Two Classes of Antagonist Interact with Receptors for the Mitogenic Neuropeptides Bombesin, Bradykinin, and Vasopressin

While screening neuropeptides for activity as growth factors we have found that bradykinin is a mitogen for Swiss 3T3 cells. It acts synergistically with insulin, and maximal effect is obtained at 10 nM. It acts through a distinct receptor, characterized as a B, subtype using bradykinin analogues. The neuropeptides bombesin and vasopressin are also potent mitogens for Swiss 3T3 cells. The substance P antagonists [DArg', DPro2, DTrp7.', Leu"] substance P and (DArg', DPhe5, DTrp7eYL, eu"]substance P are inhibitors of DNA synthesis stimulated by both bombesin and vasopressin. In the present study they were found also to inhibit bradykinin-induced mitogenesis. In contrast, the ligand-specific antagonists [LeuI31/1(CH2NH)Leu"]bombesin,[Pmp', OMeTyr2, Argx]vasopressinand [DArg", Hyp3, Thii ", DPhe7]bradykinin showed no cross-inhibition with each others receptors. We propose therefore that the receptors for the mitogenic neuropeptides bombesin, vasopressin, and bradykinin can interact with two classes of antagonist, one recognizing the ligand binding site (e.g., Le'-1/1(CH,NH)Leu'']bornbesina)nd the other recognizing a common domain shared by the three receptors (e.g., [DArg', DPhe5, D T P L,eu,l*]substanceP