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
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.