Background: Endothelial dysfunction is the hallmark of ischaemia- reperfusion (IR) injury and intercellular gap junctions appear to play a role in this process. Rotigaptide (ZP-123) is a novel anti-arrhythmic agent that increases inter-cellular communication via gap junctions. We tested the hypothesis that rotigaptide protects the human forearm arterial circulation from IR induced endothelial dysfunction.

Methods: Healthy male subjects (n=21) were recruited into a randomised double-blind cross-over study. IR injury (upper arm cuff inflated to 200 mmHg for 20min) was induced in the presence of intra-arterial rotigaptide (25 nmol/min) or saline placebo on separate visits. Using venous occlusion plethysmography, forearm arterial blood flow was measured during intra-arterial infusion of acetylcholine (ACh; 5–20 μg/min) or sodium nitroprusside (SNP; 2–8mg/min) before and after IR injury.

Results: Resting blood flow remained unchanged throughout (P=NS). ACh and SNP caused arterial vasodilatation (P<0.01) that was not affected by rotigaptide (P=NS). IR injury caused substantial impairment of ACh-induced vasodilatation (P=0.007). This effect was abolished by rotigaptide. Endothelium-independent vasodilatation evoked by SNP was unaffected by either IR injury or rotigaptide (P=NS).

Conclusion: IR injury impairs endothelium-dependent vasomotion: an effect that is reversed by rotigaptide. This is the first clinical study to demonstrate that enhanced communication via gap junctions protects the endothelium from IR injury.