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

Abstract

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I 1 -imidazoline receptors (I 1 Rs) may represent a new concept in MetS pharmacotherapy.125 I]para-iodoclonidine binding to I 1 R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I 1 Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.

Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance

“…Our present data show that I 1 R ligands can stimulate adiponectin secretion by adipocytes independently of any sympathoinhibition, since LNP509 given intraperitoneally had no impact on cardiovascular parameters and circulating catecholamines. This direct stimulatory action at adipose tissue in vivo was confirmed in primary cultured adipocytes isolated from aged rats and is in agreement with our previous report on cultured 3T3-L1 differentiated adipocytes (7). Transcription of adiponectin is regulated by numerous and complex transduction pathways (35,41,42).…”

“…Experiments were carried out in aged rats that displayed impaired glucose regulation and mild insulin resistance but no other cardiometabolic disorders. Thus, blood pressure and fasting glucose and lipid levels measured in aged animals were similar to those reported in young or healthy animals (7,11,19) and were much lower than those reported in rat models of diabetes or MetS (7,19,43). In order to target only peripheral I 1 R, the LNP509 ligand was administered intraperitoneally.…”

“…On the basis of our previous data (7) and the present results, we propose an adiponectin-mediated improvement of insulin sensitivity as a possible mechanism involved in the peripheral favorable metabolic effects of I 1 R ligands (Fig. 8).…”

“…The following transduction cascade can therefore be proposed: I 1 R ¡ inactivation of adenylate cyclase ¡ 2cAMP ¡ inactivation of SIRT1/ FOXO1 ¡ activation of PPAR␥ ¡ 1adiponectin synthesis. The direct peripheral modulation of adiponectin and AMPK signaling highlighted in the present study probably contributes to the overall beneficial effect on insulin resistance of sympathoinhibitory antihypertensive agents (39,43) and I 1 R ligands (7). Nevertheless, additionnal non-adiponectin mechanisms of action cannot be ruled out.…”

“…Chronic treatment with LNP599 had favorable effects on all the symptoms of MetS, i.e., blood pressure, body weight, glucose tolerance, and lipid profile, and increased plasma adiponectin levels, in a rat model of MetS (spontaneously hypertensive, heart failure rats, SHHF). Additionally, the drug was shown to promote adiponectin synthesis and secretion from cultured 3T3-L1 adipocytes through an I 1 R-dependent mechanism of action (7). These data demonstrated for the first time that imidazoline-like drugs may prove beneficial for the treatment of MetS.…”