# L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
## 7 Other Positive Effects of L-Citrulline  
### L-Citrulline and Cardiovascular Diseases  
Endothelial cell dysfunction, defined as impaired endothelium-dependent vasodilation caused by decreased NO bioavailability, is a primary cause of disability and death associated with cardiovascular disease [41; 83; 84]. In the vascular endothelial cells, synthesis of NO by NOS3 is essential in maintaining the dilation of blood vessels, controllingblood pressure, and also presents other vasoprotective and anti-atherosclerotic effects [28]. A strong association has been found between NO deficiency in the vascular endothelium and cardiovascular diseases, including hypertension, atherosclerosis, and diabetic vascular disease. This suggests that increased NO production could have a key role in slowing the progression of these diseases or their component processes [41; 85; 86]. Arg can be administered as a substrate in order to reach the NO levels to achieve good cardiovascular function. However, some studies have shown the drawbacks of oral supplementation with Arg: (1) Arg undergoes intense catabolism by the arginase enzymes of the gastrointestinal and hepatic systems [25; 43]. (2) High levels of Arg have been shown to induce arginase enzymes, thus further increasing Arg catabolism. Moreover, disease conditions including diabetes, trauma, pulmonary hypertension, sickle cell, heart failure, and even aging enhance arginase expression and activity, thus negatively affecting Arg therapy efficacy [41]. Conversely, CIT does not present such drawbacks, so it would be an adequate supplement in the diseases associated with Arg deficiencies. Consequently, CIT supplementation achieved better NO levels than supplementing Arg through the inhibition of reactive oxygen species (ROS) production and arginase II protein expression [33].  
Furthermore, chronic administration of a combination of CIT and Arg can revoke the effect on high cholesterol, and undo atherosclerosis progression in rabbits [87]. CIT supplementation (800 mg/day for 8 weeks) improved endothelial dysfunction in patients diagnosed with vasospastic angina, probably due to potentiating NO-dependent reactions and decreasing the state of lipoprotein oxidation in humans [88]. However, in another study, [PERSON] et al. [89] reported that acute CIT supplementation (10 g) was ineffective at improving vascular endothelial dysfunction in the older heart failure adults. These results could imply that factors other than NO synthesis per se may play a role in vascular dysfunction and/or that longer-term supplementation of either Arg or CIT is required in order to reverse the impairment in peripheral vascular function in the older heart failure adults. Recently, [PERSON] et al. [85] demonstrated that chronic NO precursor supplementation (nitrate-rich salad and citrulline, 520 mg nitrate and 6 g citrulline) in healthy older individuals can reduce resting blood pressure and increase cycling performance by improving cardiorespiratory responses. [PERSON] et al. [90] studied the effect of CIT supplementation on resting heart rate variability (HRV) and blood pressure in obese postmenopausal women, as HRV has been proven to be negatively influenced by menopause and obesity in women, which has been associated with adverse cardiac events and mortality. Those authors demonstrated that 8 weeks of CIT supplementation (6 g/day in two doses) improved cardiac autonomic function in sedentary obese postmenopausal women. Therefore, although these results could be clinically useful, there are many factors that greatly influence the positive CIT results, improving cardiovascular diseases in humans.