PHARMACOKINETIC-HEMODYNAMIC RELATIONSHIPS OF 2-CHLOROADENOSINE AT ADENOSINE A(1) AND A(2A) RECEPTORS IN-VIVO

1 The purpose of the present study was to develop an experimental stra tegy for the quantification of the cardiovascular effects of non-selec tive adenosine receptor ligands at the adenosine A(1) and A(2a) recept or in vivo. 2-Chloroadenosine (CADO) was used as a model compound. 2 T hree groups of normotensive conscious rats received an short intraveno us infusion of 1.4 mg kg(-1) CADO during constant infusions of the A(1 )-selective antagonist, 8-cyclopentyltheophylline (CPT; 20 mu g min(-1 ) kg(-1)), the A(2a)-selective antagonist, 8-(3-chlorostyryl)caffeine (CSC; 32 mu g min(-1) kg(-1)) or the vehicle. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded continuously during t he experiment and serial arterial blood samples were taken for analysi s of drug concentrations. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption t hat no changes in stroke volume occur. 3 During the infusion of CPT, C ADO produced a reduction in both blood pressure and MAP/HR by activati on of the A(2a) receptor. The concentration-effect relationships were described according to the sigmoidal E(max) model, yielding potencies based on free drug concentrations (EC(50,u)) of 61 and 68 ng ml(-1) (2 02 and 225 nM) for the reduction of blood pressure and MAP/HR, respect ively. During the infusion of CSC, an E(50,u) value of 41 ng ml(-1) (1 36 nM) was observed for the A(1) receptor-mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affiniti es (K-i(A(1)) = 300 nM and K-i(A(2a)) = 80 nM). The maximal reductions in MAP/HR and heart rate were comparable to those of full agonists, w ith the E(max) values of -12+/-1x10(-2) mmHg b.p.m.(-1) and -205 b.p.m . respectively. 4 It is concluded that this integrated pharmacokinetic -pharmacodynamic approach can be used to obtain quantitative informati on on the potency and intrinsic activity of new non-selective adenosin e receptor agonists at different receptor subtypes in vivo.