H. Cai et al., PHOSPHATE-TRANSPORT INHIBITION BY KW-3902, AN ADENOSINE A(1) RECEPTORANTAGONIST, IS MEDIATED BY CYCLIC ADENOSINE-MONOPHOSPHATE, American journal of kidney diseases, 26(5), 1995, pp. 825-830
We have previously demonstrated that 1,3-dipropyl-8-(3-noradamantyl) x
anthine (KW-3902) has an inhibitory effect on phosphate (Pi) transport
with no effect on glucose transport in the rat renal proximal tubular
cell, similar to that of parathyroid hormone (PTH), In the current st
udies we investigated the effect of KW-3902, rat PTH (1-34), and 1,3-d
ipropyl-8-cyclopentylxanthine (DPCPX), another selective adenosine A(1
) receptor antagonist, on Pi transport and the production of cyclic ad
enosine monophosphate (cAMP). We then compared these effects of KW-390
2 with those of rat PTH in rat renal proximal tubule cells, The result
s showed that both KW-3902 (30 mu mol/L) and rat PTH (1-34, 5 mu mol/L
) significantly inhibited Pi uptake in proximal cells from a control l
evel of 61 +/- 3 to 19 +/- 3 (a reduction of 69%) and 46 +/- 4 picomol
es phosphate/mg protein/min (a reduction of 25%), respectively (P < 0.
01). The inhibitory effect of 30 mu mol/L KW-3902 alone on Pi transpor
t was more than twice that of 5 mu mol/L rat PTH (1-34) alone (P < 0.0
1), KW-3902 stimulated the production of cAMP in a dose-dependent mann
er (r = 0.997, P < 0.01), Rat PTH (1-34; 5 mu mol/L) also stimulated c
AMP production, which was greater than that induced by 30 mu mol/L KW-
3902 alone, A significant increase in cAMP production by 30 mu mol/L D
PCPX was also observed, When 30 mu mol/L KW-3902 and 5 mu mol/L rat PT
H (1-34) were added to the medium together, their combined effect on P
i transport and cAMP production was additive and significantly greater
than that of either agent alone (P < 0.01), DPCPX (30 mu mol/L) also
significantly inhibited Pi uptake by proximal cells. However, when 30
mu mol/L KW-3902 and 30 mu mol/L DPCPX were combined, no additional in
hibitory effect on Pi transport was observed, In additional experiment
s, the addition of adenosine deaminase (10 units/mL) to the transport
medium, resulting in the inhibition of adenosine binding to its recept
ors, also decreased phosphate uptake (by 42.6%, P < 0.01) in renal pro
ximal cells. These data suggest that the inhibitory effect of both KW-
3902 and PTH on Pi transport is mediated through the stimulation of cA
MP. The effect of KW-3902 and PTH on cAMP production was additive, sug
gesting that their effects on Pi transport are mediated by different m
echanisms. (C) 1995 by the National Kidney Foundation, Inc.