Bradykinin receptor subtypes linked to prostaglandin release have been assessed in a human osteosarcoma cell line with osteoblastic phenotype (MG-63). Bradykinin (BK; 1 μmol/l) caused a burst of prostaglandin E 2 release that was maximal at 10 min. When the effect on the burst of PGE 2 and PGI 2 release by a variety of kinins and kinin analogues was assessed, the following rank order of response was found: Lys-BK > BK ≥ Met-Lys-BK > Ile-Ser-BK > [Tyr 8 ]-BK ≥ [Hyp 3 ]-BK > > > des-Arg 9 -BK = des-Arg 10 -Lys-BK = des-Arg 1 -BK, [Thi 5,8 ,d-Phe 7 ]-BK = Sar-[D-Phe 8 ]-des-Arg 9 -BK = Tyr-Gly-Lys-Aca-Lys-des-Arg 9 -BK. The rapid effect of BK on PGE 2 and PGI 2 release was unaffected by des-Arg 9 -[Leu 8 ]-BK, des-Arg 10 -[Leu 9 ]-Lys-BK and des-Arg 10 -[Hoe 140], but strongly inhibited by Hoe 140 in a concentration-dependent manner. When the incubation time was extended to 48 h, it was found that des-Arg 9 -BK and des-Arg 10 -Lys-BK caused a delayed enhancement of the formation of PGE 2 . When PGE 2 formation was assessed in 24-h experiments, the following rank order of response was obtained: Tyr-Gly-Lys-Aca-Lys-des-Arg 9 -BK > > BK = Lys-BK > > des-Arg 10 -Lys-BK > Sar[d-Phe 8 ]-des-Arg 9 -BK > des-Arg 9 -BK. The stimulatory effect of BK at 24 h was unaffected by des-Arg 9 -[Leu 8 ]-BK, des-Arg 10 -[Leu 9 ]-Lys-BK and des-Arg 10 -[Hoe 140] but inhibited by Hoe 140. The stimulatory effect of des-Arg 10 -Lys-BK in 24-h experiments was inhibited by des-Arg 9 -[Leu 8 ]-BK, des-Arg 10 -[Leu 9 ]-Lys-BK and des-Arg 10 -[Hoe 140]. Similarly, the stimulatory effects of Sar[d-Phe 8 ]-des-Arg 9 -BK and Tyr-Gly-Lys-Aca-Lys-des-Arg 9 -BK was inhibited by des-Arg 10 -[Hoe 140]. The following rank order of response was seen for inhibition of [ 3 H]-BK binding to MG-63 cells: Lys-BK=BK=Hoe 140 > > > > > > des-Arg 10 -Hoe 140=des-Arg 10 -Lys-BK = des-Arg 9 -BK = Tyr-Gly-Lys-Aca-Lys-des-Arg 9 -BK. Using [ 3 H]-des-Arg 10 -Lys-BK, the following rank order of response for inhibition of binding was seen: des-Arg 10 -Lys-BK = Tyr-Gly-Lys-Aca-Lys-des-Arg 9 -BK > des-Arg 10 -Hoe 140 > des-Arg 9 -BK = Lys-BK = BK = Hoe 140. MG-63 cells expressed mRNAs for BK B1 and B2 receptors, as assessed by RT-PCR. These data indicate that the human osteoblastic osteosarcoma cell line MG-63 is equipped with functional BK receptors of both B1 and B2 receptor subtypes. The B2 receptors are linked to a burst of prostanoid release, whereas the B1 receptors mediate a delayed prostaglandin response, indicatin g that the two receptor subtypes are linked to different signal transducing mechanisms or that the molecular mechanisms involved in prostaglandin release are different. © 2002 Elsevier Science B.V. All rights reserved.
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