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.Keywords: substance P, neurokinin 1 receptor, endothelium, haemodynamics, blood flow Substance P is a member of the tachykinin family of Introduction peptides and acts through stimulation of the neurokinin receptors, having a particularly high affinity for the Substance P is a widely distributed endecapeptide which is found principally in the neural tissue of the central, type 1 (NK 1 ) receptor [9]. When given intra-arterially, substance P is a potent vasodilator [10][11][12] through an peripheral and enteric nervous systems [1][2][3][4]. The physiological functions of substance P include neuroendothelium dependent mechanism [13] which is partly mediated by nitric oxide release [14, 15]. In animal transmission in primary sensory neurones with particular involvement in nociception and emesis. In addition to studies, this response is induced via stimulation of the endothelial cell NK 1 receptor [9] although, to date, this functioning as a neurotransmitter, it also acts as an inflammatory mediator [5][6][7] and neurohumoral regulator has not been confirmed in vivo in man. Substance P is found in perivascular neural tissue [16] and has been [1, 8].postulated to play a role in the regulation of vascular