Renal endothelin ET(A)/ET(B) receptor imbalance differentiates salt-sensitive from salt-resistant spontaneous hypertension.
It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P:<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P:<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U(Na(+))) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P:<0.005, respectively). SHR animals showed a similar increase in both renal ET(A) and ET(B) receptor densities after NX-NaCl (2.2-fold, P:<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET(A) compared with ET(B) binding (4.7-fold versus 2.4-fold, P:<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET(A)/ET(B) receptor ratio only in the SHRSP-NX-NaCl (P:<0.05). Thus, activation of the renal ET system together with an increased ET(A)/ET(B) receptor ratio may contribute to the development and progression of SS-SH.
Rothermund
L
L
Institut für Klinische Pharmakologie und Toxikologie, Benjamin Franklin Hospital, Freie Universität Berlin, Berlin, Germany.
Luckert
S
S
Kossmehl
P
P
Paul
M
M
Kreutz
R
R
D000419:Albuminuria; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001667:Binding, Competitive; D001794:Blood Pressure / Q000502:physiology; D015152:Blotting, Northern; D001835:Body Weight; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism / Q000652:urine; D000072396:Endothelin-Converting Enzymes; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008666:Metalloendopeptidases; D009392:Nephrectomy; D009929:Organ Size; D011507:Proteinuria; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D012982:Sodium, Dietary / Q000008:administration & dosage*; D014554:Urination
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012982:Sodium, Dietary; D012964:Sodium; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes