title: CCCP enhances catecholamine release from the perfused rat adrenal medulla.
abstract: The present study was designed to investigate the effect of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, on secretion of catecholamines from the isolated perfused model of the rat adrenal gland and to establish the mechanism of its adrenomedullary secretion. The perfusion of CCCP (3x10(-5) M) into an adrenal vein of for 90 min caused a great increase in catecholamine secretion. Tachyphylaxis to catecholamine-releasing effect of CCCP was not observed by repeated perfusion of it. The net catecholamine-releasing effects of CCCP were depressed by pretreament with pirenzepine (a selective muscarinic M(1)-receptor antagonist), chlorisondamine (a selective neuronal nicotinic receptor antagonist), nicardipine (an L-type Ca2+-channel antagonist), TMB-8 (an intracellular Ca2+-antagonist), and the perfusion of EGTA plus Ca2+-free medium, respectively. In the presence of CCCP (3x10(-5) M), catecholamine secretory responses induced by ACh (5.32x10(-3) M), high K+ (5.6x10(-2) M, a direct membrane depolarizer), DMPP (10(-4) M, (a selective neuronal nicotinic receptor agonist), and McN-A-343 (10(-4) M, (a selective muscarinic M1-receptor agonist) were significantly enhanced. CCCP also significantly enhanced the catecholamine secretory responses evoked by Bay-K-8644 (10(-5) M), L-type Ca2+ channel activator, and cyclopiazonic acid (10(-5) M), an inhibitor of Ca2+-ATPase. Furthermore, the perfusion of FCCP (3x10(-5) M), a similar mitochondrial uncoupler, into an adrenal vein of for 90 min also caused a great increase in catecholamine secretion in a similar pattern with CCCP. Taken together, the results demonstrate that CCCP causes the catecholamine secretion from the perfused rat adrenal medulla in a calcium-dependent fashion. It is thought that this catecholamine secretory enhancement of CCCP may be mediated by both cholinergic receptor stimulation and membrane depolarization, which are relevant to the cytoplasmic Ca2+ increase by stimulation of the Ca2+ influx as well as by the inhibition of Ca2+ uptake into the cytoplasmic Ca2+ stores (both endoplasmic reticulum and mitochondria in chromaffin cells). It also seems that protonophores, such as CCCP, suppress mitochondrial Ca2+ uptake and increase the stimulated secretion of catecholamine by the secretagogues. These results indicate that mitochondria modulate catecholamine secretion by regulating the Ca2+ mobilization for exocytosis.
authors.affiliation: Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501-759, Korea. dylim@chosun.ac.kr
authors.forename: Dong-Yoon
authors.initials: DY
authors.lastname: Lim
authors.forename: Hyeon-Gyoon
authors.initials: HG
authors.lastname: Park
authors.forename: Soichi
authors.initials: S
authors.lastname: Miwa
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000031:analogs & derivatives* / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002395:Catecholamines; D002614:Chelating Agents; D018679:Cholinergic Agonists; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D011950:Receptors, Cholinergic; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000252:Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium