined by Western blotting. Phosphorylation of NOS3 was decreased in arteries from DOCA-salt rats compared with placebo at serine residues 1179 and 635. These findings indicate that diminished NO/cGMP signaling in mesenteric arteries from DOCA-salt rats is caused by reduced phosphorylation of NOS3 at serine 1179 and serine 635, rather than NO scavenging by superoxide.

Key Words: mesenteric arteries • cyclic GMP • nitric oxide synthase • phosphorylation • deoxycorticosterone

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