Are L-arginine (L-arginine) and citrulline proven to have vasodilatory effects?

L-Arginine and Citrulline Have Proven Vasodilatory Effects

L-arginine and L-citrulline have demonstrated vasodilatory effects through their role in nitric oxide (NO) production, with evidence showing they can reduce blood pressure and vascular resistance in specific clinical contexts. 1

Mechanism of Action

• L-arginine is the sole substrate for nitric oxide synthase (NOS) enzymes, which produce nitric oxide, a potent vasodilator essential for maintaining normal vascular function 1
• L-citrulline is converted to L-arginine in the body, effectively serving as a precursor that increases plasma L-arginine levels 2, 3
• The vasodilatory effect occurs through the metabolism of L-arginine by NOS to produce NO, which causes relaxation of vascular smooth muscle 1

Evidence for Vasodilatory Effects

L-Arginine Studies

• Short-term administration of L-arginine (500 mg/kg infused over 30 min) in pulmonary arterial hypertension (PAH) patients demonstrated a 15.8% reduction in mean pulmonary arterial pressure (mPAP) and 27% decrease in pulmonary vascular resistance (PVR) 1
• Oral supplementation of L-arginine (0.5 g/10 kg body weight) in 19 PAH patients produced a 9% decrease in mPAP and 16% decrease in PVR 1
• A randomized, placebo-controlled trial in 10 healthy males showed that L-arginine infusion (0.5 g/kg) produced a significant fall in mean blood pressure of 9.3% associated with increased expired NO concentration 4

L-Citrulline Studies

• L-citrulline supplementation raises plasma L-arginine concentration more effectively than direct L-arginine supplementation and augments NO-dependent signaling in a dose-dependent manner 3
• The highest studied dose of citrulline (3g twice daily) significantly improved the L-arginine/ADMA ratio (an indicator of NO production capacity) and increased urinary nitrate and cGMP (markers of NO activity) 3

Combination Effects

• Combined oral L-citrulline and L-arginine supplementation causes a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability than either amino acid alone 2
• This combination significantly increased blood flow in the central ear artery in rabbits compared to control 2
• In human athletes, combined L-citrulline and L-arginine supplementation improved cycling performance and reduced perceived exertion, effects potentially related to vasodilation 5

Limitations and Inconsistencies

• Results have been mixed across studies, with some showing minimal effects on hemodynamics 1
• A small study of acute L-arginine infusion in four IPAH patients demonstrated little favorable effect on pulmonary hemodynamics 1
• Another short-term study of L-arginine infusion in normotensive volunteers and systemic sclerosis patients with PAH showed no significant effect on hemodynamics 1
• Clinical trial evidence for chronic blood pressure reduction in the general population shows significant heterogeneity in study designs and outcomes 6

Clinical Implications

• Despite growing use of oral arginine supplements, rigorous randomized trials of long-term oral arginine supplementation in relevant patient populations are lacking 1
• Potential drawbacks of arginine supplementation may include increased concentration of proproliferative polyamines 1
• The short-term vasodilatory effects observed in controlled settings may not necessarily translate to long-term benefits 1
• The vasodilatory effects appear to be dose-dependent, with higher doses generally showing more pronounced effects 3

In summary, while L-arginine and L-citrulline have demonstrated acute vasodilatory effects through NO-mediated pathways in specific clinical contexts, the evidence for consistent long-term benefits remains limited, and results vary across different patient populations and dosing regimens.