title: Cardiovascular and electrocardiographic effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious beagle dogs.
abstract: To confirm recent in vitro findings, we examined the cardiovascular and electrocardiographic (ECG) effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious dogs. Intravenous (i.v.) infusions of ropinirole totaling 20 microg/kg maximally reduced mean arterial pressure (MAP; -16 mm Hg) and the ECG PR interval (-13 milliseconds) and increased heart rate (HR; +29 b/min) and QTc length (+33 ms) at a peak plasma drug concentration (p[drug]) of 3.5 ng/ml. I.V. PNU-142774E was better tolerated through 66 microg/kg and a maximal p[drug] of 5.9 ng/ml with negligible cardiovascular changes and mild QTc reduction (13 ms). Apomorphine (25 microg/kg i.v.) was intermediate to ropinirole and PNU-142774E for emesis and peak changes in MAP (-6 mm Hg), HR (+24 b/min), and QTc (+15 milliseconds) at a mean p[drug] of 3.4 ng/ml. By comparison, the class III antiarrhythmic trecetilide (2.0 mg/kg bolus) increased QTc (+58 ms) without affecting mean arterial pressure or heart rate. This study establishes that in conscious dogs, the selective dopamine receptor agonist PNU-142774E has fewer cardiovascular and emetic effects than ropinirole and apomorphine and supports prior in vitro findings that ropinirole and apomorphine but not the PNU-142774E imidazoquinolin analog sumanirole reduces the delayed rectifier current in HERG transfected cells.
authors.affiliation: Department of Pharmacology, Global Pharmaceutical Research and Development, Pfizer Inc., Kalamazoo, Michigan, USA. sjhumphrey@pharmoptima.com
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Humphrey
authors.forename: Chauncey N
authors.initials: CN
authors.lastname: Turman
authors.forename: James T
authors.initials: JT
authors.lastname: Curry
authors.forename: Gracella J
authors.initials: GJ
authors.lastname: Wheeler
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001058:Apomorphine / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D018491:Dopamine Agonists / Q000494:pharmacology*; D004361:Drug Tolerance; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000502:physiology; D050637:Receptors, Dopamine D3 / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D007093:Imidazoles; D007211:Indoles; C511515:PNU-142774E; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole; D001058:Apomorphine