The present study was undertaken to investigate the effect of doxorubicin (DX) on secretion of catecholamines (CA) evoked by ACh, high K+, DMPP and McN-A-343 from the isolated perfused rat adrenal gland and to establish the mechanism of its action. DX (10(-7)~10(-6) M) perfused into an adrenal vein for 60 min produced relatively dose- and time-dependent inhibition of CA secretory responses evoked by ACh (5.32 X 10(-3) M), DMPP (10(-4) M) and McN-A-343 (10(-4) M). However, lower dose of DX did not affect CA secretion by high K+ (5.6 X 10(-2) M), but its higher doses depressed time-dependently CA secretion evoked by high K+. DX itself did also fail to affect basal CA output. In adrenal glands loaded with DX (3 X 10(-7) M), CA secretory responses evoked by Bay-K-8644, an activator of L-type Ca2+ channels and cyclopiazonic acid, an inhibitor of cytoplasmic Ca2+-ATPase were time-dependently inhibited. Furthermore, daunorubicin (3 X 10(-7) M), given into the adrenal gland for 60 min, attenuated CA secretory responses evoked by ACh, high K+, DMPP and McN-A-343. Taken together, these results suggest that DX causes relatively dose- and time-dependent inhibition of CA secretory responses evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors from the isolated perfused rat adrenal gland. However, lower dose of DX did not affect CA secretion by high K+, and higher doses of DX reduced time-dependently CA secretion of high K+. It is thought that these effects of DX may be mediated by inhibiting both influx of extracellular calcium into the rat adrenomedullary chromaffin cells and intracelluar calcium release from the cytoplasmic store. Also, there was no difference in the mode of action between DX and daunorubicin in rat adrenomedullary CA secretion.
(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* ; Animals ; Calcium ; Catecholamines ; Chromaffin Cells ; Cytoplasm ; Daunorubicin ; Dimethylphenylpiperazinium Iodide ; Doxorubicin* ; Rats* ; Veins

The present study was attempted to investigate the effect of nicorandil, which is an ATP-sensitive potassium (KATP) channel opener, on secretion of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused rat adrenal glands. The perfusion of nicorandil (0.3~3.0 mM) into an adrenal vein for 90 min produced relatively dose-and time-dependent inhibition in CA secretion evoked by ACh (5.32 mM), high K+ (a direct membrane depolarizer, 56 mM), DMPP (a selective neuronal nicotinic receptor agonist, 100micrometer for 2 min), McN-A-343 (a selective muscarinic M1 receptor agonist, 100micrometer for 4 min), Bay-K-8644 (an activator of L-type dihydropyridine Ca2+ channels, 10micrometer for 4 min) and cyclopiazonic acid (an activator of cytoplasmic Ca2+-ATPase, 10micrometer for 4 min). In adrenal glands simultaneously preloaded with nicorandil (1.0 mM) and glibenclamide (a nonspecific KATP-channel blocker, 1.0 mM), the CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were recovered to the considerable extent of the control release in comparison with that of nicorandil-treatment only. Taken together, the present study demonstrates that nicorandil inhibits the adrenal CA secretion in response to stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization from the isolated perfused rat adrenal glands. It seems that this inhibitory effect of nicorandil may be mediated by inhibiting both Ca2+ influx and the Ca2+ release from intracellular store through activation of KATP channels in the rat adrenomedullary chromaffin cells. These results suggest that nicorandil-sensitive KATP channels may play an inhibitory role in the regulation of the rat adrenomedullary CA secretion.
(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* ; Animals ; Catecholamines ; Chromaffin Cells ; Cytoplasm ; Dimethylphenylpiperazinium Iodide ; Glyburide ; KATP Channels ; Membranes ; Neurons ; Nicorandil* ; Perfusion ; Potassium ; Rats* ; Receptor, Muscarinic M1 ; Receptors, Nicotinic ; Veins