Systemic hemodynamics including forearm blood flow and ventilatory parameters were evaluated in 21 subjects before and after exposure to eight hours of poikilocapnic hypoxia. To evaluate the role of sympathetic nervous system activation in the changes, 10 of these subjects had muscle sympathetic nerve activity (MSNA) measured before and after exposure and the remaining 11 subjects received intra-arterial phentolamine infusion in the brachial artery to define vascular tone in the absence of sympathetically mediated vasoconstriction. Short-term ventilatory acclimatization occurred as evidenced by a decrease in resting PCO2 (42 ± 1.4 mmHg pre vs. 37± 0.96 mmHg post) and by an increase in the slope of the ventilatory response to acute hypoxia (0.7 ± 0.1 l/min/%Sp(O2) pre vs. 1.2 ± 0.2 l/min/%Sp(O2) post) after exposure. Subjects demonstrated a significant increase in resting heart rate (61± 2 bpm pre vs. 65 ± 2 bpm post) and diastolic blood pressure (64.8 ± 2.7 mmHg vs. 70.4 ± 2.0 mmHg). MSNA did not change significantly after exposure, although there was a trend towards a decrease in burst frequency (19.8 ± 4.1 bursts/min vs. 14.3 ± 1.2 bursts/min). Forearm vascular resistance showed a significant decrease after termination of exposure (37.7 ± 3.6 mmHg/ml/min/100g tissue pre vs. 27.6 ± 2.7 mmHg/ml/min/100g tissue post, P<0.05). Initially, progressive isocapnic hypoxia elicited significant vasodilation but after 8-hours of poikilocapnic hypoxic exposure the acute challenge failed to change forearm vascular resistance. Local alpha blockade with phentolamine restored the vasodilatory response to acute hypoxia in the post exposure setting.