Tolerance to peripheral, but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist.
Studies were conducted to determine possible development, and underlying mechanisms, of tolerance to the hypotensive effects of ropinirole (4-[2-(dipropylamino)ethyl]-1-3-dihydro-2H-indol-2-one HCl), a selective dopamine receptor agonist, following twice daily oral administration to cynomolgus monkeys and spontaneously hypertensive rats (SHR). Tolerance to the hypotensive effects of the compound developed in both species within one week of repeated dosing. Tolerance which developed in rats was dose-related and could not be attributed to altered plasma/drug concentrations or be overcome by increasing the i.v. challenge dose of ropinirole. Cross-tolerance was shown to the dopamine receptor agonist bromocriptine. Similar hypotensive responses to bethanidine were seen in rats treated with ropinirole or vehicle. Tolerance to hypolocomotor effects of the compound were not apparent in the same time frame. The dopamine D2 receptor antagonist, domperidone, caused hypertension in ropinirole-but not vehicle-treated rats. Results reported in this paper are not consistent with a down-regulation of peripheral dopamine D2-like receptors but suggest a compensatory increase in basal sympathetic tone.
Parker
S G
SG
SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire, UK.
Raval
P
P
Yeulet
S
S
Eden
R J
RJ
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001627:Bethanidine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D001971:Bromocriptine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003655:Decerebrate State; D004294:Domperidone / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004361:Drug Tolerance; D005260:Female; D006973:Hypertension / Q000188:drug therapy; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D014661:Vasoconstriction / Q000187:drug effects
D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D017448:Receptors, Dopamine D2; C046649:ropinirole; D001971:Bromocriptine; D004294:Domperidone; D001627:Bethanidine; D009638:Norepinephrine