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(Hypertension. 2004;43:420.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Decreased Endothelium-Dependent NO-cGMP Vascular Relaxation and Hypertension in Growth-Restricted Rats on a High-Salt Diet

From the Department of Physiology and Biophysics (J.A.P., B.T.A.), University of Mississippi Medical Center, Jackson, and Research and Development (R.A.K.), Veterans Affairs Medical Center, West Roxbury, and Department of Medicine, Harvard Medical School, Boston, Mass.

Correspondence to Raouf A. Khalil, MD, PhD, Harvard Medical School, VA Boston Healthcare–Research, 1400 VFW Pkwy, 3/2B123, Boston, MA 02132. E-mail raouf_khalil{at}hms.harvard.edu

Low birth weight caused by placental insufficiency increases the risk of hypertension in young adults, particularly while ingesting a high-salt diet; however, the vascular mechanisms involved are unclear. We tested whether intrauterine fetal growth restriction results in salt-sensitive offspring that exhibit impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension during high-salt diet feeding. Male offspring of control pregnant rats and pregnant rats with reduced uterine perfusion pressure (intrauterine growth restricted [IUGR]) were fed either a normal-sodium (NS, 1%) or a high-sodium (HS, 8%) diet. Body weight was less in IUGR/NS and IUGR/HS than in NS and HS rats. Arterial pressure was greater in IUGR/NS (144±4 mm|Hg) than in NS (131±3 mm|Hg) rats and far greater in IUGR/HS (171±12 mm|Hg) than in HS (129±2 mm|Hg) rats. In isolated, endothelium-intact aortic strips, phenylephrine (Phe, 10^-5 mol/L) caused an increase in active stress that was greater in IUGR/NS (13.9±0.9 N/m²) than in NS (8.5±0.6 N/m²) animals and far greater in IUGR/HS (18.2±1.2 N/m²) than in HS (9.4±0.8x10⁴ N/m²) rats. Acetylcholine caused relaxation of the Phe-mediated contraction and induced vascular nitrite/nitrate production that was less in IUGR/NS than in NS animals and far less in IUGR/HS than in HS rats. N^G-nitro-L-arginine methyl ester, which inhibits nitric oxide (NO) synthase, or ODQ, which inhibits cGMP production in smooth muscle, inhibited acetylcholine relaxations and enhanced Phe contractions in NS and HS rats but not in IUGR/NS or IUGR/HS rats. Endothelium removal enhanced Phe-induced stress in NS and HS rats but not in IUGR/NS or IUGR/HS rats. Thus, endothelium-dependent relaxation via the NO-cGMP pathway is inhibited in systemic vessels of IUGR rats, particularly during intake of an HS diet. This might explain the increased vasoconstriction and arterial pressure in low-birth-weight offspring during ingestion of an HS diet.

Key Words: arterial pressure • endothelium • nitric oxide • muscle, vascular, smooth • constriction • hypertension, pregnancy

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