Vol. 287, Issue 1, 21-30, October 1998

Metabolic and Cardiovascular Effects of the Adenosine A₁ Receptor Agonist N⁶-(p-Sulfophenyl)Adenosine in Diabetic Zucker Rats: Influence of the Disease on the Selectivity of Action

E. A. van Schaick, K. P. Zuideveld, H. E. Tukker, M. W. E. Langemeijer, A. P. Ijzerman and M. Danhof

Leiden/Amsterdam Center for Drug Research, Divisions of Pharmacology (E.A.V.S., K.P.Z., E.E.T., M.W.E.L., M.D.) and Medicinal Chemistry (A.P.IJ.), 2300 RA Leiden, The Netherlands

Studies were designed to investigate differences in pharmacokinetics and pharmacodynamics of the adenosine A₁ receptor agonist N⁶-(p-sulfophenyl)adenosine (SPA) between lean and obese Zucker rats. In conscious rats, time courses of the effect on heart rate and parameters of lipid metabolism (fatty acids, glycerol) were monitored in combination with the decline of drug concentrations after i.v. administration of 100 µg SPA in 15 min. Small differences in pharmacokinetics of SPA were observed between lean and obese rats. Values for clearance and volume of distribution were 1.2 ± 0.2 ml/min and 88 ± 10 ml in lean, and 1.6 ± 0.1 ml/min and 110 ± 7 ml in obese animals, respectively. Modelling of the concentration-heart rate relationship on the basis of the sigmoidal E_max model revealed no difference in EC₅₀ (99 ± 12 and 118 ± 17 ng/ml) or E_max (191 ± 16 and 185 ± 22 bpm) between the lean and obese rats. The metabolic effects of SPA were totally different between lean and obese rats. Potent (EC₅₀ = 18 ± 3 ng/ml) inhibition of lipolysis was observed in the lean rats. In obese rats, SPA was less potent (EC₅₀ = 109 ± 36 ng/ml) resulting in short lasting antilipolytic effect. Furthermore, administration of SPA resulted in a significant decrease in insulin concentrations. These findings show that changes in glucose and lipid metabolism may be associated with an altered sensitivity to the antilipolytic actions of adenosine A₁ receptor agonists.