AimThe aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). MethodsSix healthy male volunteers (mean age 29.5 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 x 5min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20min cuff inflation to 200mmHg, 20min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). ResultsRIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by similar to 26% (from 118 +/- 9 to 87 +/- 5nmoll(-1)) locally in the left arm (P=0.008) overall, with an independent effect of -58.70nmoll(-1) (95% confidence intervals -116.1 to -1.33) at 15min reperfusion, and by similar to 24% (from 109 +/- 9 to 83 +/- 7nmoll(-1)) systemically in the right arm (P=0.03). ConclusionsRIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by similar to 25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required.