Inhibitory mechanism of pinacidil on catecholamine secretion from the rat perfused adrenal gland evoked by cholinergic stimulation and membrane depolarization

1. The present study attempted to investigate the effect of potassium channel openers on secretion of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from rat isolated perfused adrenal gland. 2. The perfusion of pinacidil (30-300 microM) into an adrenal vein for 20 min produced dose-dependent inhibition of CA secretion evoked by acetylcholine (ACh; 5.32 mM), high K+ (56 mM), 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; 100 microM for 2 min), 3-(m-chloro-phenyl-carbamoyl-oxy)-2-butynyl trimethyl ammonium chloride (McN-A-343; 100 microM for 2 min), cyclopiazonic acid (CPA; 10 microM for 4 min) and methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyri dine-5-carboxylate (Bay-K-8644; 10 microM for 4 min). 3. In the presence of minoxidil (100 microM), which is also known to be a potassium channel activator, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and CPA were also significantly depressed. 4. In adrenal glands preloaded with pinacidil (100 microM) in the presence of glibenclamide (GB; 1 microM), a specific blocker of ATP-regulated potassium channels, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and CPA were restored to a considerable extent of the control release as compared with that of pinacidil only. 5. These results suggest that pinacidil causes marked inhibition of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors, as well as by membrane depolarization, indicating that this effect may be mediated by inhibiting influx of extracellular calcium and release of intracellular calcium in the rat adrenomedullary chromaffin cells. Furthermore, these findings suggest that these potassium channel opener-sensitive membrane potassium channels also play a modulatory role in regulating CA secretion.