N-[3-(R)-tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats.

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 micro g/kg). Significant bradycardia was observed at 50 micro g/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 micro g/kg) given at 40 min postinjection of NE reversed the rise in NEFA (69% reduction). When CVT-510 (20 micro 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 > or =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 MVO(2) and would be expected to improve cardiac efficiency.

Tonic activity of the rat adipocyte A1-adenosine receptor.

1. Adipocyte A(1)-adenosine receptors (A(1) AdoR) tonically inhibit adenylyl cyclase and lipolysis. Three potential explanations for tonic activity of A(1)AdoR of rat epididymal adipocytes were investigated: high affinity of adenosine for the receptor, efficient coupling of receptor activation to response, and spontaneous activity of the receptor in the absence of agonist. 2. The affinity of adenosine for the adipocyte A(1)AdoR was determined as 4.6 microM by analysis of effects of an irreversible receptor antagonist on agonist concentration-response relationships. In contrast, the potency of adenosine to decrease cyclic AMP in isolated adipocytes was 1.4 nM. 3. Occupancy by agonist of the A(1)AdoR was efficiently coupled to functional response (decrease of adipocyte cyclic AMP content). Activation by adenosine of less than 1% of A(1)AdoRs caused a near-maximal decrease of cyclic AMP in adipocytes. Thus the receptor reserve for adenosine to decrease cyclic AMP content of adipocytes was greater than 99%. 4. Affinities and receptor reserves for other A(1)AdoR agonists were determined. Agonists appeared to differ more in their affinity for the receptor than in their intrinsic efficacy to activate it. 5. A(1)AdoRs were inactive in the absence of agonist. 6. It is concluded that adipocyte A(1)AdoR are tonically activated by endogenous adenosine at nanomolar concentrations. The expression of a high density of A(1)AdoR that are efficiently coupled to a functional response enables the adipocyte to respond with high sensitivity to the low-affinity agonist, adenosine. Adipocytes may be a model for cells whose functions are tonically modulated by adenosine present in the interstitium of well-oxygenated tissues.