Abstract
Enhanced arginase-induced arginine consumption is believed to play a key role in the pathogenesis of sickle cell disease-induced end organ failure. Enhancement of arginine availability with l-arginine supplementation exhibited less consistent results; however, l-citrulline, the precursor of l-arginine, may be a promising alternative. In this study, we determined the effects of l-citrulline compared to l-arginine supplementation on arginine-nitric oxide (NO) metabolism, arginine availability and microcirculation in a murine model with acutely-enhanced arginase activity. The effects were measured in six groups of mice (n = 8 each) injected intraperitoneally with sterile saline or arginase (1000 IE/mouse) with or without being separately injected with l-citrulline or l-arginine 1 h prior to assessment of the microcirculation with side stream dark-field (SDF)-imaging or in vivo NO-production with electron spin resonance (ESR) spectroscopy. Arginase injection caused a decrease in plasma and tissue arginine concentrations. l-arginine and l-citrulline supplementation both enhanced plasma and tissue arginine concentrations in arginase-injected mice. However, only the citrulline supplementation increased NO production and improved microcirculatory flow in arginase-injected mice. In conclusion, the present study provides for the first time in vivo experimental evidence that l-citrulline, and not l-arginine supplementation, improves the end organ microcirculation during conditions with acute arginase-induced arginine deficiency by increasing the NO concentration in tissues.
Highlights
Sickle cell disease can be affected by acute life-threatening complications, such as recurrent vaso-occlusive events, pulmonary hypertension and severe hemolysis [1,2]
Arginase injection resulted in a
L-citrulline supplementation mediated a >4-fold significant increase in plasma arginine concentration in arginase-treated animals, whereas arginine supplementation was unable to mediate a significant increase in plasma arginine concentration in arginase-injected animals (Figure 3A)
Summary
Sickle cell disease can be affected by acute life-threatening complications, such as recurrent vaso-occlusive events, pulmonary hypertension and severe hemolysis [1,2]. In an acute crisis with intravascular hemolysis [3,4], arginase is released in large quantities by damaged red blood cells [1,4,5]. This arginase rapidly consumes the locally-available arginine, leading to a diminished production of the main vasodilator of the microcirculation, nitric oxide (NO) production [6], which contributes to an impaired microvascular flow, resulting in end-organ damage [1,2]. Other mechanisms possibly contributing to the decreased microvascular flow are increased oxidative stress and the release of hemoglobin from the damaged red blood cells, which consumes NO [3,4]. Supplementing arginine to restore the depleted arginine pools was suggested to be a good therapeutic approach to treat end-organ damage in sickle cell disease [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
