A dose-response study of nitric oxide synthase inhibition in different vascular beds in man

• Published in: European journal of clinical pharmacology 2003-10, Vol.59 (7), p.499-505
• Main Authors: LASSEN, Lisbeth Hjorth, IVERSEN, Helle Klingenberg, OLESEN, Jes
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Blood Flow Velocity - drug effects; Blood Pressure - drug effects; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug toxicity and drugs side effects treatment; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacology; Female; Heart Rate - drug effects; Humans; Male; Medical sciences; Middle Cerebral Artery - diagnostic imaging; Middle Cerebral Artery - drug effects; Middle Cerebral Artery - physiology; Nitric Oxide Synthase - antagonists & inhibitors; omega-N-Methylarginine - administration & dosage; omega-N-Methylarginine - blood; omega-N-Methylarginine - pharmacology; Pharmacology. Drug treatments; Radial Artery - diagnostic imaging; Radial Artery - drug effects; Radial Artery - physiology; Toxicity: cardiovascular system; Ultrasonography, Doppler, Transcranial
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-003-0662-7

Nitric oxide (NO) is an almost ubiquitous messenger molecule and is implicated in several disorders. NG monomethyl L-arginine ( L-NMMA:546C88) is an inhibitor of all three NO synthases (NOS), the enzymes that catalyse the production of NO. The present study was performed to evaluate the dose-response relation of L-NMMA to improve the design and interpretation of studies in migraine sufferers and other diseases. In a double-blind, placebo-controlled, cross-over design, six healthy volunteers were randomised to receive three different doses of L-NMMA (0.3 mg/kg, 1 mg/kg, 3 mg/kg) or placebo (5% dextrose) intravenously (iv) over 5 min on four different days. On a fifth study day, in an open design, the same subjects received L-NMMA in the dose 6 mg/kg iv over 15 min. The effect of L-NMMA on the maximal mean blood velocity (Vmean) in the middle cerebral artery (MCA) (transcranial Doppler), the luminal diameter of the radial artery (high-frequency ultrasound), mean arterial blood pressure (MAP), heart rate and electrocardiogram were repeatedly followed every 5 min until 60 min after start of the infusion, then every 15 min during the following hour, and at 3 h and 4 h. Inhibition of NOS had no effect on Vmean in MCA or on the diameter of the radial artery, but MAP increased and heart rate decreased dose dependently. With a dose of 6-mg/kg L-NMMA infused over a 15-min period, the maximum MAP increase was 20% 20 min after the start of L-NMMA infusion. The maximum decrease of heart rate was 24% 15 min after start of the L-NMMA infusion. L-NMMA in a dose that caused marked changes in systemic blood pressure and heart rate had no effect on cerebral and radial arteries in man.