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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.114421v1 321/1/327    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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Dhalla, A. K. Articles by Belardinelli, L. Search for Related Content PubMed PubMed Citation Articles by Dhalla, A. K. Articles by Belardinelli, L.

ENDOCRINE AND DIABETES

Antilipolytic Activity of a Novel Partial A₁ Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Department of Pharmacology, CV Therapeutics, Inc., Palo Alto, California

Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A₁ adenosine receptor agonists are potent inhibitors of lipolysis. Several A₁ agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino] purin9-yl} (4S,5 S,2R,3R)5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A₁ receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A₁ receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p < 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A₁ agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

Address correspondence to: Dr. Arvinder Dhalla, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: arvinder.dhalla{at}cvt.com

This article has been cited by other articles:

				J. Shearer, D. L. Severson, L. Su, L. Belardinelli, and A. K. Dhalla Partial A1 Adenosine Receptor Agonist Regulates Cardiac Substrate Utilization in Insulin-Resistant Rats in Vivo J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 306 - 311. [Abstract] [Full Text] [PDF]

				A. K. Dhalla, M. Y. Wong, P. J. Voshol, L. Belardinelli, and G. M. Reaven A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1358 - E1363. [Abstract] [Full Text] [PDF]