Inhibition of Rho-kinase reduces renal Na-H exchanger activity and causes natriuresis in rat.
Rho-kinase regulates the actin cytoskeleton and therefore modulates transport. The role of Rho-kinase in Na-H exchanger (NHE) activity of rat proximal convoluted tubules (PCTs) was investigated using (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), a specific inhibitor of Rho-kinase. In spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, apical and basolateral NHE activities were determined by measuring cell pH recovery following luminal NH4+ prepulse and basolateral sodium removal, respectively. Apical NHE activity was greater in 8 to 9 week old hypertensive SHR compared with WKY. Although Y-27632 suppressed pH(i) recovery in both strains, sensitivity was 50-fold higher in adult SHR. Y-27632 suppressed basolateral NHE in both strains with similar sensitivity. Apical NHE activity was not greater in 5-week-old, not yet hypertensive, SHR rats compared with WKY. In clearance studies, Na excretion was less in SHR than in WKY rats. Y-27632 increased Na excretion and fractional excretion Na in both strains but more so in SHR. (22)Na uptake of the brush border membrane vesicle taken from Y-27632-treated rats decreased more than that from vehicle-treated animals in both adult SHR and WKY. We conclude that apical NHE activity is increased in SHR PCT compared with controls and that inhibition of Rho-kinase reduces PCT NHE activities and causes natriuresis.
Nishiki
Kenta
K
Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi, Kawachi, Tochigi, Japan.
Tsuruoka
Shuichi
S
Kawaguchi
Atsuhiro
A
Sugimoto
Kohichi
K
Schwartz
George J
GJ
Suzuki
Makoto
M
Imai
Masashi
M
Fujimura
Akio
A
D000577:Amides / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D017923:Sodium-Hydrogen Exchangers; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases