Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

Abstract

1 The aim of the present investigation was to determine the relationship between the blood concentration and haemodynamic effects of the adenosine Au receptor agonist, CGS 21680C (the sodium salt of 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine) in conscious normotensive rats.2 Chronically cannulated rats were randomly assigned to three groups which received 300, 1000 or 3000 jLg kg-' (0.56, 1.9 or 5.6 pmol kg-') 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 E. model. The concentration-effect relationships were consistent for the different treatment groups. The potency based on free drug concentrations (ECm,u) was 5.8 ng ml' (11 nM) (mean ± s.e.; n = 19) and correlated well with the reported adenosine Au4 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 Au 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 A,4 activation, provided that possible changes of the stroke volume are also assessed.

Tachycardia Caused by A2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

“…The effects of regadenoson on MAP and HR described in the present study are consistent with those reported previously using known selective A 2A agonists (Webb et al, 1990;Koos et al, 1993;Mathot et al, 1995;Nekooeian and Tabrizchi, 1996;Alberti et al, 1997;Schindler et al, 2005). Hence, the decrease in MAP and tachycardia are commonly observed pharmacological effects of A 2A agonists.…”

“…The sinus tachycardia has been attributed to the baroreceptor reflex caused by the decrease in arterial pressure (Webb et al, 1990(Webb et al, , 1991Nekooeian and Tabrizchi, 1996;Alberti et al, 1997). However, there is also evidence that adenosine-mediated tachycardia can occur independent of a decrease in MAP (Lappe et al, 1992;Mathot et al, 1995;Koos and Chau, 1998;Schindler et al, 2005). Thus, the purpose of this study was to establish the role of A 2A adenosine receptors and the mechanism underlying the sinus Regadenososn is highly selective for the A 2A receptor subtype, has a rapid onset and short duration of action, is readily reversible, and causes sinus tachycardia in humans (Gao et al, 2001;Trochu et al, 2003;Hendel et al, 2005).…”

Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

“…However, systemic administration of selective A 2A R agonists can increase HR, probably due to reflex activation secondary to reduced blood pressure (6,31,32,34,35). In addition, there is evidence that there are ARs in the brain stem regulating cardiovascular control centers (2)(3)(4).…”

Involvement of Adenosine A1 and A2A Receptors in the Motor Effects of Caffeine after its Acute and Chronic Administration

“…Adenosine, by acting on both A 1 and A 2A receptors, is implicated in the regulation of motor activity. There is clear experimental evidence for a central mediation of the motor-depressant effects of A 1 and A 2A receptor agonists (Snyder et al, 1981;Katz and Goldberg, 1987;Nikodijevic et al, 1990;Barraco et al, 1993;Marston et al, 1998), independent of their pronounced cardiovascular effects (Appel et al, 1995;Mathot et al, 1995). In contrast, some contradictory results exist regarding the motor-activating effects of adenosine antagonists and there is no consensus about the relative involvement of A 1 and A 2A receptors in caffeine-induced motor activation.…”