Serotonin-induced vasodilatation in the human forearm is mediated by the "nitric oxide-pathway": no evidence for involvement of the 5-HT3-receptor.
The "nitric oxide (NO)-pathway" is presumed to be involved in acetylcholine (ACh)- and serotonin (5-hydroxytryptamine, 5-HT)-mediated vasodilatation. In addition, both the 5-HT-induced transient and persistent vasodilator responses in the forearm vascular bed are abolished by the 5-HT3/5-HT4-receptor antagonist ICS 205-930 ([1H]-indol-3-carbonic-acid-tropine-ester HCl, tropisetron). We studied 5-HT-mediated vasodilatation in the forearm vascular bed of normotensive volunteers, using venous occlusion plethysmography. Intraarterial (i.a.) infusions of 5-HT, ACh, and sodium nitroprusside (SNP) all caused an increase in forearm blood flow (FBF). Single infusions of ondansetron and granisetron also caused an increase in FBF. Infusion of the NO scavenger and guanylate-cyclase antagonist methylene blue (MB) did not change FBF, whereas the arginine analogue NG-monomethyl-L-arginine (L-NMMA) caused a decrease in FBF, which became less pronounced when infusions were repeated. Unlike ICS 205-930, concomitant infusions of the selective 5-HT3-receptor antagonists ondansetron (OND) and granisetron (GRAN) did not antagonize the transient or persistent vasodilator responses to 5-HT. These findings suggest the involvement of a 5-HT4-receptor. L-NMMA and MB both reduced the persistent vasodilator response to 5-HT, indicating involvement of the NO pathway. Neither MB nor L-NMMA influenced the endothelium-independent vasodilator response to SNP. ACh-induced vasodilatation was markedly potentiated by MB but was not affected by L-NMMA. The mechanism by which MB enhances the vasodilator response to ACh remains unclear.
Bruning
T A
TA
Department of Nephrology, University Hospital, Leiden, The Netherlands.
Chang
P C
PC
Blauw
G J
GJ
Vermeij
P
P
van Zwieten
P A
PA
D000328:Adult; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply*; D016166:Free Radical Scavengers; D017829:Granisetron; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D009599:Nitroprusside / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D000594:Amino Acid Oxidoreductases; D001120:Arginine; D016166:Free Radical Scavengers; D017829:Granisetron; D006162:Guanylate Cyclase; D007191:Indazoles; D008751:Methylene Blue; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009599:Nitroprusside; D017294:Ondansetron; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D019323:omega-N-Methylarginine