Endothelial Function, Ischemia Reperfusion Injury
Conditions
Brief summary
In acute myocardial infarction early restoration of coronary blood flow is the most effective strategy to limit infarct-size. Paradoxically, reperfusion itself also aggravates myocardial injury and contributes to final infarct size, a process termed 'reperfusion injury'. Ischemia and reperfusion (IR)-induced endothelial dysfunction seems to play a pivotal role in this process, resulting in vasoconstriction and reduced blood flow to the already ischemic tissue. Recently, it has been shown that the glucose-lowering drug metformin is able to limit IR-injury in murine models of myocardial infarction, probably by increased formation of the endogenous nucleoside adenosine. In the current research proposal, the investigators aim to translate this finding to the human in vivo situation, using flow-mediated dilation (FMD) of the brachial artery as a well-validated model of (endothelial) IR-injury.
Interventions
DRUGMetformin
metformin 500 mg three times a day, for 3 days
DRUGPretreatment with metformin in combination of infusion of caffeine.
Pretreatment with metformin 500 mg three times a day for 3 days, in combination with pretreatment with caffeine (4 mg/kg intravenously over 10 minutes) prior to FMD measurement
DRUGNo pretreatment with metformin in combination with infusion of caffeine
No pretreatment with metformin in combination with pretreatment with caffeine (4 mg/kg intravenously over 10 minutes).
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 30-50 years * Written informed consent
Exclusion criteria
* Smoking * Hypertension (in supine position: systolic BP \> 140 mmHg, diastolic BP \> 90 mmHg) * Hyperlipidaemia (fasting total cholesterol \> 5.5 mmol/L or random \> 6.5 mmol/L) * Diabetes Mellitus (fasting glucose \> 7.0 mmol/L or random glucose \> 11.0 mmol/L) * History of any cardiovascular disease * Concomitant use of medication * Renal dysfunction (MDRD \< 60 ml/min) * Professional athletes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metformin-FMD trial: The effect of pretreatment with metformin on FMD of the brachial artery after forearm ischemia and reperfusion. | approx. 6 months | Metformin-FMD trial: To study the effect of oral pretreatment with metformin (500 mg three times ad ay for 3 days) on flow mediated dilation of the brachial artery after 20 minutes of forearm ischemia and 20 minutes of reperfusion in healthy volunteers. |
| Control trial: the effect of caffeine on the protective effect of metformin on FMD after ischemia and reperfusion. | approx. 6 months | Control trial: when metformin displays a protective effect on endothelial function, we will conduct a second experiment to study whether caffeine, an adenosine receptor antagonist, attenuates the protective effect of metformin on flow mediated dilation after 20 minutes of ischemia and 20 minutes of reperfusion in healthy volunteers. |
Countries
Netherlands
Outcome results
None listed