title: A dose-response study of nitric oxide synthase inhibition in different vascular beds in man.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
mesh_terms: D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020768:Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D017534:Radial Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology; D017585:Ultrasonography, Doppler, Transcranial; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase