Short-term vs. sustained inhibition of proximal tubule Na,K-ATPase activity by dopamine: cellular mechanisms.
Dopamine (DA) produces a natriuresis attributed in part to inhibition of Na,K-ATPase activity (NKA) in the proximal tubule (PCT), and impairment in this inhibition has been linked to several forms of hypertension in animals. Here we examined whether the intracellular signaling mechanisms involved are the same in the early and late phases of this phenomenon. DA (1 microM) inhibited NKA similarly after 15 min (by 38%) or 180 min (by 36%) incubation, taken to represent short-term (ST) and sustained (Sd) pump regulation, respectively. Calphostin C, a specific inhibitor of protein kinase C (PKC), completely blocked the ST action of DA on NKA, whereas IP20, a specific inhibitor of protein kinase (PKA), had no effect. In contrast, IP20 completely abolished the Sd (180 min) inhibition by DA, whereas calphostin C had only a partial or variable effect. The DA-1 agonist fenoldopam (which does not activate PKC but increases cAMP) alone failed to inhibit the pump at 180 min (as it does also in the short-term in PCT), suggesting that ST inhibition is required for the Sd effect to occur. Furthermore, PTH1-34, a known ST inhibitor of NKA suppressed the pump at 180 min (by 46%), but unlike in the short-term, this effect was completely prevented by IP20. In contrast, PTH3-34, which does not stimulate adenylyl cyclase or activate PKA, caused only a small (19%) and variable Sd inhibition. In conclusion, short-term inhibition of the PCT pump by dopamine is mediated via PKC, whereas the sustained inhibition requires the PKA pathway in addition to the ongoing PKC-mediated effect.
Pinto-do-O
P C
PC
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Chibalin
A V
AV
Katz
A I
AI
Soares-da-Silva
P
P
Bertorello
A M
AM
D000818:Animals; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D000242:Cyclic AMP; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; C058819:calphostin C; D018818:Fenoldopam; D004298:Dopamine