An Endogenous Ligand of α-1 Sodium Pump in Hypertensive Dahl Salt Sensitive Rats
Dahl salt sensitive rats (DS), due to a mutation of α-1 subunit of Na/K ATPase (NKA), exhibit impaired pressure natriuresis and on a high NaCl diet retain Na and increase their blood pressure (BP). Recently, we demonstrated that mammalian tissues contain marinobufagenin (MBG), a bufodienolide with a high affinity to α-1 subunit of NKA. The present study investigated possible roles of MBG and another endogenous NKA inhibitor, ouabain (Ou) in hypertension which develops in DS on a high NaCl intake. Dahl salt resistant rats (DR; n=12) and DS (n=12) were put on an 8% NaCl diet for 4 weeks. In DS the excretion of Ou peaked at week 1 of NaCl loading (78±20 pmol vs. 6.4±1.1 pmol in baseline; P<0.01)and then returned to baseline. In contrast, MBG exhibited a sustained increase (66±13 pmol at week 4 vs. 11±1 pmol in baseline; p<0.01) which paralled the sustained increases in systolic BP (174±10 mm Hg at week 4 vs. 110±2 mm Hg in baseline; p<0.01). No such effects occured in DR on an 8% NaCl intake. MBG-immunoreactive (MBG-ir) material was purified from urine of hypertensive DS via three steps of reverse phase HPLC and compared with ouabain and MBG from Bufo marinus toad for its ability of inhibit the NKA from rat kidney (which expresses only α-1 NKA) an the level of high- and low-affinity binding sites (Table). MBG acts as a selective inhibitor of ouabain-resistant α-1 NKA subunit, as one could expect from a putative natriuretic hormone. Our results sugest that in hypertensive DS, the α-1 ligand, MBG, is elaborated to promote natriuresis and contributes to the sustained BP elevation.