This study examined the mitogenic effects of
bradykinin (BK,
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), the
peptide bradykinin B(2) receptor antagonist
Hoe 140 (D-Arg(0)[Hyp(3)-Thi(6)-D-
Tic(7)-Oic(8)]BK, and the orally active, nonpeptide
B(2) receptor antagonist
FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-2-4-dichloro-3-[(2-methyl-8-quino linyl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl]acrylamide) in three different human tumour cell lines: the
small cell lung carcinoma (SCLC) cell line H-69, the
breast carcinoma cell line EFM-192A, and the colon
carcinoma cell line SW-480. In these cell lines activation of
mitogen-activated protein kinase (MAPK) is involved in BK-induced stimulation of cell proliferation and may be mediated by both G(q)
proteins (SW-480) and G(i)
proteins (EFM-192A; H-69). In these cells BK as well as
Hoe 140 increased the rate of
DNA synthesis measured with the [(3)H]-
thymidine uptake assay.
Hoe 140 did neither antagonize nor potentiate the effect of BK.
FR 173657 did not stimulate [(3)H]-
thymidine incorporation but clearly antagonized the mitogenic effects of BK as well as
Hoe 140. In H-69 cells,
FR 173657 induced a decrease in the basal rate of
DNA synthesis. In all three cell lines BK and
Hoe 140 stimulated the activity of MAPK. Their effect on MAPK activity was completely abolished by
FR 173657 which itself did not increase the activity of MAPK. In H-69 cells, the basal activity of MAPK was slightly inhibited by
FR 173657. In the cell lines SW-480 and H-69 both BK and
Hoe 140 but not
FR 173657 stimulated
phosphatidylinositol hydrolysis. In H-69 cells,
FR 173657 decreased basal
inositol phosphate formation. Our results show that in certain tumour cell lines the classical
peptide B(2) receptor antagonist,
Hoe 140, may act as mitogenic
B(2) receptor agonist whereas the nonpeptide
B(2) receptor antagonist,
FR 173657, does not. In H-69 cells
FR 173657 was found to exhibit properties of an inverse agonist.