Orthostatic challenge increases total peripheral resistance (TPR) which is not completely explained by α-adrenergic control. It is not known whether non-α-adrenergic mechanisms are involved during exercise. Twelve healthy subjects underwent lower-body negative pressure LBNP (5 min, −40 mmHg) and static handgrip exercise HG (5 min, 20% of MVC) followed by post-exercise circulatory occlusion (PECO, 5 min) with and without α-adrenergic blockade by phentolamine (PHE). Aortic blood flow and finger blood pressure were measured to calculate cardiac output (Q) and TPR during the last minute of each intervention. LBNP resulted in a greater reduction in Q with PHE than without PHE (p<0.05). Response in Q was larger during HG and PECO with PHE than without PHE (p<0.05, for both). TPR increased similarly during LBNP with and without PHE (+6.2±5.3 vs. +3.6±3.3 L/min/mmHg, p=0.110). In contrast, PHE abolished the increases in TPR during HG (+3.1±4.0 vs. −0.8±3.4 L/min/mmHg, p<0.001) and PECO (+6.5±7.9 vs. +0.3±3.9 L/min/mmHg, p=0.005). These data suggest that while α-adrenergic control is not responsible for increasing TPR during LBNP, α-adrenergic inhibition blunts the responses in TPR during prolonged 5-min model of static handgrip exercise and muscle metaboreflex activation. Supported by Academy of Finland, TEKES Finland, Canadian Institutes of Health Research and Finnish Foundation of Cardiovascular Research