L-citrulline for protection of endothelial function from ADMA–induced injury in porcine coronary artery

Abstract

Endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. We tested the hypothesis that L-citrulline may ameliorate the endothelial function altered by ADMA in porcine coronary artery (PCA). Myograph study for vasorelaxation, electrochemical measurement for NO, RT-PCR, and Western blot analysis for expression of eNOS, argininosuccinate synthetase (ASS), and p-eNOSser1177 were performed. cGMP was determined by enzyme immunoassay. Superoxide anion (O2.−) production was detected by the lucigenin-enhanced chemiluminescence method. Compare with controls (96.03% ± 6.2%), the maximal relaxation induced by bradykinin was significantly attenuated (61.55% ± 4.8%, p < 0.01), and significantly restored by L-citrulline (82.67 ± 6.4%, p < 0.05) after 24 hours of ADMA exposure. Expression of eNOS, p-eNOSser1177, and ASS in PCA significantly increased after L-citrulline incubation. L-citrulline also markedly restored the NO production, and cGMP level which was reduced by ADMA. The increased O2.− production by ADMA was also inhibited by L-citrulline. L-citrulline restores the endothelial function in preparations treated with ADMA by preservation of NO production and suppression of O2.− generation. Preservation of NO is attributed to the upregulation of eNOS expression along with activation of p-eNOSser1177. L-citrulline improves endothelium-dependent vasodilation through NO/ cGMP pathway.

Endothelial dysfunction of internal thoracic artery graft in patients with chronic kidney disease

“…In a future study, several possibilities are needed to be investigated to explain the mechanism, including abnormalities in signal transduction, reduced expression of NO synthase, reduced availability of substrate such as L-arginine, reduced availability of cofactor (tetrahydrobiopterin), increased antagonism of NO synthase (ADMA), and accelerated inactivation of NO caused by high levels of oxygen-derived free radicals. Furthermore, we need to examine the beneficial effects of some materials such as L-citrulline 31 and AVE3085, 32 which have been shown to protect endothelium from impairment of ADMA on CABG conduits in patients with CKD.…”

Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches

“…In fact, it has been proposed that L-citrulline supplementation could represent an alternative to L-Arg supplementation to improve vascular function, 204,205 and it attenuated blood pressure in young normotensive men. 206 In animal models, ex vivo pre-incubation with L-citrulline prevented endothelial dysfunction induced by ADMA in porcine coronary artery; indeed, such incubation favors L-citrulline to L-Arg recycling and the restoration of NO production, as a consequence of eNOS expression and activity up-regulation, the inhibition of superoxide anion production, and activation of the cyclic guanosine monophosphate (cGMP) 207 Such direct beneficial effects of L-citrulline on endothelium-dependent relaxation suggest that L-citrulline supplementation could be an efficient way to improve endothelial function in individuals born after fetal growth restriction.…”

Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review

“…[94][95][96] Studies have shown antioxidant and anti-inflammatory effects for citrulline through both NO-dependent and NO-independent pathways. 38,39,[97][98][99] Therefore, evaluating the effects of citrulline on AGEs levels might enhance our understanding of citrulline effects on microvascular complications related to diabetes.…”