Vol. 305, Issue 1, 225-231, April 2003

N-[3-(R)-Tetrahydrofuranyl]-6-aminopurine Riboside, an A₁ Adenosine Receptor Agonist, Antagonizes Catecholamine-Induced Lipolysis without Cardiovascular Effects in Awake Rats

Heather Fraser¹, Zhenhai Gao¹, Mark J. Ozeck and Luiz Belardinelli

CV Therapeutics, Palo Alto, California

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 of N-[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.