Kinetic studies on gonadotropin-releasing-hormone (gonadoliberin, GnRH)-stimulated luteinizing-hormone (lutropin, LH) release in the cultured rat gonadotrope demonstrated a biphasic pattern of LH release. The first rapid phase of release was unaffected by the voltage-gated Ca2+-channel blockers methoxyverapamil (D600) and nifedipine [a dihydropyridine (DHP)], whereas the later second phase was partially inhibited by both drugs. These results suggested that the initial phase of LH release is independent of Ca2+ entry through dihydropyridine (DHP)-sensitive Ca2+ channels and might depend on entry of extracellular Ca2+ by another mechanism. These mechanisms were further studied by utilizing Ba2+ as a Ca2+ substitute. Ba2+, which freely permeates DHP-sensitive Ca2+ channels in the absence of GnRH, induced LH release which was sensitive to blockade by D600 and nifedipine. However, in the presence of the channel blockers, Ba2+-induced LH release could be elicited when GnRH was added to the system. This indicates that GnRH stimulates LH release by initially activating a DHP-insensitive Ca2+-entry mechanism and then a DHP-sensitive mechanism. The DHP-sensitive mechanism freely allows Ba2+ entry in the absence of GnRH-receptor occupancy, whereas the DHP-insensitive mechanism requires GnRH-receptor activation for Ba2+ entry.

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