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+ channels (KATP 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 [3H]norepinephrine ([3H]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 microM), a KATP channel-agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a KATP channel-antagonist (30 microM). Diazoxide (30-300 microM), another activator of the KATP channels reduced the resting release of NE, and also attenuated the evoked release at a single concentration (100 microM), and this latter action was also counteracted by glibenclamide (30 microM). 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 microM), suggesting that it acts as an antagonist. Glibenclamide (30-300 microM), by itself enhanced the stimulation-evoked release of [3H]NE, and also increased the resting release of NE. On the other hand, 5-hydroxydecanoate, an ischemia-selective inhibitor of cardiac KATP channels did not change NE release. Adenosine, (30-300 microM), an A1-receptor agonist, clonidine (3 microM), an alpha 2-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 microM) all reduced the evoked release of [3H]NE, but these effects were not modified by glibenclamide (300 microM), indicating that neuronal adenosine (A1), adrenergic (alpha 2) and muscarinic (M3) receptors do not act on KATP channels. In the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [3H]NE. However, glibenclamide (30-300 microM) and pinacidil (30-300 microM) enhanced dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release.


CONCLUSIONS
Our results indicate that sympathetic nerve endings of the human and guinea-pig atrium are endowed with ATP-sensitive K+ channels. These channels responded to agonists and antagonists under the experimental conditions applied and they could modulate the release of NE thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions.
Oe
K
K
Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Sperlágh
B
B
Sántha
E
E
Matkó
I
I
Nagashima
H
H
Foldes
F F
FF
Vizi
E S
ES
D000241:Adenosine / Q000494:pharmacology; D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000294:innervation; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists*; D013268:Stimulation, Chemical; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*
D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D003652:Decanoic Acids; D006880:Hydroxy Acids; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019806:Cromakalim; D010095:Oxotremorine; C052853:5-hydroxydecanoic acid; D020110:Pinacidil; D000241:Adenosine; D003000:Clonidine; D003981:Diazoxide; D005905:Glyburide; D009638:Norepinephrine