The purpose of this study was to examine the electrical and mechanical responses of cat middle cerebral arteries to electrical stimulation of the adventitial vs. intimal surface of the vessels and to determine the responses as a function of transmural pressure. Middle cerebral arteries were cannulated at both ends. Within each cannula was a stimulating electrode. Electrical stimulation (0.5-msec square current pulses at 0.5 Hz yielding 160 μA of current between electrodes) resulted in significant reduction in diameter that was greater at both 40 and 80 mm Hg vs. 100 or 140 mm Hg. Conversely, adventitial stimulation of perivascular nerves with transmural platinum stimulating electrodes resulted in significant vasodilation. The constrictor response to intimal stimulation, as well as the dilatory response to adventitial stimulation, was blocked by tetrodotoxin. The constrictor response to luminal stimulation was enhanced by scorpion toxin demonstrating a functional role for tissues containing fast Na+channels. Perfusion with collagenase to disrupt the endothelium also abolished the constrictor response to luminal stimulation. The divergence of responses between adventitial and luminal surface stimulation may suggest that different cell layers within a blood vessel serve different functions, one to increase resistance and another to decrease resistance. For example, in cat middle cerebral arteries, the adventitial nerves (i.e., via reflexes) may increase flow, while blood-borne substances may mediate release of agents that reduce flow.