Inhibition of EDHF by two new combinations of K+-channel inhibitors in rat isolated mesenteric arteries.
It is widely established that in rat mesenteric arteries, endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation evoked by acetylcholine is abolished by a combination of charybdotoxin plus apamin. 4-Aminopyridine, an inhibitor of voltage-gated (Kv) K(+)-channels, in combination with apamin had moderate effects on the EDHF-mediated relaxation. Maurotoxin (MTX), an inhibitor of Kv and intermediate-conductance Ca(2+)-activated K(+)-channels (IK), had no effect on EDHF-mediated relaxation. However, MTX in combination with apamin completely abolished EDHF-mediated relaxation and endothelial cell hyperpolarization. The selective IK inhibitor 2-(2-chlorophenyl)-2,2-diphenyl acetonitrile (TRAM-39) had no significant effect on EDHF-mediated relaxation. EDHF-mediated vasorelaxation and hyperpolarization was abolished by a combination of TRAM-39 and apamin. These data demonstrate two new combinations of K(+)-channel inhibitors for the investigation of EDHF. Furthermore, by using TRAM-39, a potent selective inhibitor of IK channels, we provide the first direct evidence that abolition of EDHF requires the simultaneous presence of intermediate- and small-conductance Ca(2+)-activated K(+)-channel inhibitors.
Hinton
Jane M
JM
Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. J.Hinton@bristol.ac.uk
Langton
Philip D
PD
D015761:4-Aminopyridine / Q000494:pharmacology; D000097:Acetonitriles / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000037:antagonists & inhibitors*; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012604:Scorpion Venoms / Q000494:pharmacology; D012605:Scorpions; D014320:Triphenylmethyl Compounds / Q000494:pharmacology
C478958:(2-Chlorophenyl)(diphenyl)acetonitrile; D000097:Acetonitriles; D001562:Benzimidazoles; D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D014320:Triphenylmethyl Compounds; C067410:endothelium-dependent hyperpolarization factor; C104498:maurotoxin; D018999:Charybdotoxin; D001030:Apamin; D015761:4-Aminopyridine; C102635:1-ethyl-2-benzimidazolinone