Pharmacokinetic‐haemodynamic relationships of 2‐chloroadenosine at adenosine A₁ and A_2a receptors in vivo

Abstract

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 Al and A2A 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-' CADO during constant infusions of the Al-selective antagonist, 8-cyclopentyltheophylline (CPT; 20 yig min-' kg-'), the A2u-selective antagonist, 8-(3-chlorostyryl)caffeine (CSC; 32 yg min' kg-') 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 A2, receptor. The concentration-effect relationships were described according to the siginoidal E. model, yielding potencies based on free drug concentrations (EC50,u) of 61 and 68 ng ml-' (202 and 225 nM) for the reduction of blood pressure and MAP/HR, respectively. During the infusion of CSC, an EC50,u value of 41 ng ml-' (136 nM) was observed for the Al receptor-mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affinities (Ki(Al) = 300 nM and Ki(Au) = 80 nM). The maximal reductions in MAP/HR and heart rate were comparable to those of full agonists, with the E,,, values of -12+1 x 10-2 mmHg b.p.m.r 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.

Effects of adenosine receptor agonist on the rocuroniuminduced neuromuscular block and sugammadex-induced recovery

“…With micromolar concentrations of ADO, the evoked quantal release or spontaneous release of ACh was decreased [ 16 , 17 ]; whereas, the opposite effect was exerted when submicromolar concentrations of ADO at the neuromuscular junction were made [ 18 ]. However, the inhibitory coefficients (Ki) for rat A 1 and A 2A receptors were 300 and 80 nM, respectively [ 19 ]. In other words, the affinity of CADO to A 1 receptor is relatively lower than that to A 2A receptors; hence, A 2A receptor activation might occur first at lower CADO concentrations.…”

Adenosine relaxation in isolated rat aortic rings and possible roles of smooth muscle Kv channels, KATP channels and A2a receptors

“…These inhibitors were applied to intact endothelium rings in the presence of L-NAME and indomethacin, and without the presence of L-NAME and indomethacin in denuded aortic rings. The adenosine A 2a receptor inhibitor was 100 μM 8-(3-chlorostyryl) caffeine (CSC) [ 35 , 36 ], and the A 2b receptor inhibitor was 10 μM 8-(4-(4-(4-chlorobenzyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (PSB-0788) [ 37 ]. In rat striatal membranes, these antagonists have reported K i values of 24 nM for CSC [ 38 ] and 0.393 nM for PSB-0788 [ 37 ], and the micromolar concentrations used in the present study were based on previous published studies [ 39 – 41 ].…”

The impact of commercially available purinergic ligands on purinergic signalling research

“…Interestingly, ZM 2141385 a potent A 2A receptor antagonist (K i value=255 nM, 1 nM, 50 nM and >19 μM at A 1 , A 2A , A 2B and A 3 ) [19], has also been implicated in neurodegeneration and similarly to caffeine has been shown to afford neuroprotection in Alzheimer's disease models by protecting against β-amyloid neurotoxicity [60]. Furthermore in a Parkinson's disease model, ZM 241385 has also been shown to enhance L-DOPA-induced dopamine release by antagonising the A 2A receptor, suggesting potential therapeutic use [60].…”