Endothelin receptor coupling to potassium and chloride channels in isolated rat pulmonary arterial myocytes.
Endothelin (endothelin)-1 may in important role in the control of pulmonary arterial tone, part of its action being due to a putative ability to regulate membrane ion channel activity. Consequently, we have examined its effects on membrane currents in pulmonary arterial myocytes by using the patchclamp recording technique. Endothelin-1 (0.1-50 nM) activated an oscillatory inward current and caused a brief enhancement, followed by inhibition of the outward K+ current. Pharmacological and anion substitution experiments revealed that the oscillations of inward current were due to ET(A) receptor stimulation and subsequent activation of Ca(+2)-activated Cl- channels (EC50 > or = 16 nM). Enhancement of K+ current was inhibited by FR139317 (an ET(A) receptor antagonist) and by buffering intracellular Ca+2, which suggests that ET(A) receptor stimulation also activates Ca(+2)-activated K+ channels. Inhibition of K+ current (IC50 approximately 0.5 nM) by endothelin-1 was not dependent on phosphorylation or intracellular Ca+2 and was unaffected by FR139317 but was mimicked by ET(B) receptor agonists. It appears, therefore, that ET(A) and ET(B) receptors in pulmonary arterial myocytes are differentially coupled to Cl- and K+ channels. Modulation of these channels by endothelin-1 may prove to play an important role in regulating pulmonary arterial smooth muscle tone under both physiological and pathological conditions.
Salter
K J
KJ
University Department of Pharmacology, Oxford, United Kingdom.
Kozlowski
R Z
RZ
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*
D001381:Azepines; D018118:Chloride Channels; D019332:Endothelin-1; D007211:Indoles; D015221:Potassium Channels; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C079574:FR 139317; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002118:Calcium