Cerebral blood vessels relax when extracellular K⁢ concentrations ([K⁢])e are elevated moderately (2∼15 mM, K⁢-induced vasorelaxation). We have therefore studied the underlying mechanism for this K⁢- induced vasorelaxation in the isolated middle cerebral arteries (MCAs). The effects of ouabain and Ba2⁢ on K⁢-induced vasorelaxation were examined to determine the role of sodium pump and/or Ba-sensitive process (possibly, inward rectifier K current) in the mechanism. Mulvany myograph was used to study 24 rats, 18 rabbits, and 10 humans MCAs (216⁑3 ㄍm, 347⁑7 ㄍm, and 597⁑39 ㄍm in diameter when stretched to a tension equivalent to 55 mmHg). High K⁢ (125 mM) and PGF2α (1∼10 ㄍM) induced concentration-dependent contractions in all 3 species, while histamine (10∼50 ㄍM) evoked contraction only in the rabbits and induced relaxation in the rats and humans. Addition of K⁢ (2∼10 mM) to the control solution induced vasorelaxations. These effects were inhibited by the pretreatment with both ouabain (10 ㄍM) and Ba2⁢ (0.1∼0.3 mM) in the rat, but only with ouabain (10 ㄍM) in the rabbit and human. These results suggest that K⁢-induced vasorelaxation occurs via the stimulation of electrogenic Na pump in the rabbit and human MCAs, while in the rat MCAs via the activation of both Na pump and Ba-sensitive process.