Inhibition of voltage-gated K+ current in rat intrapulmonary arterial myocytes by endothelin-1.
Although endothelin (ET)-1 is an important regulator of pulmonary vascular tone, little is known about the mechanisms by which ET-1 causes contraction in this tissue. Using the whole cell patch-clamp technique in rat intrapulmonary arterial smooth muscle cells, we found that ET-1 and the voltage-dependent K+ (Kv)-channel antagonist 4-aminopyridine, but not the Ca(2+)-activated K(+)-channel antagonist charybdotoxin (ChTX), caused membrane depolarization. In the presence of 100 nM ChTX, ET-1 (10(-10) to 10(-7) M) caused a concentration-dependent inhibition of K+ current (56.2 +/- 3.8% at 10(-7) M) and increased the rate of current inactivation. These effects of ET-1 on K+ current were markedly reduced by inhibitors of protein kinase C (staurosporine and GF 109203X) and phospholipase C (U-73122) or under Ca(2+)-free conditions and were mimicked by activators of protein kinase C (phorbol 12-myristate 13-actetate and 1,2-dioctanoyl-sn-glycerol). These data suggest that ET-1 modulated pulmonary vascular reactivity by depolarizing pulmonary arterial smooth muscle, due in part to the inhibition of Kv current that occurred via activation of the phospholipase C-protein kinase C signal transduction pathway.
Shimoda
L A
LA
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA.
Sylvester
J T
JT
Sham
J S
JS
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004594:Electrophysiology; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018999:Charybdotoxin; D015761:4-Aminopyridine; D011493:Protein Kinase C; D010738:Type C Phospholipases