INHIBITION OF PROXIMAL TUBULE NA+-K+-ATPASE ACTIVITY REQUIRES SIMULTANEOUS ACTIVATION OF DA1 AND DA2 RECEPTORS

This study examines the receptor mechanisms by which dopamine (DA) inhibits Na+-K+ -adenosinetriphosphatase (ATPase) activity in single permeabilized proximal tubule (PCT). Na+-K+-ATPase activity was inhibited in the presence of both Da1-and DA2-specific agonists but not by either agonist alone. The inhibition induced by DA (10(-6) M) was attenuated in the presence of either of the two DA2-specific antagonists S-sulpiride and YM 09151 at 10(-5) M and in the presence of the DA1 antagonist SCH 23390 (10(-5) M). PCT adenosine 3',5'-cyclic monophosphate (cAMP) levels were significantly increased in the presence of DA and DA1 agonist, but DA2 agonist had no effect on cell cAMP levels. Na+-K+-ATPase activity was significantly inhibited in PCT incubated with DA2 agonist (10(-5) M) and dibutyryl (DB)-cAMP (10(-6) M) but not with DA2 agonist (10(-5) M) only. PCT Na+-K+ -ATPase activity was also significantly inhibited in the presence of both DA2 agonist (10(-5) M) and forskolin (10(-6) M). Neither DBcAMP (10(-6) M) nor forskolin (10(-6) M) alone inhibited Na+-K+ ATPase activity. In tubules incubated with DA (10(-8) to 10(-9) M), the presence of DBcAMP (10(-6) M) enhanced the sensitivity by which DA inhibited Na+-K+-ATPase activity. We conclude that PCT Na+-K+-ATPase activity is inhibited by a synergistic action of the DA1 and DA2 receptors, with the DA1 receptor acting to increase cell cAMP levels.