Isometric (IHG) handgrip training can reduce resting arterial blood pressure (ABP), especially in hypertensives, but the mechanisms remain unclear (1). We recently showed that IHG training in healthy young men augmented peak exercise hyperaemia and reactive hyperaemia in the contralateral arm by ~30% (2,3). This suggested that IHG training of one arm improves endothelial dilator function remotely. The aim of the present study was to determine the changes in blood flow induced in the contralateral arm (FBF) and ipsilateral calf (CBF) during a single bout of IHG training, which might serve as a stimulus for improving endothelial function, and to test whether endothelium-dependent cyclooxygenase (COX) products contribute. Two different series of experiments, each on 10 men (aged 19-23 years) who were recreationally active and normotensive (SP/DP <140/90mmHg). FBF or CBF were recorded by venous occlusion plethysmography at 15 s intervals before and during IHG contractions of the dominant arm at 30% maximum voluntary contraction (5 x 3min at 5 min intervals) on 2 different days in the absence or presence of the COX inhibitor aspirin (600mg p.o.). Mean arterial pressure (MABP), recorded by finger photoplethysmography, increased from 79.3±2.1 to 90.0±2.4 mmHg in the FBF series and from 89.3±4.1 to 114.8±5.4 mmHg in the CBF series. FBF increased by an average of 30.1±2.6* and 37.0±2.8* ml/min/100g in the first and last IHG respectively (*; RMANOVA, IHG vs baseline: P<0.05). Similarly, CBF increased by 8.62± 1.42* and 10.02 ± 2.38* ml/min/100g in the first and last IHG. COX inhibition had no effect on baseline values of MABP, FBF or CBF. However, increases in FBF were attenuated to 11.7±1.9 and 11.6 ± 1.9§ ml/min/100g in the first and last IHG (§: before vs after aspirin: P<0.05) and the increases in CBF were attenuated to 0.43 ± 0.17 § and 0.72 ± 0.24§ ml/min/100g respectively. EMG activity recorded over major muscles of forearm and calf and visual observation of the limbs suggested negligible muscle contraction in forearm or calf, without or with aspirin, indicating the increases in FBF and CBF were unlikely to be exercise hyperaemia. We propose that the increase in ABP and consequently in FBF and CBF evoked by each period of IHG training leads to increased shear stress and generation of vasodilator COX products that facilitate vasodilatation in both limbs. When repeated in sessions over 4-5 weeks, IHG training may therefore act as a shear stress-dependent stimulus to improve endothelium-dependent dilator function not only in the trained arm, but also in the contralateral arm and legs and possibly other tissues. Such effects might be expected to reduce resting ABP and reduce risk of cardiovascular disease.