Activation of CBF by hypercapnia or functional stimulation has been attributed to multiple mediators, most of which are thought to interfere with cerebrovascular reactivity in a closely time-related manner. Here we describe that brief hypercapnia produces marked up-regulation of somatosensory activation of blood flow that outlasts carbon dioxide exposure for at least 60 min. In chloralose-anesthetized, mechanically ventilated rats, somatosensory activation was carried out by electrical stimulation of the forepaw. Blood flow was measured in the contralateral primary somatosensory cortex by laser-Doppler flowmetry (LDF). Under control conditions, somatosensory stimulation increased LDF by 38.8 +/- 11.0%. Ventilation with 6% CO2 for 3 min caused a rise of LDF by 28.0 +/- 8.7%. Baseline CBF and PaCo2 returned to control values within 20 min. Repetition of somatosensory stimulation after hypercapnia revealed a long-lasting up-regulation of the flow response: 25 min after hypercapnia, functional stimulation increased LDF by 86.0 +/- 18.1%, and 60 min after hypercapnia even by 96.0 +/- 26.0%. This is the first demonstration of CO2-induced up-regulation of functional activation of blood flow and an example of the importance of general physiological variables for the modulation of the coupling process.