L-citrulline supplementation reduces systolic arterial pressure and myocardial infarct size in a rat model of sleep apnea syndrome

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Sleep apnea syndrome is characterized by intermittent hypoxia (IH), leading to an increase in blood pressure (BP) and infarct size. Independently, IH has been demonstrated to alter arginine (Arg) metabolism. As Arg availability directly impacts nitric oxide production, we speculate that plasmatic Arg deficiency during IH may contribute to cardiovascular alterations induced by IH. Knowing that citrulline (Cit) is a better precursor of Arg than Arg itself, we propose to assess the impact of chronic Cit supplementation on IH-induced an increase in BP and infarct size. Four groups of rats ( n = 11–14), were submitted to normoxia (N) or IH [14 days (d), 8 h per d, 30 s-O2 21%/30 s-O2 5%] and supplemented or not with Cit (1 g.kg −1 .d −1 ). After 14 d, BP was measured by carotid catheterization; hearts were perfused by the Langendorff method and submitted to global and total ischemia (30 min)-reperfusion (120 min) before measuring infarct size related to left ventricle area (I/V) by colorimetry and planimetry. Another set of rats was added ( n = 5–6) in order to collect the heart and aorta for histological and biochemical analyses. IH increases systolic BP (144.5 ± 3.5 vs. 165.1 ± 4.2 mmHg in N and IH respectively, n = 11–14, P < 0.01) and I/V (33.7 ± 4.4 vs. 46 ± 2.5% in N and IH, respectively, n = 10–12, P < 0.05). Cit abolishes IH-induced increase in both systolic BP (139.8 ± 4. vs. 155.6 ± 6.6 mmHg NCit and IHCit, respectively) and I/V (35.7 ± 3.3 vs. 38.2 ± 2.1% in NCit and IHCit). Preliminary western blot results show that IH decreases T495P-eNOS in heart whereas it did not affect S1177P-eNOS. Interestingly, Cit supplementation seems to decrease even more the T495P-eNOS in the IHCit group compared to IH and NCit groups. Cit supplementation abolishes the deleterious effects of IH in terms of BP and infarct size. This suggests that citrulline could be a complementary or alternative treatment to the current sleep apnea standard treatment that is not fully efficient. However, biochemical and histological studies (NOx, oxidative stress, S-nitrosylation…) are ongoing to enlighten the specific mechanisms involved in cardiovascular protection induced by citrulline chronic supplementation during IH.