ALPHA(1)-ADRENERGIC INHIBITION OF THE BETA-ADRENERGICALLY ACTIVATED CL- CURRENT IN GUINEA-PIG VENTRICULAR MYOCYTES

alpha-Adrenergic receptor stimulation regulates the activity of a numb er of different cardiac ion channels, including those underlying one o r more distinct Cl- conductances. The whole-cell patch-damp technique was used in the present study to investigate the effects of alpha-adre nergic stimulation on the beta-adrenergically regulated Cl- current in guinea pig ventricular myocytes. Neither alpha(1)-adrenergic receptor stimulation with methoxamine (25 to 500 mu mol/L) nor direct activati on of endogenous protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu, 100 nmol/L) evoked a Cl- current. On the contrary, the Cl- curr ent activated by 30 nmol/L isoproterenol was inhibited by methoxamine, with an EC(50) of 6.7+/-2.6 mu mol/L, and this response was blocked b y prazosin, an alpha(1)-adrenergic receptor antagonist. Prazosin also decreased the EC(50) for current activation by norepinephrine from 53/-7.1 to 18+/-3.8 nmol/L, demonstrating that the ability of this endog enous neurotransmitter to activate the Cl- current through beta-adrene rgic receptor stimulation is limited by its intrinsic ability to also activate alpha-adrenergic receptors. Methoxamine did not inhibit the C l- current evoked by either direct activation of adenylate cyclase wit h forskolin or inhibition of phosphodiesterase activity with 3-isobuty l-1-methylxanthine, indicating that alpha-adrenergic stimulation inhib its beta-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl- current activate d by histamine, suggesting that alpha-adrenergic stimulation specifica lly inhibits beta-adrenergic receptor-mediated responses. The inhibito ry effect of methoxamine was not mimicked by PDBu, and it persisted in the presence-of bisindolylmaleimide, a selective PKC inhibitor. Howev er, methoxamine inhibition of the isoproterenol-activated Cl- current was sensitive to pertussis toxin. These results suggest that alpha-adr energic receptor stimulation inhibits the beta-adrenergically activate d Cl- current, demonstrating a navel mechanism by which alpha-adrenerg ic receptors may regulate ion channel activity in the heart.