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Histamine H 1 ‐receptor‐mediated modulation of the delayed rectifier K + current in guinea‐pig atrial cells: opposite effects on I Ks and I Kr
Author(s) -
Matsumoto Yasunori,
Ogura Takehiko,
Uemura Hiroko,
Saito Toshihiro,
Masuda Yoshiaki,
Nakaya Haruaki
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702918
Subject(s) - depolarization , histamine , chemistry , histamine h1 receptor , biophysics , cimetidine , pharmacology , patch clamp , potassium channel , histamine receptor , receptor , biochemistry , biology , antagonist
Histamine receptor‐mediated modulation of the rapid and slow components of the delayed rectifier K + current (I K ) was investigated in enzymatically‐dissociated atrial cells of guinea‐pigs using the whole cell configuration of the patch clamp technique. Histamine at a concentration of 10 μ M enhanced I K recorded during strong depolarization to potentials ranging from +20 to +40 mV and inhibited I K recorded during mild depolarization to potentials ranging from −20 to −10 mV. The increase of I K was more prominent with longer depolarizing pulses, whereas the inhibition of I K was more marked with shorter depolarizing pulses, suggesting that histamine enhances I Ks (the slow component of I K ) and inhibits I Kr (the rapid component of I K ). The histamine‐induced enhancement of I Ks and inhibition of I Kr were abolished by 3 μ M chlorpheniramine but not by 10 μ M cimetidine, suggesting that these opposite effects of histamine on I Kr and I Ks are mediated by H 1 ‐receptors. In the presence of 5 μ M E‐4031, an I Kr blocker, histamine hardly affected I K during mild depolarization although it enhanced I K during strong depolarization in a concentration‐dependent manner. Histamine increased I Ks with EC 50 value of 0.7 μ M . In the presence of 300 μ M indapamide, an I Ks blocker, histamine hardly affected I Ks but inhibited I Kr in a concentration‐dependent manner. Histamine decreased I Kr with IC 50 value of 0.3 μ M . Pretreatment with 100 n M calphostin C or 30 n M staurosporine, protein kinase C inhibitors, abolished the histamine‐induced enhancement of I Ks , but failed to affect the histamine‐induced inhibition of I Kr . We conclude that in guinea‐pig atrial cells H 1 ‐receptor stimulation enhances I Ks and inhibits I Kr through different intracellular mechanisms.British Journal of Pharmacology (1999) 128 , 1545–1553; doi: 10.1038/sj.bjp.0702918