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NCT02009527 Clinical Trial

Arginase Inhibition in Ischemia-reperfusion Injury

Coronary Artery Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data
NCT number NCT02009527
Other study ID # AIR
Secondary ID
Status Completed
Phase Phase 1
First received December 8, 2013
Last updated April 17, 2015
Start date January 2012
Est. completion date September 2013

Study information
Verified date April 2015
Source Karolinska Institutet
Contact n/a
Is FDA regulated No
Health authority Sweden: Regional Ethical Review Board
Study type Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility
Status Completed
Enrollment 24
Est. completion date September 2013
Est. primary completion date April 2013
Accepts healthy volunteers No
Gender Male
Age group N/A to 80 Years
Eligibility 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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

Intervention

Drug:
• N-hydroxy-nor-arginine

• NaCl

Locations
Country Name City State
Sweden Karolinska Institutet Stockholm

Sponsors (1)
Lead Sponsor Collaborator
Karolinska Institutet

Country where clinical trial is conducted

Sweden, 

Outcome
Type Measure Description Time frame Safety issue
Primary Change in endothelial function Flow-mediated dilatation of the radial artery 20 min of reperfusion No
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