Effect of adenosine and adenosine analogues on cyclic AMP accumulation in cultured mesangial cells and isolated glomeruli of the rat

1 Changes in intracellular levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) were studied in rat isolated glomeruli and cultured glomerular mesangial cells exposed to adenosine and to the preferential A 1 receptor agonist N 6 ‐ R ‐1‐methyl‐2‐phenylethyl adenosine ( R ‐PIA), or the potent A 2 adenosine receptor agonist 5‐(N‐ethylcarboxamide)adenosine (NECA). 2 Whereas NECA and adenosine triggered a dose‐dependent increase in cyclic AMP values with EC 50 values of approximately 10 −6 m and 3 × 10 −5 m respectively, R ‐PIA lowered cyclic AMP levels at concentrations of 10 −6 m or less and increased them at higher concentrations. 3 The time‐course of the increase induced by 10 −6 m NECA was slower than that induced by 10 −4 m adenosine. Adenosine produced a maximal stimulation within the first minute, whereas the effect of NECA in both glomeruli and mesangial cells was noticeable only from the second minute of incubation. 4 The effects of the agonists R ‐PIA and NECA on the cyclic AMP system were blocked respectively by the A 1 adenosine receptor antagonist, 8‐cyclopentyl‐1, 3‐dipropylxanthihe (DPCPX) at 10 −6 m and the A 2 antagonist N‐(2‐dimethylaminoethyl)‐N‐methyl‐4‐(2, 3, 6, 7‐tetrahydro‐2,b‐dioxo‐1, 3‐dipropyl‐1H‐purin‐8‐yl) benzene sulphonamide (PD115,199) at 10 −6 m . Theophylline, a known antagonist of adenosine receptors, inhibited the action of adenosine on cyclic AMP in mesangial cells. Dipyridamole, an inhibitor of the uptake of adenosine by the cells, enhanced the response to adenosine. 5 These results suggest the existence of A 1 and A 2 adenosine receptors with opposite actions on intracellular levels of cyclic AMP in both glomeruli and mesangial cells. Adenosine seems to increase cyclic AMP through the activation of a surface adenosine receptor with pharmacological properties distinct from those exhibited by the A 2 adenosine receptor.