The effect of mepivacaine on adrenergic neuroeffector junction was studied in the isolated rabbit aorta. Mepivacaine, 5 X 10(-5) to 5 X 10(-4) M, attenuated the contractile response to transmural neural stimulation, the attenuation being greater in the response at high frequency stimulations. The attenuation of the responses by mepivacaine was not prevented by prior application of cocaine. The concentration-response curve for norepinephrine was shifted to the right by mepivacaine, 5 X 10(-5) to 2 X 10(-3) M. The attenuation of the response to transmural stimulation was greater than that of the response to an equipotent concentration of exogenous norepinephrine. Pretreatment with mepivacaine, 5 X 10(-5) to 2 X 10(-3) M, protected alpha-adrenoceptors from persistent blockade by phenoxybenzamine in a dose-dependent manner. The contractile response to histamine was not significantly altered by mepivacaine in concentrations up to 5 X 10(-4) M. Mepivacaine, 5 X 10(-4) and 2 X 10(-3) M, decreased the response to high concentrations of KCl. Ca2+-induced contractions in aortic strips previously exposed to Ca2+-free media and depolarized by excess K+ were significantly inhibited by mepivacaine, 5 X 10(-4) and 2 X 10(-3) M. It may be concluded that mepivacaine causes vasodilation through an alpha-adrenoceptor antagonism in addition to a sympathetic nerve conduction blockade. High concentrations of mepivacaine appear to interfere with the transmembrane influx of calcium in the vascular smooth muscle.