SUBSTANCE-P IN HUMAN HAND VEINS IN-VIVO - TOLERANCE, EFFICACY, POTENCY, AND MECHANISM OF VENODILATOR ACTION

Citation
Wm. Strobel et al., SUBSTANCE-P IN HUMAN HAND VEINS IN-VIVO - TOLERANCE, EFFICACY, POTENCY, AND MECHANISM OF VENODILATOR ACTION, Clinical pharmacology and therapeutics, 60(4), 1996, pp. 435-443
Citations number
42
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00099236
Volume
60
Issue
4
Year of publication
1996
Pages
435 - 443
Database
ISI
SICI code
0009-9236(1996)60:4<435:SIHHVI>2.0.ZU;2-Y
Abstract
Objectives: To study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium-dependent vasodilat or neurokinin, in human hand veins in vivo. Methods: Thirty-three heal thy subjects were studied with use of the hand vein compliance techniq ue, In hand veins preconstricted with the alpha(1)-agonist phenylephri ne, substance P and antagonists of nitric oxide formation (L-N-G-mono- methyl-arginine, L-NMMA), adenosine triphosphate (ATP)-dependent potas sium channels (glyburide), angiotensin converting enzyme (enalaprilat) , and cyclooxygenase (acetylsalicylic acid) were infused and the venod ilator 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 [ED(50)], geometric mean: 0.105 pmol/min). Rapid dev elopment of tolerance occurred in seven of eight volunteers studied, G lyburide decreased the venodilator action of a single dose of substanc e P (1.5 pmol/min) from 81% to 28% of baseline venodilation (p <0.05), suggesting that substance P acts through release of endothelium-deriv ed hyperpolarizing factor, The cyclooxygenase-inhibitor acetylsalicyli c acid reduced substance P-induced venodilation from 53%+/-7% to 34%+/ -8% (p <0.05), whereas L-NMMA had no effect. Conclusions: Unlike in ot her vessels, substance P-induced venodilation in hand veins is not med iated through nitric oxide but to a significant extent through a glybu ride-sensitive pathway, Therefore it appears likely that substance P a ctivates ATP-dependent potassium channels on vascular smooth muscle ce lls through the release of endothelium-derived hyperpolarizing factor.