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Arginase Inhibition in Ischemia-reperfusion Injury

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02009527
Recruitment Status : Completed
First Posted : December 12, 2013
Last Update Posted : April 20, 2015
Information provided by (Responsible Party):
John Pernow, 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.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Type 2 Diabetes Mellitus Drug: N-hydroxy-nor-arginine Drug: NaCl Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effect of Arginase Inhibition on Endothelial Function Induced by Ischemia-reperfusion in Patients With Coronary Artery Disease
Study Start Date : January 2012
Actual Primary Completion Date : April 2013
Actual Study Completion Date : September 2013

Resource links provided by the National Library of Medicine

Drug Information available for: Arginine

Arm Intervention/treatment
Experimental: N-hydroxy-nor-arginine
N-hydroxy-nor-arginine 0.1 mg/ min i.a. for 20 min
Drug: N-hydroxy-nor-arginine
Placebo Comparator: NaCl
NaCl 0.9%, 6 ml/min i.a. for 20 min
Drug: NaCl

Primary Outcome Measures :
  1. Change in endothelial function [ Time Frame: 20 min of reperfusion ]
    Flow-mediated dilatation of the radial artery

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02009527

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Karolinska Institutet
Stockholm, Sweden, 17176
Sponsors and Collaborators
Karolinska Institutet
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Principal Investigator: John Pernow, MD, PhD Karolinska Institutet
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: John Pernow, Professor, Karolinska Institutet Identifier: NCT02009527    
Other Study ID Numbers: AIR
First Posted: December 12, 2013    Key Record Dates
Last Update Posted: April 20, 2015
Last Verified: April 2015
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes