PII‐4

AIM The infusion of high doses (6.3 μmol/min.) of the NO‐synthase inhibitor NG‐monomethyl‐L‐arginine (L‐NMMA) exerts venodilative effects via EDHF‐mediated mechanisms. In a crossover study we aimed to quantify the amounts of L‐NMMA‐induced dilation and the amount of L‐NMMA‐induced inhibition of histamine‐induced dilation. Subjects were divided into 2 groups according to their ability to dilate to high dose L‐NMMA (responder) or not. METHODS 8 healthy male subjects (4 responders, 4 non‐responders) received on 3 study days the following infusion protocols in 80% phenylephrine‐preconstricted veins: Day 1: L‐NMMA (dose‐response‐curve: 0.2 – 6.4 μmol/min). Day 2: Histamine (135 ng/min. for 70 minutes). Day 3: Histamine (135 ng/min) and coinfusion of increasing doses of L‐NMMA (0.2 – 6.4 μmol/min.). RESULTS L‐NMMA maximum response was 50±9% basal vein size (BVS) in responders (R) and 26±8% in non‐responders (NR). Maximum histamine response was 101±13% (R) versus 73±22% BVS (NR). L‐NMMA low‐dose (0.2 μmol/min) inhibited 29% response in (R) compared to 18% in (NR), high dose (6.3 μmol/min.) inhibited 26% response in (R) compared to 7% in (NR). CONCLUSION In low doses (0.2 – 3.3 μmol/min) L‐NMMA inhibits NO‐mediated venodilation in responders and non‐responders. In high doses it exerts in addition to its NO‐inhibiting potency an additional increase of ∼20% BVS in responders most likely via EDHF‐mediated mechanisms. Our results point towards interindividual differences in the venous NO‐system. Clinical Pharmacology & Therapeutics (2005) 79 , P36–P36; doi: 10.1016/j.clpt.2005.12.129