Inhibition of renal Na+-ATPase activity by inosine is mediated by A1 receptor-induced inhibition of the cAMP signaling pathway.
We have previously demonstrated that adenosine is deaminated to inosine in the isolated basolateral membrane (BLM) of kidney proximal tubules. This work investigates the possible effect of inosine on proximal tubule Na(+)-ATPase activity. Inosine reduced Na(+)-ATPase activity by 70%. This effect of inosine was completely attenuated by 10(-8) M DPCPX, an A(1) receptor-selective antagonist, but it was not affected by either 10(-8) M DMPX or 10(-7) M MRS1523, A(2) and A(3) receptor-selective antagonists, respectively. The inhibitory effect of inosine was blocked by: (1) 10(-6) M GDPbetaS, a trimeric G protein inhibitor; (2) 1microg/ml pertussis toxin, a Gi protein inhibitor; (3) 10(-6) M forskolin, an adenylyl cyclase activator; (4) 10(-9) M cholera toxin, a Gs protein activator; (5) 10(-6)M cAMP. Our results demonstrate that the inhibitory effect of inosine on the sodium pump is mediated by the A(1) receptor/Gi/cAMP pathway.
Assaife-Lopes
Natália
N
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS Bloco G, 21949 Rio de Janeiro, RJ, Brazil.
Wengert
Mira
M
de Sá Pinheiro
Ana Acacia
AA
Leão-Ferreira
Luiz Roberto
LR
Caruso-Neves
Celso
C
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007288:Inosine / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*; D013552:Swine; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D027682:Cation Transport Proteins; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2; D014970:Xanthines; D007288:Inosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase