Enhanced ET(A)-receptor-mediated inhibition of K(v) channels in hypoxic hypertensive rat pulmonary artery myocytes.
Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+) (K(v)) channels and release of intracellular Ca(2+), were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to ET(A) receptors occurred. This switch in receptor coupling, combined with reduced I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ET(A)-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.
Department of Medicine, Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Science Center, Denver, Colorado 80262, USA.
K X
KX
Li
B
B
Fouty
I F
IF
McMurtry
D M
DM
Rodman
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D004594:Electrophysiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D006973:Hypertension / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium