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.|
|ClinicalTrials.gov Identifier: NCT02009527|
Recruitment Status : Completed
First Posted : December 12, 2013
Last Update Posted : April 20, 2015
|Condition or disease||Intervention/treatment||Phase|
|Coronary Artery Disease Type 2 Diabetes Mellitus||Drug: N-hydroxy-nor-arginine Drug: NaCl||Phase 1|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|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|
N-hydroxy-nor-arginine 0.1 mg/ min i.a. for 20 min
Placebo Comparator: NaCl
NaCl 0.9%, 6 ml/min i.a. for 20 min
- Change in endothelial function [ Time Frame: 20 min of reperfusion ]Flow-mediated dilatation of the radial artery
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 ClinicalTrials.gov identifier (NCT number): NCT02009527
|Stockholm, Sweden, 17176|
|Principal Investigator:||John Pernow, MD, PhD||Karolinska Institutet|