title: Substance P in human hand veins in vivo: tolerance, efficacy, potency, and mechanism of venodilator action.
abstract: OBJECTIVE
  To study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium-dependent vasodilator neurokinin, in human hand veins in vivo.
  
  
  METHODS
  Thirty-three healthy subjects were studied with use of the hand vein compliance technique. In hand veins preconstricted with the alpha 1-agonist phenylephrine, substance P and antagonists of nitric oxide formation (L-NG-mono-methyl-arginine, L-NMMA), adenosine triphosphate (ATP)-dependent potassium channels (glyburide), angiotensin converting enzyme (enalaprilat), and cyclooxygenase (acetylsalicylic acid) were infused and the venodilator effect was measured.
  
  
  RESULTS
  Substance P proved to be the most potent venodilator known thus far (the dose-rate exerting 50% of mean maximum dilation [ED50], geometric mean: 0.105 pmol/min). Rapid development of tolerance occurred in seven of eight volunteers studied. Glyburide decreased the venodilator action of a single dose of substance P (1.5 pmol/min) from 81% to 28% of baseline venodilation (p < 0.05), suggesting that substance P acts through release of endothelium-derived hyperpolarizing factor. The cyclooxygenase-inhibitor acetylsalicylic acid reduced substance P-induced venodilation from 53% +/- 7% to 34% +/- 8% (p < 0.05), whereas L-NMMA had no effect.
  
  
  CONCLUSIONS
  Unlike in other vessels, substance P-induced venodilation in hand veins is not mediated through nitric oxide but to a significant extent through a glyburide-sensitive pathway. Therefore it appears likely that substance P activates ATP-dependent potassium channels on vascular smooth muscle cells through the release of endothelium-derived hyperpolarizing factor.
authors.affiliation: Department of Internal Medicine, University Hospital, Basel, Switzerland.
authors.forename: W M
authors.initials: WM
authors.lastname: Strobel
authors.forename: T F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: D
authors.initials: D
authors.lastname: Simper
authors.forename: L
authors.initials: L
authors.lastname: Linder
authors.forename: W E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006225:Hand; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014680:Veins / Q000187:drug effects*
chemical_list: D007004:Hypoglycemic Agents; D014662:Vasoconstrictor Agents; D013373:Substance P; D005905:Glyburide