Cardiovascular Effects of Adenosine Derivatives in Conscious Normotensive Rats

M, Milavec-Krizman; Wagner, H.; Kralj, A.; Evenou, Jean-Pierre; Gadient, F.

doi:10.1080/07328319108047252

Cited by 8 publications

(4 citation statements)

References 6 publications

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“…The observed pharmacokinetic parameters were in accordance with previously reported values (Chovan et al, 1992). Intravenous infusion of CGS 21680C produced a reduction in blood pressure (Figure 2), which corresponded to reported observations for adenosine A2, receptor activation in the rat (Abiru et al, 1991;Webb et al, 1991;Milavec-Krizman et al, 1991). The hypotensive effect of CGS 21680C was reversible and the blood pressures of drug-treated rats were not significantly different from those of vehicle-treated rats after 110min.…”

Section: Discussionsupporting

confidence: 91%

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

Mathôt

Cleton

Soudijn

et al. 1995

British J Pharmacology

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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.

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Section: Discussionsupporting

confidence: 91%

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

Mathôt

Cleton

Soudijn

et al. 1995

British J Pharmacology

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“…administration of the adenosine agonists are consistent with reported A 1 receptor-mediated effects in normotensive (Milavec-Krizman 1991;Mathôt et al 1994) and hypertensive rats (Webb et al 1990;Abiru et al 1991). In a previous study, a PK/PD modelling approach has been developed for the in vivo quantification of the cardiovascular effects of CPA (Mathôt et al 1994).…”

Section: Discussionsupporting

confidence: 62%

Time course of action of three adenosine A1 receptor agonists with differing lipophilicity in rats: comparison of pharmacokinetic, haemodynamic and EEG effects

Schaick

Kulkarni

Künzel

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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In this study we investigated the relationship between the pharmacokinetics and the cardiovascular and electroencephalogram (EEG) effects of three adenosine agonists with differing lipophilicity. Conscious normotensive rats received either 600 microg/kg N6-(p-sulphophenyl) adenosine (SPA), 200 microg/kg N6-cyclopentyladenosine (CPA) or 600 microg/kg 1-deaza-2-chloro-N6-cyclopentyladenosine (DCCA) in a 5-min intravenous infusion. Changes in haemodynamics and EEG were monitored in conjunction with arterial blood sampling to determine blood concentrations of the compounds. The three adenosine agonists showed large differences in pharmacokinetic properties, resulting in terminal half-lives of 66 +/- 10, 8.2 +/- 0.4 and 24 +/- 1 min (mean +/- SEM) for SPA, CPA, and DCCA respectively. SPA had a significantly lower blood clearance relative to CPA and DCCA, whereas DCCA had the largest volume of distribution and degree of plasma protein binding. The relationship between concentration and heart rate could be described adequately by the sigmoidal Emax model. For SPA, CPA, and DCCA the EC50 values based on free drug concentrations were 423 +/- 92, 1.8 +/- 0.4 and 9.5 +/- 1.1 nM respectively. These in vivo values correlated closely with the affinity of the compounds for the adenosine A1 receptor as determined in radioligand binding studies, with corresponding Ki values of 1410 +/- 220, 4.7 +/- 0.6 and 102 +/- 74 nM (mean +/- SEM) respectively. In the EEG, only CPA produced a small decrease in the amplitude of beta waves. This study demonstrates that the three adenosine analogues have large differences in pharmacokinetics, which complicates comparison of their cardiovascular and central responses simply on the basis of dose. The application of an integrated PK/PD approach permits estimates of potency and activity which are independent of underlying dose and pharmacokinetics.

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“…Adenosine produces its physiological effects by interaction with membrane-bound receptors, called PI receptors, of which currently four subtypes have been defined, Al, Au, A2b and A3 (Abbrachio et al, 1993). The cardiovascular responses mediated by Al and Au receptor subtypes have been studied in conscious normotensive and hypertensive rats (Webb et al, 1990;Abiru et al, 1991;Milavec-Krizman et al, 1991). In these studies, the hypotensive effect elicited was independent of the Aland Au-selectivity of the compounds, whereas the opposite was observed for the effect on heart rate.…”

Section: Introductionmentioning

confidence: 99%

“…Selective Al receptor agonists caused significant bradycardia, whereas AU, agonists promoted a strong reflex tachycardia. It has therefore been suggested that adenosine receptor agonists with a balanced Aland A2-selectivity may be useful as antihypertensive drugs, since hypotension may be produced without an unfavourable effect on heart rate (Milavec-Krizman et al, 1991). In principle, these drugs may be partial agonists and/or full agonists for the two receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

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

Mathôt

Soudijn

Breimer

et al. 1996

British J Pharmacology

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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.

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Cardiovascular Effects of Adenosine Derivatives in Conscious Normotensive Rats

Cited by 8 publications

References 6 publications

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

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

Time course of action of three adenosine A1 receptor agonists with differing lipophilicity in rats: comparison of pharmacokinetic, haemodynamic and EEG effects

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

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Cardiovascular Effects of Adenosine Derivatives in Conscious Normotensive Rats

Cited by 8 publications

References 6 publications

Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

Time course of action of three adenosine A1 receptor agonists with differing lipophilicity in rats: comparison of pharmacokinetic, haemodynamic and EEG effects

Pharmacokinetic‐haemodynamic relationships of 2‐chloroadenosine at adenosine A1 and A2a receptors in vivo

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

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

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