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(Circulation. 2005;112:1494-1499.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Pergolide Is an Inhibitor of Voltage-Gated Potassium Channels, Including Kv1.5, and Causes Pulmonary Vasoconstriction

Zhigang Hong, MD, PhD; Andrew J. Smith, MD; Stephen L. Archer, MD; Xi-Chen Wu, PhD; Daniel P. Nelson, BS; Douglas Peterson, MD, PhD; Gerhard Johnson, MD; E. Kenneth Weir, MD

From the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota, Minneapolis (Z.H., A.J.S., D.P.N., D.P., G.J., E.K.W.); and Departments of Medicine, Division of Cardiology, and Physiology, University of Alberta, Edmonton, Alberta, Canada (S.L.A., X.W.).

Correspondence to E. Kenneth Weir, MD, Veterans Affairs Medical Center 111C, One Veteran’s Dr, Minneapolis, MN 55417. E-mail weirx002{at}umn.edu

Received April 18, 2005; revision received May 19, 2005; accepted May 31, 2005.

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 Anorexigens that modulate serotonin release and reuptake, such as dexfenfluramine, were withdrawn from sale because of CLHVD.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.

Methods and 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 K_Ca 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.

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