Article date: September 1999
By: David E. Newby, David G. Sciberras, Charles J. Ferro, Barry J. Gertz, David Sommerville, Anup Majumdar, Richard C. Lowry, David J. Webb, in Volume 48, Issue 3, pages 336-344
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<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 NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.
DOI: 10.1046/j.1365-2125.1999.00017.x
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