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.