Effects of nitric oxide synthase inhibition on dexmedetomidine-induced vasoconstriction in healthy human volunteers.
BACKGROUND
This study aimed to assess the contribution of endothelial nitric oxide synthesis to the net responses of human peripheral blood vessels in vivo to the selective alpha(2)-adrenoceptor agonist dexmedetomidine.


METHODS
Two groups of healthy young men were studied. In the first experiment, after brachial plexus block, the responses of digital arteries to systemically administered dexmedetomidine (target plasma concentration 1.2 ng ml(-1)) were studied using a photoplethysmograph (n=10) during i.a. infusions of saline and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (8 micromol min(-1)). In a separate experiment, after pre-treatment with acetylsalicylic acid, responses to increasing doses of dexmedetomidine (0.01-164 ng min(-1)) in the presence and absence of L-NMMA were compared in dorsal hand veins (DHV) (n=10) using linear variable differential transformers.


RESULTS
L-NMMA significantly augmented dexmedetomidine-induced vasoconstriction of digital arteries as assessed by an increase in light transmission through a finger and by a decrease in finger temperature. The mean (95% confidence interval) extent of the additional effect of L-NMMA over the constrictor effect of dexmedetomidine alone was 19% (14-24) (P<0.0001). In DHV, L-NMMA had variable effects on the dexmedetomidine-constriction dose-response curve. In three subjects, the curve was shifted significantly to the left (with a >10-fold difference in ED(50)), but ED(50) was only marginally affected by L-NMMA in the other subjects (difference in ED(50) <five-fold).


CONCLUSIONS
The endothelial NOS enzyme has a significant role in opposing the vasoconstrictor action of dexmedetomidine at drug concentrations within the therapeutic range.
Snapir
A
A
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland. amir.snapir@utu.fi
Talke
P
P
Posti
J
J
Huiku
M
M
Kentala
E
E
Scheinin
M
M
D000293:Adolescent; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D001917:Brachial Plexus; D020927:Dexmedetomidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005385:Fingers / Q000098:blood supply; D006801:Humans; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009407:Nerve Block; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D020927:Dexmedetomidine; D019001:Nitric Oxide Synthase