Résumé : The importance of the N-terminal His residue of VIP for stimulating adenylate cyclase was appreciated by estimating the intrinsic activity and EC50 of four VIP analogues on membranes from rat lung, liver, brain, anterior pituitary, and pancreas, and on human heart membranes. In all tissue preparations tested except one, the order of efficacy (and often potency) was: VIP greater than (Ac-His1)VIP greater than (Phe1)VIP = (3-Me-His1)VIP greater than (D-His1)VIP. In rat heart membranes, the order of efficacy was somewhat different: VIP greater than (Ac-His1)VIP = (Phe1)VIP greater than (D-His1)VIP greater than (3-Me-His1)VIP. These data demonstrated the key role of His1 in VIP in activating adenylate cyclase. They suggest that a given VIP analogue might act as full agonist in tightly coupled adenylate cyclase systems (such as those of rat lung and liver membranes) whereas the same analogue could not promote full activity in poorly coupled systems (such as that present in rat brain synaptic membranes).