Lack of adenosine A1 and dopamine D2 receptor-mediated modulation of the cardiovascular effects of the adenosine A2A receptor agonist CGS 21680

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Abstract

Some behavioral and biochemical effects of the systemically administered adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS 21680) in rats are potentiated by adenosine A1 receptor agonists and counteracted by dopamine D2 receptor agonists. In the present study we compared potentiating and antagonistic interactions between CGS 21680 and adenosine A1 and dopamine D2 receptor agonists on motor activity and on cardiovascular responses (arterial blood pressure and heart rate). The motor-depressant effects produced by CGS 21680 (0.5 mg/kg, i.p.) were potentiated by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 0.3 mg/kg, i.p.) and counteracted by the dopamine D2 receptor agonist quinpirole (0.5 mg/kg, i.p.). In contrast, neither CPA nor quinpirole significantly modified the decrease in arterial pressure or the increase in heart rate induced by CGS 21680. However, the adenosine A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3, 3 mg/kg, i.p.) counteracted both the motor-depressant and cardiovascular effects of CGS 21680. Therefore, the effects of the systemically administered adenosine A2A receptor agonist CGS 21680 on cardiovascular function, in contrast to its effects on motor behavior, appear to be independent of the effects of adenosine A1 and dopamine D2 receptor activity.

Introduction

Adenosine is a potent modulator of cardiovascular function. Its effects are mostly depressant and involve both central and peripheral mechanisms as well as different adenosine receptor subtypes, mostly adenosine A1, A2A and A2B receptors Shryock and Belardinelli, 1997, Spyer and Thomas., 2000, Tabrizchi and Bedi, 2001, Scislo et al., 2001). Adenosine A1 and A2A receptors are found in blood vessels and in cardiac tissue (Shryock and Belardinelli, 1997), as well as in the nucleus tractus solitarius, the major relay nucleus for the central processing of cardiovascular control Castillo-Meléndez et al., 1994, St. Lambert et al., 1996, Rosin et al., 1998. Systemic administration of adenosine A1 or adenosine A2A receptor agonists produces hypotension and it is currently believed that these effects are mostly due to a direct cardiac depressant effect of adenosine A1 receptor agonists and to a direct peripheral vasodilatation induced by adenosine A2A receptor agonists Evoniuk et al., 1987, Appel et al., 1995, Mathot et al., 1995a. Local administration of adenosine A2A receptor agonists in the nucleus tractus solitarius produces a pronounced decrease in blood pressure and heart rate, while adenosine A1 receptor agonists produce the opposite effects (Barraco et al., 1991). Therefore, central adenosine A2A receptors appear also to play some role in the hypotensive effects induced by the systemic administration of adenosine A2A receptor agonists.

Adenosine A2A receptors located centrally in the striatum seem to be mainly responsible for some behavioral and biochemical effects of peripherally administered adenosine A2A receptor agonists, which include depression of motor activity and expression of immediately early genes (Nikodijevic et al., 1990, Nikodijevic et al., 1991, Karcz-Kubicha et al., 2003a, Karcz-Kubicha et al., 2003b. These centrally mediated effects of adenosine A2A receptor agonists can be potentiated by co-administration of adenosine A1 receptor agonists and counteracted by dopamine D2 receptor agonists (Nikodijevic et al., 1990, Nikodijevic et al., 1991, Ferré et al., 1991, Karcz-Kubicha et al., 2003a, Karcz-Kubicha et al., 2003b. In the present study, we compared the effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the dopamine D2 receptor agonist quinpirole on adenosine A2A receptor-mediated cardiovascular and motor activity effects induced by systemic administration of 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS 21680). In contrast to the effects on motor activity Nikodijevic et al., 1990, Nikodijevic et al., 1991 and striatal immediate-early gene expression (Karcz-Kubicha et al., 2003b), the effects of the adenosine A2A receptor agonist CGS 21680 on cardiovascular function were found to be independent of the effects of adenosine A1 receptor and dopamine D2 receptor agonists.

Section snippets

Subjects and drugs

Male Sprague–Dawley rats, weighing 300–350 g, were used in all experiments. Animals were maintained in accordance with guidelines of the Institutional Animal Care and Use Committee of the Intramural Research Program, National Institute on Drug Abuse, NIH. The adenosine A1 receptor agonist CPA, the adenosine A2A receptor agonist CGS 21680 and the dopamine D2 receptor agonist quinpirole hydrochloride (quinpirole) were purchased from Sigma (St. Louis, MO). The adenosine A2A receptor antagonist

Results

Administration of either the adenosine A1 receptor or the adenosine A2A receptor agonist produced a pronounced depression of locomotor activity and their co-administration produced a significantly stronger depression of locomotor activity than when administered alone (Fig. 1). The depressant effects of both adenosine receptor agonists were less pronounced and a significant potentiating effect was not observed when general motor activity was measured. This might reflect a higher sensitivity of

Discussion

We have recently shown that the systemic administration of the adenosine A1 receptor agonist CPA potentiates and the dopamine D2 receptor agonist quinpirole counteracts an increase in striatal expression of c-fos induced by the systemic administration of the adenosine A2A receptor agonist CGS 21680 (Karcz-Kubicha et al., 2003b). In view of the possible therapeutic implications of these findings (see below), in the present study, we analyzed the cardiovascular effects of the combined systemic

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