NO/cGMP signaling modulates regulation of Na+-K+ -ATPase activity by angiotensin II in rat proximal tubules

ANG II exerts a biphasic effect on Na+ transport in the kidney through its effects on Na+-K+-ATPase activity. Beginning at 10-(13) M, ANG II increased Na+-K+-ATPase activity in freshly isolated rat proximal tubules to a maxim um stimulation at 10(-11) M of 1.43 +/- 0.08-fold above control. Stimulatio n decreased progressively at concentrations >10(-10) M to a value of 0.96 /- 0.1-fold at 10(-7) M. In the presence of additional L-arginine, the subs trate for NO synthesis, the stimulatory effect of ANG II (10(-11) M) was lo st. Conversely, N-monomethyl-L-arginine (L-NMMA), the nitric oxide (NO) syn thase inhibitor, unmasked the stimulatory effect of ANG II at 10(-7) M (1.4 0 +/- 0.1-fold). 1H-[1,2,4] oxadiazole-[4,3-a] quinoxalin-1-one, the solubl e guanylyl cyclase inhibitor, like L-NMMA, unmasked the stimulatory effect of ANG II at 10(-7) M (1.30 +/- 0.1-fold). The intracellular cGMP concentra tion was increased 1.58 +/- 0.28-fold at 10(-7) M ANG II. The ANG II AT(1) receptor antagonist SK&F 108566 blocked the stimulatory effect of ANG II at 10(-11) M. These data suggest that the NO/cGMP signaling pathway serves as a negative component in the regulation of Na+-K+-ATPase activity by ANG II .