Dopamine receptor agonists differ in their actions on cardiac ion channels.
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.
Hurst
Raymond S
RS
Department of Pharmacology, Pharmacia Corporation, Kalamazoo, MI 49007, USA. raymond.s.hurst@pfizer.com
Higdon
Nicole R
NR
Lawson
Judy A
JA
Clark
Michael A
MA
Rutherford-Root
Karen L
KL
McDonald
William G
WG
Haas
Joseph V
JV
McGrath
James P
JP
Meglasson
Martin D
MD
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*
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