643 Clinical Science (2000) 98, 643–648 (Printed in Great Britain) Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism? Gerald P. MCCANN, Helen CAHILL, Stephen KNIPE, Douglas F. MUIR, Paul D. MACINTYRE and W. Stewart HILLS Department of Medicine and Therapeutics, University of Glasgow, Gardiner Institute, Church Street, Glasgow G11 6NT, Scotland, U.K. A B S T R A C T 5-Hydroxytryptamine (5-HT ; serotonin) has been implicated in the perception of exercise- induced fatigue. Sumatriptan is a selective 5-HT 1B/D receptor agonist which does not cross the blood–brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 284108 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively ; 95 % confidence interval (CI) of difference 121 s, 591s; P  0008]. There was no significant effect on peak oxygen consumption (placebo, 50663 mlmin - 1 kg - 1 ; sumatriptan, 51776 mlmin - 1 kg - 1 ). Suma- triptan administration resulted in decreases in both heart rate (sumatriptan, 18814 beats/min, placebo, 19612 beats/min ; 95 % CI of difference 126, 26; P  0008) and respiratory exchange ratio (sumatriptan, 123006; placebo, 126007; 95 % CI of difference 005, 001; P  001) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation. INTRODUCTION 5-Hydroxytryptamine (5-HT ; serotonin) has been pro- posed as a mediator of the central component of exercise- induced fatigue. Increases in brain 5-HT levels have been observed in rats exercised until exhaustion, and admin- istration of 5-HT agonists reduces exercise capacity ; conversely, 5-HT antagonists prolong exercise capacity [1,2]. In humans, the administration of a selective 5-HT receptor re-uptake inhibitor (paroxetine [3] or fluoxetine [4], which increase 5-HT levels at all serotonergic synapses) leads to reduced exercise time to exhaustion at Key words : exercise capacity, fatigue, serotonin, 5-hydroxytryptamine. Abbreviations : BCAA, branched-chain amino acid ; CI, confidence interval ; 5-HT, 5-hydroxytryptamine (serotonin) ; RER, respiratory exchange ratio ; RPE, rate of perceived exertion ; RPP, rate pressure product; V  O  , oxygen consumption. Correspondence : Dr G. P. McCann, Pilgrim Hospital, Boston, Lincs. PE21 9QS, U.K. (e-mail gerrymccannhotmail.com). an exercise intensity of 70 % of maximal oxygen con- sumption (V  O  ). In these studies no differences in metabolic variables [such as blood glucose, body tem- perature, V  O  or respiratory exchange ratio (RER)] were seen to support a peripheral effect of these drugs, and the authors concluded that fatigue was increased secondary to a central effect of increased 5-HT [3,4]. Sumatriptan is a highly selective 5-HT  receptor agonist which has been shown to be effective in the treatment of acute migraine [5]. When administered subcutaneously, sumatriptan is absorbed rapidly, achiev- ing peak plasma concentrations in 12–13 min ; in addition,  2000 The Biochemical Society and the Medical Research Society