Premium
Substance P‐induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man
Author(s) -
Newby David E.,
Sciberras David G.,
Ferro Charles J.,
Gertz Barry J.,
Sommerville David,
Majumdar Anup,
Lowry Richard C.,
Webb David J.
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00017.x
Subject(s) - medicine , substance p , placebo , vasodilation , plethysmograph , blood pressure , crossover study , hemodynamics , nk1 receptor antagonist , anesthesia , endocrinology , pharmacology , receptor , neuropeptide , pathology , alternative medicine
Aims Following intravenous administration of its prodrug, L‐758,298, we assessed the pharmacodynamics of L‐754,030, a novel and highly selective NK 1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra‐arterial substance P infusion.Methods Sixteen healthy male volunteers participated in a double‐blind, randomised, placebo controlled crossover trial of L‐758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125–128 pmol min −1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L‐758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L‐758 298.Results L‐758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L‐758 298 (>1400–fold shift in substance P response): 0.00 (−0.49 to +0.49) ml 100 ml −1 min −1 , 1.0 (−3.2 to +5.2) mmHg and 1.9 (−5.9 to +9.7) beats min −1 , respectively. Twenty‐four hours after 1.43 mg of L‐758,298, there was ~34–fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L‐754 030 concentrations of 2–3 ng ml −1 . L‐758 298 was generally well tolerated without serious adverse events.Conclusions Substance P induced forearm vasodilatation is mediated by the endothelial cell NK 1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.