Novel 1,4‐Dihydropyridine (Bay K 8644) Facilitates Calcium‐Dependent [3H]Noradrenaline Release from PC 12 Cells

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Abstract
The effects of the novel 1,4‐dihydropyridine Bay K 8644 [methyl‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)‐pyridine‐5‐carboxylate] on the release of [3H]noradrenaline in cultured PC 12 cells were investigated. K+ in a concentration‐dependent manner evoked 3H‐transmitter release with an EC50 of 50‐56 mM. Bay K 8644 at 30 nM potentiated the K+‐evoked [3H]noradrenaline release; however, in the absence of calcium neither K+ evoked nor Bay K 8644 enhanced [3H]noradrenaline release. At a K+ concentration of 25 mM, Bay K 8644 stimulated [3H]noradrenaline release fivefold, with an EC50 of 10 nM, and 100 nM of the calcium channel blocker nitrendipine shifted the concentration response curve of Bay K 8644 to the right in an apparently competitive fashion. Nitrendipine blocked the Bay K 8644‐potentiated release with an EC50 of 700 nM in the presence of 500 nM Bay K 8644. [3H]Nitrendipine bound to a saturable population of binding sites on PC 12 cell membranes with a Bmax of 180 fmol μmg‐1 of membrane protein and a KD of 0.9 nM. Bay K 8644 inhibited [3H]nitrendipine binding with a K1 of 16 nM. It is concluded that Bay K 8644 binds to, and stabilizes, the open state of calcium channels and thus acts as a “calcium agonist” to mediate calcium‐dependent cellular events such as catecholamine release from PC 12 cells.

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