Insulin resistance may contribute to non-insulin-dependent diabetes mellitus, hypertension, and dyslipidemia; increased free fatty acid concentrations could both promote and maintain this state of insulin resistance. Therefore, agents that inhibit lipolysis and decrease plasma concentrations of free fatty acids could be of therapeutic interest. We have measured metabolic effects of clonidine, an alpha 2 adrenergic agonist, and adenosine in healthy human subjects since human fat cells have alpha 2 and adenosine A1 receptors, which inhibit lipolysis in vitro. Clonidine, as expected, significantly lowered systolic and diastolic blood pressure; clonidine also decreased the plasma concentration of free fatty acids. Although clonidine caused a transient mild increase in plasma glucose, insulin and triglyceride concentrations were unchanged. The metabolic effects of adenosine were examined with two protocols. In the first study, volunteers received a graded infusion of adenosine (at 0, 10, 20, 50 and 100 micrograms/kg.min for 30 min/dose), and glucose, insulin, free fatty acids, as well as respiratory rate, systolic and diastolic blood pressures, and heart rate were measured. There was no change in glucose, insulin, or free fatty acid concentrations. In the second study a graded infusion was used and was maintained at 100 micrograms/kg/min for 120 minutes. Heart rate and respiratory rate significantly increased. Glucose and free fatty acid concentrations were unchanged, while insulin concentrations were significantly increased. All subjects had significant symptomatic complaints (dyspnea, chest pressure) during the adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)