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Pharmacokinetic‐haemodynamic relationships of 2‐chloroadenosine at adenosine A 1 and A 2a receptors in vivo
Author(s) -
Mathôt R.A.A.,
Soudijn W.,
Breimer D.D.,
IJzerman A.P.,
Danhof M.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15412.x
Subject(s) - in vivo , antagonist , pharmacology , chemistry , heart rate , mean arterial pressure , blood pressure , receptor , adenosine receptor , adenosine a2a receptor , receptor antagonist , adenosine , hemodynamics , pharmacokinetics , cardiac output , caffeine , medicine , endocrinology , biology , agonist , biochemistry , microbiology and biotechnology
1 The purpose of the present study was to develop an experimental strategy for the quantification of the cardiovascular effects of non‐selective adenosine receptor ligands at the adenosine and A 1 and A 2a receptor in vivo . 2‐Chloroadenosine (CADO) was used as a model compound. 2 Three groups of normotensive conscious rats received an short intravenous infusion of 1.4 mg kg −1 CADO during constant infusions of the A 1 ‐selective antagonist, 8‐cyclopentyltheophylline (CPT; 20 μ m min −1 kg −1 ), the A 2a ‐selective antagonist, 8‐(3‐chlorostyryl)caffeine (CSC; 32 μ m min −1 kg −1 ) or the vehicle. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentrations. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3 During the infusion of CPT, CADO produced a reduction in both blood pressure and MAP/HR by activation 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 (202 and 225 nM) for the reduction of blood pressure and MAP/HR, respectively. During the infusion of CSC, an EC 50,u value of 41 ng ml −1 (136 nM) was observed for the A 1 receptor‐mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affinities ( 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, with the values of −12 ± 1 × 1O −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 information on the potency and intrinsic activity of new non‐selective adenosine receptor agonists at different receptor subtypes in vivo .