VASOACTIVE-INTESTINAL-PEPTIDE (VIP) AND PITUITARY ADENYLATE CYCLASE-ACTIVATING PEPTIDE (PACAP-27, BUT NOT PACAP-38) DEGRADATION BY THE NEUTRAL ENDOPEPTIDASE EC-3.4.24.11

VIP (vasoactive intestinal polypeptide) and PACAP (pituitary adenylate cyclase-activating polypeptide), which are potent relaxing agents in the airways, were submitted to in vitro degradation by the neutral end opeptidase EC 3.4.24.11 (NEP), one of the most active peptidase in the lung, to test their relative resistance to proteolysis. Both VIP and PACAP(1-27) were cleaved by NEP, but PACAP(1-38) was not. The main fra gments produced were VIP(1-22) and VIP(1-25), and PACAP(1-22) and PACA P(1-25), respectively. The degradation of VIP(1-27), PACAP(6-27), and PACAP(13-27) was also hindered by extending their C-terminal ends with the (28-38) sequence of PACAP(1-38). The sensitivity to enzyme degrad ation was gradually reduced when the C-terminal extension was increase d from PACAP(1-27) to PACAP(1-29), PACAP(1-32) and PACAP(1-38). The bi ological activities of the degradation products were evaluated on the three classes of PACAP/VIP receptors, with VIP(1-25) and PACAP(1-25) r etaining an important part of their activities on the VIP1 receptor. T hus, the degradation of VIP and PACAP(1-27) by the neutral endopeptida se 24.11 might produce a VIP1 receptor-selective active metabolite, pr ovided that very high VIP or PACAP(1-27) concentrations are achieved i n the receptor vicinity. (C) 1997 Elsevier Science Inc.