L-citrulline Supplementation, Cold Exposure, & Post-Exercise Muscle Ischemia

Cardiovascular disease (CVD) continues to be the major cause of morbidity and mortality in western countries. It has been shown that CVD events are known to be higher in the winter than in the summer. Low environmental temperatures may induce increased cardiovascular stress resulting in cold-induced hypertension (CIH), the leading risk factor for CVD events. Similar to whole-body cold exposure, the cold pressor test (CPT), an external local cold stimulus, has been used for evaluation of cardiovascular and hemodynamic reactivity to sympathetic stimulation. It has been shown that brachial blood pressure (BP), pressure pulse wave reflection, aortic BP, heart rate (HR), and arterial stiffness are increased during CPT. However, the physiologic mechanisms for the cardiovascular complications related to low temperatures are not completely clear.

Isometric-handgrip (IHG) exercise has been used as a tool for assessing cardiovascular autonomic control by a maneuver defined as post-exercise muscle ischemia (PEMI). PEMI induces exercise pressor reflex (metaboreflex) by trapping metabolites in the previous active muscle at the cessation of exercise. During PEMI, the accumulation of contraction-derived metabolites induces sympathetic mediated vascular stimulation and an increased BP, whereas the HR fully recovers. This suggests that the fall in HR is evoked by an increase in parasympathetic activity which overpowers the sympathetic activation. Implication of IHG exercise followed by PEMI provides important clinical information because impaired autonomic and cardiovascular functions are associated with cardiovascular events.

Recently, oral supplementation with the amino acid L-citrulline (L-cit) has been proposed as a possible adjunct treatment for hypertension and arterial stiffness. L-cit is known to enhance the bioavailability of L-arginine (L-arg), the endothelial substrate for nitric oxide (NO) production. Cold exposure might include a temperature-dependent inhibition of endothelial NO synthase (eNOS), the enzyme that produces NO from the amino acid L-arg and may trigger various types of CVD. It has been shown that L-cit supplementation has effectively attenuated the CIH response during cold pressor test. Thus, L-cit supplementation may be effective to reduce the cardiovascular responses associated with cold exposure and the exercise pressor reflex imposed by PEMI. Therefore, the proposed study is important for the following reasons: (1) the results of his study will add to our understanding regarding the cardiovascular and autonomic mechanisms associated with exercise and cold exposure; (2) the results of this study will contribute to the development of an adjunct therapy for the prevention of cardiovascular adverse events that are particularly increased during stress such as cold exposure and exercise.