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(Circulation Research. 1996;78:1090-1099.)
© 1996 American Heart Association, Inc.

Articles

₁-Adrenergic Inhibition of the ß-Adrenergically Activated Cl^- Current in Guinea Pig Ventricular Myocytes

Lisa M. Oleksa, Livia C. Hool, Robert D. Harvey

From the Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.

Correspondence to Robert D. Harvey, Department of Physiology and Biophysics, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH 44106-4970. E-mail rdh3@po.cwru.edu.

Abstract -Adrenergic receptor stimulation regulates the activity of a number of different cardiac ion channels, including those underlying one or more distinct Cl^- conductances. The whole-cell patch-clamp technique was used in the present study to investigate the effects of -adrenergic stimulation on the ß-adrenergically regulated Cl^- current in guinea pig ventricular myocytes. Neither ₁-adrenergic receptor stimulation with methoxamine (25 to 500 µmol/L) nor direct activation of endogenous protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu, 100 nmol/L) evoked a Cl^- current. On the contrary, the Cl^- current activated by 30 nmol/L isoproterenol was inhibited by methoxamine, with an EC₅₀ of 6.7±2.6 µmol/L, and this response was blocked by prazosin, an ₁-adrenergic receptor antagonist. Prazosin also decreased the EC₅₀ for current activation by norepinephrine from 53±7.1 to 18±3.8 nmol/L, demonstrating that the ability of this endogenous neurotransmitter to activate the Cl^- current through ß-adrenergic receptor stimulation is limited by its intrinsic ability to also activate -adrenergic receptors. Methoxamine did not inhibit the Cl^- current evoked by either direct activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine, indicating that -adrenergic stimulation inhibits ß-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl^- current activated by histamine, suggesting that -adrenergic stimulation specifically inhibits ß-adrenergic receptor–mediated responses. The inhibitory effect of methoxamine was not mimicked by PDBu, and it persisted in the presence of bisindolylmaleimide, a selective PKC inhibitor. However, methoxamine inhibition of the isoproterenol-activated Cl^- current was sensitive to pertussis toxin. These results suggest that -adrenergic receptor stimulation inhibits the ß-adrenergically activated Cl^- current, demonstrating a novel mechanism by which -adrenergic receptors may regulate ion channel activity in the heart.

Key Words: phorbol 12,13-dibutyrate • acetylcholine • protein kinase C • isoproterenol • methoxamine

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