Abstract 171: Urea Cycle Intermediates and Nitric Oxide Synthase Metabolites Decrease Whilst Asymmetric Dimethylarginine Remained Unchanged Following Cardiac Surgery

Abstract

Background: Within the endothelium, Nitric Oxide Synthase (NOS) activity through the conversion of Arginine to Citrulline and Nitric Oxide (NO) is largely seen as beneficial. NO is a powerful bioactive molecule which elicits an antithrombotic and antioxidant effect preventing platelet aggregation and atherosclerosis. In immune cells NOS however is largely thought to be beneficial as a microbicidal agent involved in inflammatory responses. Systemic inflammation is also a common outcome in patients undergoing cardiac surgery and those receiving Cardiopulmonary Bypass (CPB) due to contact with foreign surfaces and surgical trauma. Through the Urea Cycle, Citrulline is converted back to Arginine via intermediate Ornithine. Asymmetric Dimethylmethylarginine (ADMA) is an inhibitor of all NOS isoforms, with circulating ADMA being an independent risk factor for mortality within ICU patients and is associated with an increased cardiovascular disease risk profile. Relatively recent studies have demonstrated the beneficial role of ADMA within diseases where iNOS production is overactive such as pulmonary fibrosis. Hypothesis: Cardiac surgery and CPB will alter NOS inhibitor ADMA and other metabolites . Results: Cardiac surgery patients (n=44) had arterial blood sampled over 4 time points: Morning of surgery (A), Pre (B) and post cardiac injury (C), and post-operative morning (D). Dimethylarginines (ADMA and SDMA) and Urea Cycle intermediates (Arginine, Citrulline and Ornithine) were measured via HPLC-MS/MS. Both Dimethylarginines are released as a function of proteolysis, ADMA remained unchanged over surgery (0.48±0.09μM Vs 0.46±0.08μM Vs 0.50±0.09μM Vs 0.43±0.07μM, p< 0.05) whilst SDMA increased during surgery (B) from morning of the surgery (A) (0.73±0.21μM Vs 0.89±0.25μM; p<0.01 ) then decreasing post-surgery (D) (0.77±0.33μM) and Arginine (A; 111.83±53.74μM Vs B; 67.91±48.96μM; p<0.01, D; 60.41±34.26μM, A Vs D; p< 0.001) and other metabolites steadily decreased. Conclusions: These findings indicate that the regulation of circulating ADMA compared to SDMA is homeostatic even within cardiac surgery. NOS substrate Arginine and Urea Cycle intermediates are consumed which may be predictive of post-operative morbidity.