Arginase Inhibition in Ischemia-reperfusion Injury

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of Arginase Inhibition on Endothelial Function Induced by Ischemia-reperfusion in Patients With Coronary Artery Disease

Conditions
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Coronary Artery Disease, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: N-hydroxy-nor-arginine
* Drug: NaCl


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-hydroxy-nor-arginine<br>N-hydroxy-nor-arginine 0.1 mg/ min i.a. for 20 min | Drug: N-hydroxy-nor-arginine<br> <br> |
| Placebo Comparator: NaCl<br>NaCl 0.9%, 6 ml/min i.a. for 20 min | Drug: NaCl<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in endothelial function | Flow-mediated dilatation of the radial artery | 20 min of reperfusion |