Evidence for a role of bradykinin neurons in the control of gonadotropin-releasing hormone secretion

The present study provides evidence of a novel neuronal pathway for the control of GnRH secretion involving bradykinin neurons. Bradykinin neurons were shown by immunohistochemistry to be densely localized in several regions of the brain including the cortex, hippocampus and supraoptic nucleus, as well as two regions critical in the control of GnRH secretion, the organum vasculosum of the lamina terminalis and arcuate nucleus. Bradykinin dose-dependently stimulated GnRH release from male and proestrous female rat hypothalami in vitro. Antagonist studies revealed that bradykinin effects are mediated by the bradykinin B₂ receptor. The effect of bradykinin on GnRH release is not mediated by the classical major transmitter, glutamate, as glutamate antagonists had no effect on bradykinin stimulation of GnRH release. Rather, bradykinin appears to act directly on the GnRH neuron as bradykinin stimulated GnRH release directly from immortalized GnRH (GT1-7) neurons in vitro, and immunoblot studies revealed that the bradykinin B₂ receptor is present in GT1-7 neurons. The bradykinin B₂ receptor was also demonstrated in the rat hypothalamus and pituitary by immunoblotting. Bradykinin-induced exocytosis of GnRH appears to involve activation of the PKC signaling pathway, as a PKC inhibitor blocked bradykinin-induced GnRH release. Finally, bradykinin neurons appear to be important mediators of steroid signals in the hypothalamus to produce the LH surge, as central administration of a B₂ antagonist, but not a B₁ antagonist, significantly attenuated the steroid-induced LH surge in the ovariectomized female rat.