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.

Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

“…This is consistent with the much smaller effect of chronic moxonidine treatment on insulin resistance in SHR than in SHROB (Ernsberger et al, 1999a;Velliquette and Ernsberger, 2003a). Furthermore, the lipid-lowering actions of moxonidine can be detected in SHROB but not in SHR (Velliquette et al, 2006). In human studies, beneficial metabolic effects have been detected in diabetic and insulin-resistant subjects, but in unselected hypertensive subjects (Kaan et al, 1995;Lithell, 1998).…”

“…Moxonidine may alter adipocyte gene expression indirectly by affecting another organ, such as the pancreas or the liver. Recently, we have shown that moxonidine has a direct action on the liver to reduce the production and secretion of triglycerides into the plasma (Velliquette et al, 2006). Reduced delivery of triglycerides to adipocytes might produce long-lasting changes in their insulin sensitivity.…”

Rilmenidine improves hepatic steatosis through p38-dependent pathway to higher the expression of farnesoid X receptor

“…The imidazoline I-1 receptor mediates sympathoinhibitory actions to reduce plasma catecholamine levels Bousquet 2000). Also, activation of I-1 receptors by specific agonist rilmenidine significantly improved hypertension in obese spontaneously hypertensive rats named Koletsky rats (Velliquette et al 2006). Activation of I-2 receptor increases plasma β-endorphin level to facilitate glucose uptake in the muscle for improvement of hyperglycemia (Lui et al 2010).…”

A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

“…It has been suggested that the beneficial metabolic effects of these compounds are related to their action on I 1 Rs, whereas targeting a 2 -adrenergic receptors is thought to be rather detrimental in this context (Ernsberger et al, 1999;Velliquette and Ernsberger, 2003a,b;Velliquette et al, 2006). However, to date, the lack of selectivity of the ligands has not permitted determination of the respective contributions of a 2 -adrenergic-and I 1 R-mediated effects.…”