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[D‐Arg 1 , D‐Phe 5 ,D‐Trp 7,9 ,Leu 11 ] substance P, a neuropeptide antagonist, blocks binding, Ca 2+ ‐mobilizing, and mitogenic effects of endothelin and vasoactive intestinal contractor in mouse 3T3 cells

1990; Wiley; Volume: 145; Issue: 1 Linguagem: Inglês

10.1002/jcp.1041450113

1097-4652

Isabel Fabregat, Enrique Rozengurt,

Neuropeptides and Animal Physiology

Abstract Endothelin (ET 1 ) 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‐Arg 1 ‐D‐Phe 5 ,D‐Trp 7,9 Leu 11 ” substance P has been identified as a broad spectrum neuropeptide antagonist which blocks the binding and biological effects of the Ca 2+ ‐mobilizing neuropeptides bombesin, vasopressin, and bradykinin. In the present study we show that [D‐Arg 1 ,D‐Phe 5 ,D‐Trp 7,9 ,Leu 11 ] substance P also acts as an ET 1 /VIC antagonist as judged by the following criteria: (a) inhibition of specific 125 l‐labelled ET 1 binding to a ET 1 /VIC receptor in a competitive and dose‐dependent manner; (b) blocking of the rapid increase in the cytosolic Ca 2+ concentration promoted by ET 1 or VIC; and (c) inhibition of DNA synthesis stimulated by VIC in the presence of EGF. The inhibitory effects of [D‐Arg 1 ,D‐Phe 5 ,D‐Trp 7,9 ,Leu 11 ] substance P on Ca 2+ mobilization and DNA synthesis were reversed by increasing the concentration of VIC. This is the first time that a peptide structurally unrelated to ET 1 or VIC is shown to block the binding and mitogenic effects of peptides of the endothelin family.