[D‐Arg1, D‐Phe5,D‐Trp7,9,Leu11] substance P, a neuropeptide antagonist, blocks binding, Ca2+‐mobilizing, and mitogenic effects of endothelin and vasoactive intestinal contractor in mouse 3T3 cells

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Abstract
Endothelin (ET1) and vasoactive intestinal contractor (VIC) stimulate quiescent Swiss 3T3 cells to resume DNA synthesis acting synergistically with epidermal growth factors (EGF) and other mitogens. The peptide “D-Arg1-D-Phe5,D-Trp7,9Leu11” substance P has been identified as a broad spectrum neuropeptide antagonist which blocks the binding and biological effects of the Ca2+-mobilizing neuropeptides bombesin, vasopressin, and bradykinin. In the present study we show that [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P also acts as an ET1/VIC antagonist as judged by the following criteria: (a) inhibition of specific 125l-labelled ET1 binding to a ET1/VIC receptor in a competitive and dose-dependent manner; (b) blocking of the rapid increase in the cytosolic Ca2+ concentration promoted by ET1 or VIC; and (c) inhibition of DNA synthesis stimulated by VIC in the presence of EGF. The inhibitory effects of [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P on Ca2+ mobilization and DNA synthesis were reversed by increasing the concentration of VIC. This is the first time that a peptide structurally unrelated to ET1 or VIC is shown to block the binding and mitogenic effects of peptides of the endothelin family.

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