© 1995 American Heart Association, Inc.
Articles |
-Adrenergic Control of Volume-Regulated Cl- Currents in Rabbit Atrial Myocytes
Characterization of a Novel Ionic Regulatory Mechanism
From the Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; the Department of Medicine, University of Montreal; and the Department of Medicine and the Research Center, Montreal Heart Institute.
Correspondence to Stanley Nattel, Research Center, Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8.
Abstract 
-Adrenergic stimulation is known to play a role
in cardiac arrhythmogenesis and to modulate a variety of cardiac
K+ currents. The effects of -adrenergic stimulation on
Cl- currents are largely unknown. Many cardiac cell types
show a volume-sensitive Cl- current induced by cell
swelling (ICl.swell). The present experiments were
designed to assess the potential -adrenergic modulation of
ICl.swell in rabbit atrial myocytes. ICl.swell
was induced with the use of a hypotonic superfusate, under conditions
designed to prevent currents carried by K+,
Na+, and Ca2+ ions. A basal
Cl- current (ICl.b) was observed under
isotonic conditions in 128 of 150 cells (85%), had the same dependency
on [Cl-]o as ICl.swell,
and was reduced by cell shrinkage induced by hypertonic superfusion,
suggesting that ICl.b is carried by the same
volume-sensitive Cl- conductance as ICl.swell.
Phenylephrine produced a concentration-dependent and
near-complete inhibition of ICl.b and
ICl.swell, with EC50 values of 86±5 and
72±7 (mean±SEM) µmol/L, respectively, at +20 mV.
Norepinephrine (administered in the presence of 1 µmol/L
propranolol) also inhibited ICl.b and
ICl.swell, with EC50 values of 2.6±0.1
and 2.8±0.4 µmol/L, respectively. The concentration-response curve
for phenylephrine was shifted significantly
(P<.001) to the right by the 1-adrenoceptor
antagonist prazosin and by the 1A-receptor
antagonists (+)-niguldipine and 5-methylurapidil but was
unaltered by the 1B-receptor antagonist
chloroethylclonidine (100 µmol/L). Inhibition of protein
kinase C (PKC) with staurosporine, H-7, or 18-hour
preincubation with the phorbol ester 4ß-phorbol 12-myristate
13-acetate (PMA, 500 nmol/L) blocked the effects of
phenylephrine on ICl.swell, and the
highly selective PKC inhibitor bisindolylmaleimide blocked
the effects of norepinephrine on ICl.swell and
ICl.b. Both PMA and 1-oleoyl-2-acetylglycerol inhibited
ICl.swell in a concentration-dependent fashion. In blinded
studies, the phorbol ester phorbol 12,13-didecanoate (PDD) reduced
ICl.swell by 91±3%; its inactive analogue 4-PDD had no
effect (mean change, 3±1%). Preincubation with pertussis toxin (PTX)
prevented the actions of phenylephrine on
ICl.swell, indicating a role for a PTX-sensitive
guanine nucleotide–binding (G) protein. We conclude that
-adrenergic agonists inhibit volume-sensitive Cl-
currents in rabbit atrial cells by interacting with an
1A-adrenoceptor mechanism that is coupled to PKC via a
PTX-sensitive G protein. These results suggest a potentially novel
mechanism of -adrenergic control of cardiac electrical activity, the
inhibition of volume-sensitive Cl- currents, and indicate
that PKC, well known to elicit
phosphorylation-dependent Cl- currents in
cat and guinea pig ventricular myocytes, is also capable of
potently inhibiting other forms of cardiac Cl- current.
Key Words: action potential • Cl- currents • ion channels • autonomic nervous system • phenylephrine
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