Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction.
BACKGROUND
Pergolide produces clinical benefit in Parkinson disease by stimulating dopamine D1 and D2 receptors. An increased incidence of carcinoid-like heart valve disease (CLHVD) has been noted in pergolide users, reminiscent of that induced by certain anorexigens used for weight reduction. Anorexigens that modulate serotonin release and reuptake, such as dexfenfluramine, were withdrawn from sale because of CLHVD. Interestingly, the anorexigens also caused pulmonary arterial hypertension (PAH). Anorexigens were shown to enhance hypoxic pulmonary vasoconstriction, in part by inhibiting voltage-gated K+ channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). Although PAH has not been associated with pergolide use, we hypothesized that pergolide might have similar effects on hypoxic pulmonary vasoconstriction and Kv channels.


RESULTS
Pergolide enhanced hypoxic pulmonary vasoconstriction in the isolated perfused rat lung compared with control lungs (mean pulmonary artery pressure 32+/-3 versus 21+/-2 mm Hg; P<0.01). Pergolide also caused vasoconstriction in rat pulmonary artery rings. Pergolide inhibited PASMC potassium current density, resulting in membrane depolarization (from -51+/-2 to -44+/-1 mV) and increased cytosolic calcium in both rat and human PASMCs. Pergolide directly inhibited heterologously expressed Kv1.5 and KCa channels.


CONCLUSIONS
Pergolide causes Kv channel inhibition and, despite being from a different class of drugs, has pulmonary vascular effects reminiscent of dexfenfluramine. Coupled with their shared proclivity to induce CLHVD, these findings suggest that clinical monitoring for pergolide-induced PAH should be considered.
Hong
Zhigang
Z
Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN, USA.
Smith
Andrew J
AJ
Archer
Stephen L
SL
Wu
Xi-Chen
XC
Nelson
Daniel P
DP
Peterson
Douglas
D
Johnson
Gerhard
G
Weir
E Kenneth
EK
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010479:Pergolide / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects*
D018491:Dopamine Agonists; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D010479:Pergolide; D002118:Calcium