ABSTRACT
The present study was designed to establish comparatively the inhibitory effects of cilnidipine (CNP), nifedipine (NIF), and omega-conotoxin GVIA (CTX) on the release of CA evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. CNP (3 micrometer), NIF (3 micrometer), and CTX (3 micrometer) perfused into an adrenal vein for 60 min produced greatly inhibition in CA secretory responses evoked by ACh (5.32 x 10(-3) M), DMPP (10(-4) M for 2 min), McN-A-343 (10(-4) M for 2 min), high K+ (5.6 x 10(-2) M), Bay-K-8644 (10(-5) M), and cyclopiazonic acid (10(-5) M), respectively. For the CA release evoked by ACh and Bay-K-8644, the following rank order of potency was obtained: CNP > NIF > CTX. The rank order for the CA release evoked by McN-A-343 and cyclopiazonic acid was CNP > NIF > CTX. Also, the rank orders for high K+ and for DMPP were NIF > CTX > CNP and NIF > CNP > CTX, respectively. Taken together, these results demonstrate that all voltage-dependent Ca2+ channels (VDCCs) blockers of cilnidipine, nifedipine, and omega-conotoxin GVIA inhibit greatly the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization without affecting the basal release from the isolated perfused rat adrenal gland. It seems likely that the inhibitory effects of cilnidipine, nifedipine, and omega-conotoxin GVIA are mediated by the blockade of both L- and N-type, L-type only, and N-type only VDCCs located on the rat adrenomedullary chromaffin cells, respectively, which are relevant to Ca2+ mobilization. It is also suggested that N-type VDCCs play an important role in the rat adrenomedullary CA secretion, in addition to L-type VDCCs.
Subject(s)
Animals , Rats , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester , Adrenal Glands , Adrenal Medulla , Calcium Channels , Calcium Channels, L-Type , Calcium Channels, N-Type , Chromaffin Cells , Dimethylphenylpiperazinium Iodide , Membranes , Nifedipine , omega-Conotoxin GVIA , omega-Conotoxins , VeinsABSTRACT
The aim of this study was to investigate the role of Ca2+-channel blockers in norepinephrine (NE) release from rat hippocampus. Slices and synaptosomes were incubated with [3H]-NE and the releases of the labelled products were evoked by 25 mM KCl stimulation. Nifedipine, diltiazem, nicardipine, flunarizine and pimozide did not affect the evoked and basal release of NE in the slice. But, diltiazem, nicardipine and flunarizine decreased the evoked NE release with a dose-related manner without any change of the basal release from synaptosomes. Also, a large dose of pimozide produced modest decrement of NE release. omega-conotoxin (CTx) GVIA decreased the evoked NE release in a dose-dependent manner without changing the basal release. And omega-CTxMVIIC decreased the evoked NE release in the synaoptosomes without any effect in the slice, but the effect of decrement was far less than that of omega-CTxGVIA. In interaction experiments with omega-CTxGVIA, omega-CTxMVIIC slightly potentiated the effect of omega-CTxGVIA on NE release in the slice and synaptosomal preparations. These results suggest that the NE release in the rat hippocampus is mediated mainly by N-type Ca2+-channels, and that other types such as L-, T- and/or P/Q-type Ca2+-channels could also be participate in this process.