title: Lipid-lowering actions of imidazoline antihypertensive agents in metabolic syndrome X.
abstract: Agonists active at I1-imidazoline receptors (I1R) not only lower blood pressure but also ameliorate glucose intolerance, insulin resistance, and hyperlipidemia with long-term treatment. We sought to determine the possible mechanism for the lipid-lowering actions of imidazolines in a model of metabolic Syndrome X, the spontaneously-hypertensive obese (SHROB) rat. The acute actions of moxonidine and rilmenidine, selective I1R agonists, were compared to a specific alpha2-adrenergic receptor agonist, guanabenz, with and without selective receptor blockers. Moxonidine and rilmenidine rapidly reduced plasma triglyceride (20+/-4% and 21+/-5%, respectively) and cholesterol (29+/-9% and 27+/-9%). In contrast, the specific alpha2-adrenergic receptor agonist guanabenz failed to reduce plasma lipids. Blocking experiments showed that moxonidine's actions were mediated by I1R and not alpha2-adrenergic receptors. To evaluate a hepatic site of action, radioligand binding studies with liver plasma membranes confirmed the presence of I1R. Intraportal moxonidine reduced plasma triglycerides by 23+/-3% within 10 min. Moxonidine inhibited hepatic triglyceride secretion by 75% compared to vehicle treatment. Tracer studies with 2H2O suggested that moxonidine inhibits de novo fatty acid synthesis. Thus, activation of I1R lowers plasma lipids, with the main site of action probably within the liver to reduce synthesis and secretion of triglycerides. More selective I1R agonists might provide monotherapy for hyperlipidemic hypertension.
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106-4906, USA.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Velliquette
authors.forename: Rachel
authors.initials: R
authors.lastname: Kossover
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.forename: Paul
authors.initials: P
authors.lastname: Ernsberger
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003000:Clonidine / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006143:Guanabenz / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077769:Rilmenidine; D014280:Triglycerides / Q000097:blood
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D054755:Imidazoline Receptors; D010080:Oxazoles; D011955:Receptors, Drug; D014280:Triglycerides; C410887:imidazoline I1 receptors; D002784:Cholesterol; C043482:moxonidine; D006143:Guanabenz; D003000:Clonidine; D000077769:Rilmenidine