Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?

Rationale: Statins form a class of drugs that is widely prescribed for hypercholesterolaemia, specifically to reduce the risk on atherosclerosis by lowering LDL-cholesterol. Next to the effect for which the drug was originally developed, it became obvious that statins have several other beneficial effects. Such pleiotropic effects include the activation of ecto-5'-nucleotidase which can increase endogenous adenosine production (by dephosphorylation adenosine monophosphate into adenosine) and subsequently cause vasodilation. A recent study of Meijer et al (not yet published) showed that rosuvastatin significantly augments vasodilation after a brief period of ischemia (post occlusive reactive hyperaemia). However, it is not yet verified whether this increase in post occlusive reactive hyperaemia is truly caused by a rise of extracellular adenosine and subsequent adenosine receptor stimulation. In this study, the mechanism by which rosuvastatin augments post occlusive reactive hyperaemia will be investigated by blocking adenosine receptors with caffeine, a competitive A1 and A2 adenosine receptor antagonist. Caffeine is a substance that can be safely used in normal concentrations to block the adenosine receptor. Hypothesis: The augmenting effect of rosuvastatin on PORH is caused by an increase of extracellular adenosine formation and this effect can be diminished by blocking the adenosine receptor using caffeine. Objective: To study the influence of caffeine on post occlusive reactive hyperaemia before and after 7 days treatment with rosuvastatin. Study design: Open label cross-over design Study population: Healthy volunteers, 18-50 years of age Intervention: Eight volunteers will receive a 7 day treatment with rosuvastatin 20 mg daily before and after rosuvastatin treatment caffeine will be administrated intra-arterially. Main study parameters/endpoints: Forearm blood flow (FBF) will be measured as an indicator for post occlusive reactive hyperaemia (PORH).

forearm bloodflow after 2,3, and 5 minutes of forearm ischemia with concommitant administration of caffeine (90 ug/min/100ml forearm volume) into the brachial artery of the experimental (=non dominant) arm

forearm bloodflow after 2,3, and 5 minutes of forearm ischemia after 7 days oral treatment with rosuvastatin 1dd 20mg

forearm bloodflow after 2,3, and 5 minutes of forearm ischemia after 7 days oral treatment with rosuvastatin 1dd 20mg with concommitant administration of caffeine (90 ug/min/100ml forearm volume) into the brachial artery of the experimental (=non dominant) arm

intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes

before and after 7 day treament with rosuvastatin, with and without concommitant intra-arterial treatment with caffeine

Inclusion Criteria: Age 18-50 Written informed consent Exclusion Criteria: History of any cardiovascular disease Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg) Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L) Hyperlipidemia (fasting total cholesterol >5.5 mmol/L or random cholesterol >6.5 mmol/L) Alanine amino transferase >90 U/L Creatin kinase >440 U/L Raised rhabdomyolysis risk (GFR <80 ml/min and/or overt clinical signs of hypothyroidism and/or myopathy in family history Alcohol abuse Concommitant chronic use of medication Participation to any drug-investigation during the previous 60 days as checked with VIP check

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