Histamine H1-receptor-mediated modulation of the delayed rectifier K+ current in guinea-pig atrial cells:: opposite effects on IKs and IKr

1 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. 2 Histamine at a concentration of 10 mu 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). 3 The histamine-induced enhancement of I-Ks and inhibition of I-Kr were abolished by 3 mu M chlorpheniramine but not by 10 mu M cimetidine, suggesting that these opposite effects of histamine on I-Kr and I-Ks are mediated by H-1-receptors. 4 In the presence of 5 mu 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 EC50 value of 0.7 mu M. In the presence of 300 mu M indapamide, an I-Ks, blocker, histamine hardly affected IKs but inhibited I-Kr in a concentration-dependent manner. Histamine decreased I-Kr with IC50 value of 0.3 mu M. 5 Pretreatment with 100 nM calphostin C or 30 nM staurosporine, protein kinase C inhibitors, abolished the histamine-induced enhancement of I-Ks but failed to affect the histamine-induced inhibition of I-Kr,. 6 We conclude that in guinea-pig atrial cells H-1-receptor stimulation enhances I-Ks and inhibits I-Kr through different intracellular mechanisms.