Arginase Inhibition in Ischemia-reperfusion Injury

Sponsor

Karolinska Institutet (Other)

Overall Status

Completed

CT.gov ID

NCT02009527

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

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 :

Jan 1, 2012

Actual Primary Completion Date :

Apr 1, 2013

Actual Study Completion Date :

Sep 1, 2013

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Change in endothelial function [20 min of reperfusion]
Flow-mediated dilatation of the radial artery

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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.