Both α1A‐ and α1B‐adrenergic receptor subtypes couple to the transient outward current (ITo) in rat ventricular myocytes
- 1 March 2000
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 129 (6) , 1113-1120
- https://doi.org/10.1038/sj.bjp.0703179
Abstract
Regulation of transient outward current (ITo) by α1‐adrenergic (α1AR) plays a key role in cardiac repolarization. α1ARs comprise a heterogeneous family; two natively expressed subtypes (α1A and α1B) and three cloned subtypes (α1a, α1b and α1d) can be distinguished. We have examined the electrophysiological role of each α1AR subtype in regulating ITo in isolated rat ventricular myocytes. Reverse transcription‐PCR study revealed the presence of three subtype mRNAs (α1a, α1b and α1d) in rat myocytes. Radioligand binding assay using [125I]‐HEAT showed that the inhibition curves for α1AAR‐selective antagonists (WB4101, 5‐methylurapidil, (+)‐niguldipine and KMD‐3213) in rat ventricles best fit a two‐site model, with 30% high and 70% low affinity binding sites. The high affinity sites were resistant to 100 μM chloroethylclonidine (CEC), while the low affinity sites were highly inactivated by CEC. Whole cell voltage clamp study revealed that methoxamine reduced a 4‐aminopyridine(4‐AP)‐sensitive component of ITo in the isolated rat ventricle myocytes. Lower concentrations of KMD‐3213 (1 nM) or 5‐MU (10 nM) did not affect the methoxamine‐induced reduction of ITo. On the other hand, CEC treatment (100 μM) of isolated myocytes reduced the methoxamine‐induced reduction of ITo by 46%, and the remaining response was abolished by lower concentrations of KMD‐3213 or 5‐MU. The results indicate that rat ventricular myocytes express transcripts of the three α1AR subtypes (α1a, α1b and α1d); however, two pharmacologically distinct α1AR subtypes (α1A and α1B) are predominating in receptor populations, with approximately 30% α1AAR and 70% α1BAR. Although both α1A and α1BAR subtypes are coupled to the cardiac ITo, α1BARs predominantly mediate α1AR‐induced effect. British Journal of Pharmacology (2000) 129, 1113–1120; doi:10.1038/sj.bjp.0703179Keywords
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