The Metformin-FMD Trial (MetFMD)

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.

to study whether caffeine (4 mg/kg intravenously over 10 minutes) attenuates the protective effect of metformin (500 mg three times a day for 3 days) on FMD after ischemia/reperfusion

No pretreatment with metformin, FMD measurement after forearm ischemia/reperfusion and infusion of caffeine (4 mg/kg intravenously over 10 minutes).

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

No pretreatment with metformin in combination with pretreatment with caffeine (4 mg/kg intravenously over 10 minutes).

Metformin-FMD trial: The effect of pretreatment with metformin on FMD of the brachial artery after forearm ischemia and reperfusion.

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.

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.

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

El Messaoudi S, Schreuder TH, Kengen RD, Rongen GA, van den Broek PH, Thijssen DH, Riksen NP. Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study. PLoS One. 2014 Apr 22;9(4):e96062. doi: 10.1371/journal.pone.0096062. eCollection 2014.