OBJECTIVES: 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.
OBJECTIVES: 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: Ruth Fricker; Christiane Hesse; Johanna Weiss; Yorki Tayrouz; Michael M Hoffmann; Kristina Unnebrink; Ulrich Mansmann; Walter E Haefeli Journal: Br J Clin Pharmacol Date: 2004-08 Impact factor: 4.335