Substance P‐induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man

Aims Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 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 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 NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.