title: Effects of selective dopamine receptor subtype agonists on cardiac contractility and regional haemodynamics in rats.
abstract: 1. Activation of dopamine (DA) receptors produces cardiovascular responses such as vasodilation and hypotension. However, knowledge of the role of specific dopamine receptor subtypes (especially D3 and D4) in the cardiovascular system is limited. The objective of the present study was to characterize the haemodynamic and cardiac responses to agonists with selectivity for D1, D2, D3 and D4 receptor subtypes. 2. Inactin-anaesthetized rats were instrumented to measure regional haemodynamic and cardiac contractility responses with slow intravenous infusion of agonists. 3. Fenoldopam (a D1 receptor agonist) decreased (P < 0.05) renal vascular resistance beginning at a dose of 3 micromol/kg. Infusion of PNU-95666E (a D2 receptor agonist) produced dose-dependent decreases (P < 0.05) in mean arterial pressure (MAP), heart rate (HR) and hindquarter vascular resistance (HQVR). Administration of BP897 (a partial D3 receptor agonist) decreased (P < 0.05) MAP and HQVR at 3 micromol/kg. PD168077 (a D4 receptor agonist) caused significant increases in HQVR at 1 micromol/kg. None of the compounds tested elicited significant changes in cardiac contractility. 4. Using selective agonists of dopamine receptor subtypes, the present studies characterize distinct cardiovascular effects in anaesthetized rats. Consistent with its well-defined effects as a D1 receptor agonist, fenoldopam administration resulted in renal vasodilation. Similar to earlier studies using the non-selective D2-like receptor agonist quinpirole, selective agonism at the D2 receptor using PNU-95666E resulted in bradycardia, hindquarter vasodilation and decreases in arterial pressure. Partial agonism at the D3 receptor with BP897 had no effect on heart rate, but did produce depressor responses driven by decreases in HQVR. Conversely, agonism of the D4 receptor using PD168077 resulted in modest hindquarter vasoconstriction that was not dose dependent. Hence, by comparison, agonism of the D4 receptor has little effect in the cardiovascular system of the rat relative to the other dopamine receptor subtype agonists tested.
authors.affiliation: Pharmaceutical Discovery, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. jim.polakowski@abbott.com
authors.forename: James S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D011954:Receptors, Dopamine