The nitric oxide synthase inhibitor L-NMMA potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine.
OBJECTIVE
Alpha2-adrenoceptors can be found both on vascular smooth muscle cells and on the endothelium, where they exert opposing effects on vascular tone. In vitro, the stimulation of alpha2-adrenoceptors on endothelial cells leads to the release of vasodilating substances like nitric oxide (NO) and prostanoids. Little is known of this mechanism in vivo.


METHODS
We investigated the effects of the NO-synthase inhibitor L-NMMA (10(-6) mol) and the alpha2-adrenoceptor antagonist yohimbine (YO, 10(-10)-10(-6) mol) on noradrenaline (NA, 10(-12)-10(-8) mol)-induced vasoconstriction in the forearm skin microcirculation of 16 healthy volunteers using double injection technique and laser Doppler flowmetry. Results are expressed in perfusion units (PU) as differences from baseline and control in mean +/- SEM; the area under the time-response-curve was calculated (AUC).


RESULTS
NA (10(-8)- 10(-12) mol) caused a marked, dose-dependent reduction in blood flow (mean effect -745 +/- 84 AUC PU; P< 0.001 versus saline). NA-induced vasoconstriction was enhanced by L-NMMA (mean effect -916 +/- 72 AUC PU; P< 0.001 versus NA). YO (10(-6)-10(-10) mol) induced a significant, dose-dependent vasodilation (mean effect +/- 446 +/- 110 AUC PU; P < 0.05 versus control); high doses of YO (10(-6) mol) inhibited NA constriction (P < 0.001 versus NA), whereas lower doses of YO (10(-8)/10(-10) mol) had no effect or even increased NA-induced constriction. In the presence of L-NMMA, YO (10(-8) and 10(-10) mol) further potentiated NA-induced vasoconstriction (mean effect -1165 +/- 108 AUC PU; NS versus NA).


CONCLUSIONS
These data demonstrate, that in humans in vivo, endogenous NO attenuates noradrenergic constriction. The effects of YO suggest that endothelial alpha2-adrenoceptors are involved in the release of NO and other vasodilating substances. Furthermore, there is an additive NO-independent vasodilation, which can be unmasked by L-NMMA.
Bruck
H
H
Department of Internal Medicine, University Hospital Essen, Germany.
Gössl
M
M
Spitthöver
R
R
Schäfers
R F
RF
Kohnle
M
M
Philipp
T
T
Wenzel
R R
RR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001808:Blood Vessels / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005542:Forearm; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D015016:Yohimbine; D019001:Nitric Oxide Synthase; D009638:Norepinephrine