N-[3-(R)-Tetrahydrofuranyl]-6-aminopurine Riboside, an A₁Adenosine Receptor Agonist, Antagonizes Catecholamine-Induced Lipolysis without Cardiovascular Effects in Awake Rats

Abstract

Elevated serum nonesterified free fatty acid (NEFA) concentrations are detrimental to both the mechanical and electrical function of the heart. A 1 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 A 1 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 g/kg). Significant bradycardia was observed at 50 g/kg. Norepinephrine (NE) increased NEFA from 0.5 Ϯ 0.01 to 0.9 Ϯ 0.2 mM and this effect lasted for 2 h. CVT-510 (10 g/kg) given at 40 min postinjection of NE reversed the rise in NEFA (69% reduction). When CVT-510 (20 g/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 (MVO 2 ) by 11%. Thus, CVT-510 at doses Ն5-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 MVO 2 and would be expected to improve cardiac efficiency.

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

“…These data are consistent with previous reports showing that other A 1 agonists decrease FFA levels (Hoffman et al, 1986b;Gardner et al, 1994;Fraser et al, 2003;Schoelch et al, 2004). The FFA-lowering effect of CVT-3619 was completely antagonized by pretreatment with an A 1 antagonist, DPCPX, confirming that these effects are mediated via A 1 receptors.…”

“…The antilipolytic actions of adenosine that are mediated by A 1 receptors have been known for many years (Hoffman et al, 1986b;Gardner et al, 1994;Fraser et al, 2003;Schoelch et al, 2004). The metabolic responses after acute administration of many A 1 agonists have been reported previously; however, no compound has been developed and approved for clinical use thus far.…”

“…The cardiac effects mediated by A 1 receptors include slowing of heart rate and atrioventricular nodal conduction, and depression of atrial contractility (Belardinelli et al, 1989). However, due to a greater receptor reserve in adipose tissue compared with cardiac tissue (Wu et al, 2001;Liang et al, 2002), significant antilipolytic effects of A 1 agonists have been reported at doses that have either minimal or no cardiac effects (Gardner et al, 1994;Fraser et al, 2003). These findings suggest that it is possible to achieve organ selectivity for A 1 receptor-mediated responses.…”

“…A 1 adenosine receptor agonists are well recognized antilipolytic agents due to their effect of reducing the formation and release of FFA from adipose tissue (Hoffman et al, 1986b;Gardner et al, 1994;Dhalla et al, 2003;Fraser et al, 2003;Schoelch et al, 2004;Fatholahi et al, 2006). A 1 agonists reduce lipolysis [breakdown of triglyceride (TG) to FFA] in adipose tissue by inhibiting adenylyl cyclase activity and cAMP formation (Fain et al, 1972;Schwabe et al, 1974).…”

Adenosine receptors as therapeutic targets

“…Arrhythmia A 1 AR activation has a number of effects in the cardiovascular system, including a reduction in heart rate and atrial contractility, and the attenuation of the stimulatory actions of catecholamines on the heart 63,64 . Activation of the A 1 AR by intravenous infusion of adenosine (Adenocard; Astellas Pharma) is used to restore normal heart rhythm in patients with paroxysmal supraventricular tachycardia (PSVT).…”