Modulation of norepinephrine release by ATP-dependent K+-channel activators and inhibitors in guinea-pig and human isolated right atrium

Objective: The aim of this study was to show, whether ATP sensitive K+ chan nels (K-ATP channels), are involved in the modulation of norepinephrine (NE ) release from the sympathetic nerves innervating the guinea-pig and human right atrium. Methods: The resting and stimulation-evoked release of [H-3]n orepinephrine ([H-3]NE) was measured from the isolated guinea-pig and human right atrium and the effect of activators and inhibitors of ATP sensitive K+ channels was studied. Results: Cromakalim (30-300 mu M), a K-ATP channel -agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a K-ATP channel-antagonist (30 mu M). Diazoxide (30-300 mu M), another act ivator of the K-ATP channels reduced the resting release of NE, and also at tenuated the evoked release at a single concentration (100 mu M), and this latter action was also counteracted by glibenclamide (30 mu M). Pinacidil, increased dose-dependently the resting and stimulation-evoked release of NE in a glibenclamide-sensitive manner and reversed the inhibitory effect of cromakalim (100 mu M), suggesting that it acts as an antagonist. Glibenclam ide (30-300 mu M), by itself enhanced the stimulation-evoked release of [H- 3]NE, and also increased the resting release of NE. On the other hand, 5-hy droxydecanoate, an ischemia-selective inhibitor of cardiac K-ATP channels d id not change NE release. Adenosine, (30-300 mu M), an A(1)-receptor agonis t, clonidine (3 mu M), an alpha(2)-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 mu M) all reduced the evoked release of [H -3]NE, but these effects were not modified by glibenclamide (300 mu M), ind icating that neuronal adenosine (A(1)), adrenergic (alpha(2)) and muscarini c (M-3) receptors do not act on K-ATP channels, in the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [H-3] NE. However, glibenclamide (30-300 mu M) and pinacidil (30-300 mu M) enhanc ed dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release. Conclusions: Our results indicate that sympathetic ner ve endings of the human and guinea-pig atrium are endowed with ATP-sensitiv e K+ channels. These channels responded to agonists and antagonists under t he experimental conditions applied and they could modulate the release of N E thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions. (C) 1999 Elsevier Science B.V. All rights reserved.