RT Journal Article
SR Electronic
T1 <em>N</em>-[3-(<em>R</em>)-Tetrahydrofuranyl]-6-aminopurine Riboside, an  A<sub>1</sub> Adenosine Receptor Agonist, Antagonizes  Catecholamine-Induced Lipolysis without  Cardiovascular Effects in Awake Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 225
OP 231
DO 10.1124/jpet.102.046821
VO 305
IS 1
A1 Heather Fraser
A1 Zhenhai Gao
A1 Mark J. Ozeck
A1 Luiz Belardinelli
YR 2003
UL http://jpet.aspetjournals.org/content/305/1/225.abstract
AB Elevated serum nonesterified free fatty acid (NEFA) concentrations are detrimental to both the mechanical and electrical function of the heart. A1 adenosine receptor agonists are potent and efficacious inhibitors of lipolysis; however, their cardiovascular effects have limited their use to lower serum NEFA. Our objective was to determine whether the antilipolytic effect ofN-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), an A1 agonist, could be distinguished from its bradycardia effect and demonstrated in rats with normal or elevated serum NEFA. Rats were instrumented with telemetry transmitters for continuous recording of heart rate, and catheterized, for delivery of drugs and blood sampling. CVT-510 caused a rapid and sustained dose-dependent decrease in NEFA at doses that did not cause bradycardia (2, 5, and 20 μg/kg). Significant bradycardia was observed at 50 μg/kg. Norepinephrine (NE) increased NEFA from 0.5 ± 0.01 to 0.9 ± 0.2 mM and this effect lasted for 2 h. CVT-510 (10 μg/kg) given at 40 min postinjection of NE reversed the rise in NEFA (69% reduction). When CVT-510 (20 μg/kg) was given 15 min before a 30-min long infusion of NE, the lipolytic response to NE was prevented. To mimic the antilipolytic effect of CVT-510 in awake rats, hearts were perfused with palmitate at concentrations similar to those observed in the in vivo studies (0.8 and 0.2 mM), which decreased myocardial oxygen consumption (MVO2) by 11%. Thus, CVT-510 at doses ≥5-fold lower than those that slow heart rate caused a marked and sustained lowering of normal or elevated NEFA, that when mimicked in vitro decreased MVO2 and would be expected to improve cardiac efficiency. The American Society for Pharmacology and Experimental Therapeutics