Arginase Inhibition in Ischemia-reperfusion Injury

Phase 1

Completed

• Conditions: Coronary Artery Disease; Type 2 Diabetes Mellitus
• Interventions: Drug: N-hydroxy-nor-arginine; Drug: NaCl

• Registration Number: NCT02009527
• Lead Sponsor: Karolinska Institutet

Brief Summary

The present project is designed to test the hypothesis that arginase contributes to endothelial dysfunction induced by ischemia-reperfusion in patients with coronary artery disease.

Detailed Description

Background: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes.

Methods: Male patients with CAD (n=12) or CAD + type 2 diabetes (n=12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (N-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.

Results: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P\<0.05). N-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P\<0.01). Endothelium-independent vasodilatation did not differ between the occasions.

Conclusions: Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.

Study Timeline

• Study Start: 2012-01
• Primary Completion: 2013-04
• Study Completion: 2013-09
• Study First Submitted: 2013-12-08
• Study First Submitted QC: 2013-12-09
• Study First Posted: 2013-12-12
• Status Verified: 2015-04
• Last Update Submitted: 2015-04-17
• Last Update Posted: 2015-04-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 24

Inclusion Criteria

• Coronary artery disease

Exclusion Criteria

• Age >80 years, Myocardial infarction/unstable angina within 6 weeks prior to the study, Raynaud's phenomenon, peripheral vasculopathies, arterial shunting or other vascular surgery of the study arm, Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol, Participant in an ongoing study, Unwillingness to participate following oral and written information.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
N-hydroxy-nor-arginine	N-hydroxy-nor-arginine	N-hydroxy-nor-arginine 0.1 mg/ min i.a. for 20 min
NaCl	NaCl	NaCl 0.9%, 6 ml/min i.a. for 20 min

Primary Outcome Measures

Name	Time	Method
Change in endothelial function	20 min of reperfusion	Flow-mediated dilatation of the radial artery

Trial Locations

Locations (1)

Karolinska Institutet; 🇸🇪 Stockholm, Sweden