Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats.
1. The aim of the present investigation was to determine the relationship between the blood concentration and haemodynamic effects of the adenosine A2a receptor agonist, CGS 21680C (the sodium salt of 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethylcarboxamidoadeno sin e) in conscious normotensive rats. 2. Chronically cannulated rats were randomly assigned to three groups which received 300, 1000 or 3000 micrograms kg-1 (0.56, 1.9 or 5.6 mumol kg-1) of CGS 21680C intravenously over 15 min. The mean arterial blood pressure (MAP) and heart rate (HR) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. 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. For each individual rat the reduction in mean arterial pressure was related to the blood concentration according to the sigmoidal Emax model. The concentration-effect relationships were consistent for the different treatment groups. The potency based on free drug concentrations (EC50,u) was 5.8 ng ml-1 (11 nM) (mean +/- s.e.; n = 19) and correlated well with the reported adenosine A2a receptor affinity (Ki 19 nM). In comparison with the reduction in blood pressure, CGS 21680C exhibited a greater potency for the reduction of the ratio MAP/HR. 4. It is concluded that estimates can be obtained for the potency and intrinsic activity of adenosine A2a receptor agonists in vivo by pharmacokinetic-pharmacodynamic analysis of mean arterial pressure data in a rat model. In future studies, total peripheral resistance may also be useful as a pharmacodynamic parameter for A24 activation, provided that possible changes of the stroke volume are also assessed.
Mathôt
R A
RA
Division of Pharmacology, University of Leiden, The Netherlands.
Cleton
A
A
Soudijn
W
W
IJzerman
A P
AP
Danhof
M
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D008956:Models, Chemical; D010627:Phenethylamines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D012044:Regression Analysis; D013047:Specific Pathogen-Free Organisms; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000959:Antihypertensive Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine