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(Hypertension. 2007;50:1077.)
© 2007 American Heart Association, Inc.

Original Articles

Maternal Supplementation With Citrulline Increases Renal Nitric Oxide in Young Spontaneously Hypertensive Rats and Has Long-Term Antihypertensive Effects

Maarten P. Koeners; Ernst E. van Faassen; Sebastiaan Wesseling; Monique de Sain-van der Velden; Hein A. Koomans; Branko Braam; Jaap A. Joles

From the Departments of Nephrology and Hypertension (M.P.K., S.W., H.A.K., J.A.J.) and Metabolic and Endocrine Diseases (M.d.S-v.d.V.), University Medical Center, Utrecht, The Netherlands; Interface Physics (E.E.v.F.), Debye Institute, Utrecht University, Utrecht, The Netherlands; and Division of Nephrology and Immunology (B.B.), Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Correspondence to Jaap A. Joles, Department of Nephrology and Hypertension F03.226, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands. E-mail j.a.joles{at}umcutrecht.nl

NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46±0.01 versus 0.68±0.05 nmol/g of kidney weight, respectively; P<0.001) but not in their heart. Furthermore, perinatal supplementation with citrulline increased renal NO to 0.59±0.02 nmol/g of kidney weight (P<0.001) at 2 weeks and persistently ameliorated the development of hypertension in females and until 20 weeks in male SHR offspring. Defects in both the renal citrulline-arginine pathway and in arginine reabsorption precede hypertension in SHRs. We propose that the reduced cationic amino acid transporter disables the developing SHR kidney to use arginine reabsorption to compensate for reduced arginine synthesis, resulting in organ-specific NO deficiency. This early renal deficiency and its adverse sequels can be corrected by perinatal citrulline supplementation persistently in female and transiently in male SHRs.

Key Words: NO • amino acids • hypertension • developmental plasticity • electron paramagnetic resonance • citrulline

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