Inhibition of voltage-gated K(+) currents by endothelin-1 in human pulmonary arterial myocytes.
Recent studies demonstrate that endothelin-1 (ET-1) constricts human pulmonary arteries (PA). In this study, we examined possible mechanisms by which ET-1 might constrict human PA. In smooth muscle cells freshly isolated from these arteries, whole cell patch-clamp techniques were used to examine voltage-gated K(+) (K(V)) currents. K(V) currents were isolated by addition of 100 nM charybdotoxin and were identified by current characteristics and inhibition by 4-aminopyridine (10 mM). ET-1 (10(-8) M) caused significant inhibition of K(V) current. Staurosporine (1 nM), a protein kinase C (PKC) inhibitor, abolished the effect of ET-1. Rings of human intrapulmonary arteries (0.8-2 mm OD) were suspended in tissue baths for isometric tension recording. ET-1-induced contraction was maximal at 10(-8) M, equal to that induced by K(V) channel inhibition with 4-aminopyridine, and attenuated by PKC inhibitors. These data suggest that ET-1 constricts human PA, possibly because of myocyte depolarization via PKC-dependent inhibition of K(V). Our results are consistent with data we reported previously in the rat, suggesting similar mechanisms may be operative in both species.
Shimoda
L A
LA
Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA. shimodal@welch.jhu.edu
Sylvester
J T
JT
Booth
G M
GM
Shimoda
T H
TH
Meeker
S
S
Undem
B J
BJ
Sham
J S
JS
D015761:4-Aminopyridine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D002648:Child; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D018999:Charybdotoxin; D015761:4-Aminopyridine; D019311:Staurosporine; C070515:bisindolylmaleimide I