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

Studies were designed to investigate differences in pharmacokinetics and pharmacodynamics of the adenosine A1 receptor agonist N-(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 mg 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 6 0.2 ml/min and 88 6 10 ml in lean, and 1.6 6 0.1 ml/min and 110 6 7 ml in obese animals, respectively. Modelling of the concentration-heart rate relationship on the basis of the sigmoidal Emax model revealed no difference in EC50 (99 6 12 and 118 6 17 ng/ml) or Emax (2191 6 16 and 2185 6 22 bpm) between the lean and obese rats. The metabolic effects of SPA were totally different between lean and obese rats. Potent (EC50 5 18 6 3 ng/ml) inhibition of lipolysis was observed in the lean rats. In obese rats, SPA was less potent (EC50 5 109 6 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. Adenosine A1 receptor agonists may be used as modulators of glucose and lipid metabolism (Hoffman et al., 1986) in NIDDM. NIDDM is generally characterized by a decreased action of insulin, which is associated with an elevation of circulating NEFA. These elevated NEFA concentrations diminish the insulin-induced glucose utilization (Ferrannini et al., 1983), glucose oxidation and suppression of hepatic glucose production in normal, obese and NIDDM subjects (Reaven and Chen, 1988). Inhibitors of fatty acid release from adipocytes (e.g., adenosine A1 receptor agonists) suppress these elevated NEFA concentrations and offer the potential of reducing hyperglycemia via the so-called glucosefatty acid cycle (Foley, 1992). Selective adenosine A1 receptor agonists have been developed as antilipolytic agents and have been shown to lower plasma circulating NEFA concentrations in normal (Strong et al., 1993) and streptozotocin-induced diabetic rats (Reaven et al., 1988). A major drawback for the use of A1 receptor agonists in type 2 diabetes is the occurance of severe hemodynamic actions after peripheral administration (Jacobson et al., 1991). Recent in vitro studies, however, have shown that the antilipolytic effects occur at lower concentrations of A1 receptor agonists than the hemodynamic depressor effects (Gurden et al., 1993). In normal Wistar rats, an integrated pharmacokinetic-pharmacodynamic modelling approach was used to investigate the in vivo selectivity of action of the adenosine A1 receptor agonist SPA. In these experiments the EC50 for the antilipolytic effect was 6-fold lower than the EC50 for the effect on heart rate (Van Schaick et al., 1997a). It is, however, important to investigate whether changes in selectivity of action occur in disease due to adaptive alterations in pharmacokinetics or pharmacodynamics. NIDDM is frequently associated with obesity, which may influence the distribution and clearance of compounds (Shum and Jusko, 1984). In addition, high levels of free fatty acids may compete for plasma protein binding and as such affect active drug concentrations. Furthermore, alterations at the adenosine receptor level have been reported in animal models (VanReceived for publication February 6, 1997. ABBREVIATIONS: SPA, N-(p-sulfophenyl)adenosine; NIDDM, non-insulin-dependent diabetes mellitus; NEFA, nonesterified fatty acids; CPA, N-cyclopentyladenosine; P/B, plasma-to-blood ratio; fu, free fraction in plasma; HPLC, high performance liquid chromatography; AUC, area under the concentration-time curve; MAP, mean arterial pressure. 0022-3565/98/2871-0021$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 1 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 287:21–30, 1998 21 at A PE T Jornals on A ril 7, 2017 jpet.asjournals.org D ow nladed from nucci et al., 1990) and human obesity (Kaartinen et al., 1994). Disease-induced changes in the adenosine receptor-effector complex on adipocytes may influence the effectiveness and tissue selectivity of adenosine analogues in NIDDM. The purpose of the present study was to investigate the pharmacokinetic-pharmacodynamic relationship of the adenosine A1 receptor agonist SPA in an insulin-resistant animal model of NIDDM. SPA was choosen as a model compound since it is a selective A1 adenosine receptor agonist with a modest potency. As a result the plasma concentrations required for suppression of lipolysis are rather high. By selecting SPA as a model compound it is possible to determine the complete plasma concentration versus time profile in the pharmacokinetic-pharmacodynamic experiments. An additional advantage of SPA is that as a result of the low lipophilicity, it is expected to cross the blood-brain barrier with difficulty. This diminishes the contribution of central effects to the pharmacodynamics in vivo. The successful analysis of the haemodynamic and antilipolytic effects of SPA has been convincingly demonstrated in previous investigations (Van Schaick et al., 1997a; Van Schaick et al., in press). The genetically obese Zucker rat (fa/fa) is a useful animal model of insulin resistance in NIDDM (McCaleb and Sredy, 1992) and obesity (Bray, 1977). The obese Zucker rats are characterized by mild hyperglycaemia, abnormal oral glucose tolerance (Rohner-Jeanrenaud et al., 1986) and insulin-resistance of both liver and muscle tissue (Terrattaz et al., 1986). These metabolic abnormalities in the obese rats are inherited as a single gene defect (Zucker and Zucker, 1961) and are not present in the lean (Fa/?) Zucker rats. The effects on both hemodynamics and lipid metabolism were investigated after intravenous administration of SPA. For both effects, concentration-effect relationships were determined and quantified on the basis of integrated pharmacokinetic-pharmacodynamic models. The pharmacokinetic and pharmacodynamic parameters were used to detect differences between lean and obese animals and to investigate the selectivity of action of SPA between lipid metabolism and hemodynamics.