Ca2+ dependence of the response of three adenosine type receptors in rat hepatocytes

The effect of three different receptor-specific adenosine agonists on the rate of ureagenesis by isolated rat hepatocytes and the dependence on the external free Ca2+ concentration ([Ca2+]e) were investigated. In the presence of high [Ca2+]e all adenosine receptor agonists increased ureagenesis to similar levels. However, with low [Ca2+]e the effects of each agonist varied as follows: (i) the adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyl-adenosine, increased ureagenesis depending partially on [Ca2+]e, (ii) the adenosine receptor A2 agonist, 2-p-(-2-carboxy-ethyl) phenethylamino-5'-N-ethylcarboxyamido adenosine hydrochloride, increased ureagenesis independently of [Ca2+]e and (iii) in contrast, the adenosine receptor A3 agonist N6-2-(-4-aminophenyl) ethyladenosine, increased ureagenesis only in the presence of high [Ca2+]e. The adenosine receptor A1 antagonist, 1-allyl-3,7-dimethyl-8-phenyl xanthine, inhibited the effect of the adenosine receptor A1 agonist on ureagenesis, but not the effect of the adenosine A2 or A3 receptor agonists. The adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine, inhibited only the effect of the adenosine A2 receptor agonist. Thus, in addition to A1 and A2 type adenosine receptors, rat hepatocytes possess an A3-like adenosine receptor which responds to the addition of an adenosine A3 agonist by accelerating ureagenesis a [Ca2+]e dependent manner. Moreover, it was observed that in the presence of extracellular Ca2+ each agonist increased [Ca2+]i and this effect was inhibited by the appropriate specific antagonist.