Because one manifestation of diabetes is an enhancement of the lipolytic process, we evaluated the antilipolytic effects of adenosine A1 agonists in vitro and in vivo in streptozotocin (STZ)-treated diabetic rats. In vitro, we examined the responses to norepinephrine (NE) and adenosine deaminase (ADA), as well as several adenosine A1 agonists, in isolated adipocytes from normal and diabetic rats. Both NE and ADA caused dose-dependent stimulation of lipolysis, elevating glycerol release twofold to threefold over baseline. The sensitivity to both NE and ADA was significantly enhanced in adipocytes from STZ-treated as compared with normal rats. N-5'-ethyl-N(6)(cyclopentyl) adenosine-5'-uronamide (RG14202) was by far the most potent A agonist in inhibiting NE-stimulated lipolysis [50% effective concentration (EC50): 0.014 +/- 0.0008 nM), approximately 1 and 2 log units more potent than N(6)-cyclopentyladenosine (CPA) and N(6)-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994), respectively. In vivo we established a model for evaluating the therapeutic utility of adenosine A1 agonists, emphasizing duration of action. In STZ rats instrumented with telemetry transmitters, the metabolic effects of CPA, RG14202, and SDZ WAG 994 were assessed 6 h after oral administration. Under those conditions, RG14202 and SDZ WAG 994, but not CPA, significantly reduced triglycerides (TRIs) and TRI/free fatty acids (FFAs), respectively. However, all three A1 agonists dose-dependently reduced mean arterial pressure (MAP) and heart rate (HR) concurrently. Thus adenosine A1 agonists can inhibit lipolysis in vitro and in vivo; however, oral administration produces long-lasting beneficial metabolic effects only at doses that also produce a significant bradycardia.