QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.143594v1 328/1/306    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shearer, J. Articles by Dhalla, A. K. Search for Related Content PubMed PubMed Citation Articles by Shearer, J. Articles by Dhalla, A. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE

CARDIOVASCULAR

Partial A₁ Adenosine Receptor Agonist Regulates Cardiac Substrate Utilization in Insulin-Resistant Rats in Vivo

Departments of Biochemistry and Molecular Biology (J.S., L.S.) and Pharmacology and Therapeutics (D.L.S.), Faculty of Medicine and Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada (J.S., L.S.); and Department of Pharmacological Sciences, CV Therapeutics, Palo Alto, California (L.B., A.K.D.)

Reducing the availability and uptake of fatty acids is a plausible pharmaceutical target to ameliorate glucose intolerance and insulin resistance. CVT-3619 [2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino]purin-9-yl(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol] is a partial A₁ adenosine receptor agonist with antilipolytic properties. Aims of the present study were to examine the acute effects of CVT-3619 on whole-body and cardiac glucose and fatty acid kinetics in vivo in normal and diet-induced insulin-resistant rats. Male Sprague-Dawley rats were fed either a chow (CH) or high-fat (HF) diet for 4 weeks. Catheters were then chronically implanted in the carotid artery and jugular vein for sampling and infusions, respectively. After 5 days of recovery, fasted animals (10 h) received either saline or CVT-3619 (0.4 mg/kg bolus + 1 mg/kg/h). Indices of glucose and fatty acid utilization were obtained by the administration of 2-deoxy[¹⁴C]glucose and [9,10-³H]-(R)-2-bromopalmitate. HF feeding resulted in elevated, fasting insulin and free fatty acid (FFA) levels compared with CH. CVT-3619 caused a 64 and 86% reduction of FFA and insulin in HF (p < 0.05) but less (N.S.) in CH diet-fed animals. In HF diet-fed rats, CVT-3619 increased whole-body glucose clearance with no change in fatty acid kinetics. Likewise, analysis of cardiac tissue metabolism showed that CVT-3619 caused an increased glucose but not fatty acid clearance in HF-fed animals. Results show that the acute administration of CVT-3619 lowers circulating fatty acid levels, leading to improved whole-body and cardiac glucose clearance in a model of diet-induced insulin resistance. As such, CVT-3619 may be a treatment option for the restoration of substrate balance in the insulin-resistant heart.

Address correspondence to: Dr. Jane Shearer, Biochemistry and Molecular Biology, 2500 University Drive NW, University of Calgary, Calgary, Alberta, Canada T2N 1N4. E-mail: jshearer{at}ucalgary.ca