Abstract:
:alpha-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 alpha-adrenergic stimulation on the beta-adrenergically regulated Cl- current in guinea pig ventricular myocytes. Neither alpha 1-adrenergic receptor stimulation with methoxamine (25 to 500 mumol/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 mumol/L, and this response was blocked by prazosin, an alpha 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 beta-adrenergic receptor stimulation is limited by its intrinsic ability to also activate alpha-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 alpha-adrenergic stimulation inhibits beta-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl- current activated by histamine, suggesting that alpha-adrenergic stimulation specifically inhibits beta-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 alpha-adrenergic receptor stimulation inhibits the beta-adrenergically activated Cl- current, demonstrating a novel mechanism by which alpha-adrenergic receptors may regulate ion channel activity in the heart.
journal_name
Circ Resjournal_title
Circulation researchauthors
Oleksa LM,Hool LC,Harvey RDdoi
10.1161/01.res.78.6.1090subject
Has Abstractpub_date
1996-06-01 00:00:00pages
1090-9issue
6eissn
0009-7330issn
1524-4571journal_volume
78pub_type
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