title: Importance of imidazoline-preferring receptors in the cardiovascular actions of chronically administered moxonidine, rilmenidine and clonidine in conscious rabbits.
abstract: OBJECTIVE
  To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine.
  
  
  METHODS
  In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade.
  
  
  RESULTS
  Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2)
  
  
  CONCLUSIONS
  The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade
authors.affiliation: Neuropharmacology Laboratory, Baker Heart Research Institute, Commercial Road Prahran, St Kilda Road Central, Melbourne, Victoria 8008, Australia.
authors.forename: Monique L
authors.initials: ML
authors.lastname: Parkin
authors.forename: Shirley J
authors.initials: SJ
authors.lastname: Godwin
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001572:Benzofurans / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003000:Clonidine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D020546:Fourth Ventricle; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan / Q000008:administration & dosage / Q000031:analogs & derivatives; D007093:Imidazoles / Q000008:administration & dosage*; D054755:Imidazoline Receptors; D007276:Injections, Intraventricular; D008297:Male; D010080:Oxazoles / Q000008:administration & dosage*; D011817:Rabbits; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077769:Rilmenidine
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000959:Antihypertensive Agents; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D010080:Oxazoles; D011955:Receptors, Drug; C043482:moxonidine; C058525:2-methoxyidazoxan; C062597:efaroxan; D003000:Clonidine; D000077769:Rilmenidine; D019329:Idazoxan