The contraction elicited by norepinephrine (NE) and histamine (H) in the rabbit aortic strip occurs after a shorter latency and increases at a higher initial velocity to a greater steady state level when drug entry is limited to the intimal compared with the adventitial surface. Differences in the steady state contraction, but not in latency or initial velocity, disappear when intramural disposition pathways of the two agonists are blocked pharmacologically by deoxycorticosterone and a combination of iproniazid and 17-β-estradiol, respectively. These and other observations are consistent with the hypothesis that inner vascular smooth muscle cells respond more than outer cells to submaximal concentrations of NE and H, an explanation that accounts for the persistence of differences in latency and initial velocity of response after disposition blockade. Although the effectiveness of disposition mechanisms in reducing agonist concentration may be uniform through the aortic medial thickness, because of differences in muscle sensitivity, the consequence of disposition on the contractile response to agonists entering through the adventitia would be greater than that through the intima. Thus, disposition mechanisms in the outer smooth muscle lamellae provide a functional barrier to susceptible agonists entering through the outside vessel wall surface. Circ Res 46: 22-28, 1980