Oral citrulline administration enhances NO‐dependent vasodilation

L‐citrulline (L‐Cit) is the precursor of L‐arginine (L‐Arg), substrate for NOS in NO production. L‐Cit is converted into L‐arg via arginosuccinate synthase and lyase. Our purpose was to determine the efficacy of L‐Cit versus L‐Arg supplementation in the production of NO, both in bovine aortic endothelial cells (BAEC) and in intact rabbits. Preincubation of BAEC with supplemental L‐arginine (5 x 10 −4 M) for 2 hrs increased NO production in response to ionomycin (10 −6 M) by 38% compared to control conditions (5 x 10 −5 M, L‐Arg), while incubation with L‐Cit (5 x 10 −4 M) did not augment the rise in NO. Because the duration (T 1/2 )of the hypotensive blood pressure response (DBPR) to acetylcholine (ACh) in intact animals is dependent on amount of NO released, we examined the effect of i.v. administration of L‐Cit or L‐Arg ‐ both at 30 mg/kg, initially, followed by 10 mg/kg/min for 60 min ‐ on the DBPR to Ach (0.1 to 5μg/kg, i.v.) in anesthetized rabbits. Administration of L‐Arg markedly lengthened DBPR to Ach by 210 to 350%, but treatment with L‐Cit was far less effective (only 20 to 70%). However, after 3 days of oral administration of L‐Cit (~0.2 gm/kg/day), the duration of the responses to Ach was increased by 40 to 220%. In contrast, the same oral dose of L‐Arg resulted in either no enhancement or a 36% reduction in DBPR to highest dose of ACh. Treatment with the NOS inhibitor L‐NAME (5 mg/kg, i.v.) shortened DBPR and prevented any effects of L‐Arg or L‐Cit. Our data indicate that acute supplemental L‐Arg augments NO responses to Ach, but longer periods of administration can reduce responses, possiblly through induction of arginase. Conversely, supplemental L‐Cit, while less effective acutely in augmenting NO production to Ach, when given over three days appears to effectively raise L‐arg levels and availability, and NO production. Lack of metabolism of L‐Cit by arginase may be involved.