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Characterization of bradykinin receptors mediating catecholamine release in PC12 cells

Abstract

The rat pheochromocytoma cell line PC12, which is a widely used model for analyzing stimulus-secretion coupling, was investigated for the effects of kinins on catecholamine release. Subtypes of kinin receptors were characterized using the B1 agonist desArg9-bradykinin, the B2 agonist bradykinin and the B2 antagonists [Thi5,8, D-Phe7]-bradykinin, D-Arg[Hyp3, D-Tic7, Oic8]-bradykinin (HOE 890307) and D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (HOE 140). The effectiveness of acute and chronic exposure to angiotensin I converting enzyme inhibitors as well as pretreatment of the cells with bacterial lipopolysaccharides in modulating B1 or B2 receptor systems was also tested.

Bradykinin stimulated noradrenaline release from PC12 cells at low concentrations (EC50 = 1 nM), maximally inducing a release of 43.7% of the cellular content within 15 min. In comparison with acetylcholine and K+-induced depolarization, bradykinin was the most effective stimulus. DesArg9-bradykinin was only effective at very high concentrations (> 30 μM). Like in other neuronal cells, the B2-specific partial antagonist [Thi5,8, D-Phe7]-bradykinin acted as a low-affinity agonist without any antagonistic effects. The B2 antagonists HOE 890307 and HOE 140 exerted no agonistic effects and concentration-dependently inhibited bradykinin-induced noradrenaline release, showing competitive antagonism with Ki values of 1.38 nM and 0.66 nM, respectively. Only at the highest concentration used (1 μM), HOE 140 did depress the maximal response to bradykinin. HOE 890307 also abolished the effects of desArg9-bradykinin and [Thi5,8, D-Phe7]-bradykinin. Acute or chronic inhibition of the angiotensin I converting enzyme or application of lipopolysaccharides, which all can lead to induction of the B1 receptor subtype in vivo, did not alter the secretory response of PC12 cells to either bradykinin (0.1 and 30 nM) or desArg9-bradykinin (1 μM).

In conclusion, noradrenaline release from PC12 cells is stimulated via B2, but not B1, receptors. Despite the fact that the receptor system is highly susceptible to stimulation by low-affinity ligands, HOE 890307 and HOE 140 are pure antagonists, with only high concentrations of HOE 140 (> 1 μM) showing a non-competitive type of inhibition. Induction of B1 receptors which could stimulate noradrenaline release could not be demonstrated in this model. The possible role of bradykinin in modulating sympathetic neurotransmission during inhibition of angiotensin I converting enzyme is discussed.

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Dendorfer, A., Dominiak, P. Characterization of bradykinin receptors mediating catecholamine release in PC12 cells. Naunyn-Schmiedeberg's Arch Pharmacol 351, 274–281 (1995). https://doi.org/10.1007/BF00233247

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Key words

  • Bradykinin
  • desArg9-bradykinin
  • PC12 cells
  • Kinin receptors
  • Catecholamines
  • HOE 890307
  • HOE 140