We have previously shown that the increase in mean arterial pressure (MAP) during isometric handgrip is maintained during alternations in preload during an ongoing contraction (Hisdal et al. 2004). In a recent study, Shoemaker et al. (2007) concluded that elevation of cardiac output (CO) was the primary determinant of the exercise pressor response during voluntary contraction. This is contrary to what our results have previously indicated. The aim of the present study was therefore to investigate the respective roles of CO and TPR in the pressor response to isometric exercise. We continuously measured stroke volume, heart rate and blood pressure in twelve volunteers [age 23.6 (5.6) years] during and after a 2 min voluntary handgrip contraction. Preload was reduced by introducing lower body negative pressure (LBNP) both prior to and transiently during contractions. On average, mild LBNP (­20 mmHg) reduced resting SV by 18.2 % without affecting HR. More marked LBNP (­40 mmHg) reduced resting SV by 35.9 % and increased HR by 8.9 %. In all cases, the pressor response to isometric handgrip was maintained by a marked increase in TPR. The increase in TPR perfectly compensated for the reduction in CO due to reduced preload. In conclusion, there is considerable flexibility in the cardiovascular control mechanisms used to increase MAP during isometric exercise, but TPR is the most important, whether or not preload and CO are reduced prior to or during contraction. Hisdal et al. Eur J Appl Physiol (2004) 91,336– 341 Shoemaker et al. J Appl Physiol. (2007) Apr 5; [Epub ahead of print].