title: Dopamine receptor agonists differ in their actions on cardiac ion channels.
abstract: Four dopamine receptor agonists used for the treatment of Parkinson's disease (apomorphine, pergolide, ropinirole and sumanirole) were evaluated for the ability to block human ether-a-go-go related gene (hERG) K(+) channels and to modify the duration of canine Purkinje fiber action potentials. Apomorphine, pergolide and ropinirole blocked the hERG-mediated currents with IC(50) values of 2.4, 0.12 and 1.2 microM, respectively. When evaluated in an action potential duration assay, pergolide significantly shortened action potential duration at 90% repolarization (APD(90)) whereas apomorphine and ropinirole significantly prolonged repolarization. Sumanirole only partially blocked hERG K(+) channels at the highest tested concentration (10 microM) and did not modify action potential duration over the tested concentration range (0.65-65 microM). Taken together, these data provide evidence that dopamine receptor agonists developed for the treatment of Parkinson's disease differentially influence hERG K(+) channel function and cardiac action potential duration.
authors.affiliation: Department of Pharmacology, Pharmacia Corporation, Kalamazoo, MI 49007, USA. raymond.s.hurst@pfizer.com
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Higdon
authors.forename: Judy A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Clark
authors.forename: Karen L
authors.initials: KL
authors.lastname: Rutherford-Root
authors.forename: William G
authors.initials: WG
authors.lastname: McDonald
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Haas
authors.forename: James P
authors.initials: JP
authors.lastname: McGrath
authors.forename: Martin D
authors.initials: MD
authors.lastname: Meglasson
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006224:Cricetinae; D004285:Dogs; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D066298:In Vitro Techniques; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000502:physiology*
chemical_list: D027682:Cation Transport Proteins; D018491:Dopamine Agonists; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011954:Receptors, Dopamine