**6. Nitric oxide donors or precursors**

Nitric oxide is an important endothelium-derived relaxing factor that plays a pivotal role in the maintenance of vascular tone. NO is synthesized from L-arginine through the effects of endothelial NO synthase (eNOS) with the critical cofactor tetrahydrobrobiopterin (BH4). BH4 depletion induces NOS uncoupling which shifts the enzymatic activity from NO production towards superoxide anion (O2 <sup>−</sup> ) production [64]. Endothelial dysfunction (ED) promotes oxidative stress and inflammation and also impairs NO dependent vaso-relaxation. Endothe‐ lial dysfunction with decreased NO production has been implicated on the development of atrial fibrillation [65, 66].

It has been indicated that L-Arginine supplementation, as a NO precursor, increases plasma nitrite levels, decreases MDA release and attenuates ROS mediated myocardial injury [67]. In a canine tachypacing model of heart failure, Nishijima et al. [68] found increased inducible NOS in the left atrium which was associated with BH4 depletion, NOS2 uncoupling, and increased superoxide anion production. These biochemical changes were associated with atrial electrophysiological changes with increased AF inducibility. BH4 supplementation reduced atrial oxidative stress and inducibility of atrial fibrillation. Thus, modulation of NOS activity may be an interesting therapeutic approach to prevent AF [69]. At the clinical level, a pilot randomized placebo-controlled study examined the potential role of sodium nitroprusside (SNP), as a NO donor, in the prevention of POAF [70]. Specifically, 100 consecutive patients undergoing CABG surgery were randomized to receive SNP (0.5 μg /Kg.min) or placebo (dextrose 5% in water) during the rewarming period. The occurrence of AF was significantly lower in the SNP group (*P*<0.005). Furthermore, the inflammatory biomarker CRP was higher postoperatively in the control group compared to the SNP group (*P*<0.05). However, a recent study didn't find any association between the use of sodium nitroprusside during cardio‐ thoracic surgery and POAF in a retrospective cohort of 1025 patients undergoing bypass surgery [71]. Therefore, anti-inflammatory and antioxidant effects of NO may have beneficial effects on the prevention of POAF. Further randomized controlled studies are urgently needed to clarify the role of NO and its donor or precursor on the AF prevention.
