ALPHA-ADRENERGIC CONTROL OF VOLUME-REGULATED CL- CURRENTS IN RABBIT ATRIAL MYOCYTES - CHARACTERIZATION OF A NOVEL IONIC REGULATORY MECHANISM

被引:88
作者
DUAN, D
FERMINI, B
NATTEL, S
机构
[1] MONTREAL HEART INST,DEPT MED,MONTREAL,PQ H1T 1C8,CANADA
[2] MCGILL UNIV,DEPT PHARMACOL & THERAPEUT,MONTREAL,PQ,CANADA
[3] UNIV MONTREAL,DEPT MED,MONTREAL,PQ H3C 3J7,CANADA
关键词
ACTION POTENTIAL; CL-; CURRENTS; ION CHANNELS; AUTONOMIC NERVOUS SYSTEM; PHENYLEPHRINE;
D O I
10.1161/01.RES.77.2.379
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
alpha-Adrenergic stimulation is known to play a role in cardiac arrhythmogenesis and to modulate a variety of cardiac K+ currents. The effects of alpha-adrenergic stimulation on Cl- currents are largely unknown. Many cardiac cell types show a volume-sensitive Cl- current induced by cell swelling (I-Cl.swell). The present experiments were designed to assess the potential alpha-adrenergic modulation of I-Cl.swell in rabbit atrial myocytes. I-Cl.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 (I-Cl.b) was observed under isotonic conditions in 128 of 150 cells (85%), had the same dependency on [Cl-](o) as I-Cl.swell, and was reduced by cell shrinkage induced by hypertonic superfusion, suggesting that I-Cl.b is carried by the same volume-sensitive Cl- conductance as I-Cl.swell. Phenylephrine produced a concentration-dependent and near-complete inhibition of I-Cl.b and I-Cl.swell with EC(50) values of 86+/-5 and 72+/-7 (mean+/-SEM) mu mol/L, respectively, at +20 mV. Norepinephrine (administered in the presence of 1 mu mol/L propranolol) also inhibited I-Cl.b and I-Cl.swell, with EC(50) values of 2.6+/-0.1 and 2.8+/-0.4 mu mol/L, respectively. The concentration-response curve for phenylephrine was shifted significantly (P<.001) to the right by the alpha(1)-adrenoceptor antagonist prazosin and by the alpha(1A)-receptor antagonists (+)-niguldipine and 5-methylurapidil but was unaltered by the alpha(1B)-receptor antagonist chloroethylclonidine (100 mu mol/L). Inhibition of protein kinase C (PKC) with staurosporine, H-7, or 18-hour preincubation with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) blocked the effects of phenylephrine on I-Cl.swell, and the highly selective PKC inhibitor bisindolylmaleimide blocked the effects of norepinephrine on I-Cl.swell and I-Cl.b. Both PMA and 1-oleoyl-2-acetylglycerol inhibited I-Cl.swell in a concentration-dependent fashion. In blinded studies, the phorbol ester phorbol 12,13-didecanoate (PDD) reduced I-Cl.swell by 91+/-3%; its inactive analogue 4 alpha-PDD had no effect (mean change, 3+/-1%). Preincubation with pertussis toxin (PTX) prevented the actions of phenylephrine on I-Cl.swell, indicating a role for a PTX-sensitive guanine nucleotide-binding (G) protein. We conclude that alpha-adrenergic agonists inhibit volume-sensitive Cl- currents in rabbit atrial cells by interacting with an alpha(1A)-adrenoceptor mechanism that is coupled to PKC via a PTX-sensitive G protein. These results suggest a potentially novel mechanism of alpha-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.
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页码:379 / 393
页数:15
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