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Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500
Endothelin (ET)-1 has potent renal and
systemic vasoconstrictor properties, and thus we investigated whether
ET-1 plays a role in increasing blood pressure and decreasing renal
function in DOCA-salt hypertension. After a right nephrectomy, rats had DOCA or placebo pellets implanted subcutaneously and were given saline
or tap water to drink, respectively. Additional groups of rats were
given the ETA receptor antagonist
A-127722 in their water. Rats were maintained in metabolic cages for
monitoring excretory function and food and water intake. Three weeks
after surgery, mean arterial pressure (MAP) was recorded in the
conscious rats via a carotid artery catheter. As expected, DOCA-salt
rats had significantly higher MAP compared with uninephrectomized
controls (197 ± 6 vs. 133 ± 3 mmHg). Creatinine clearance, used
as an estimate of glomerular filtration rate, was significantly reduced
in DOCA-salt rats (2.9 ± 0.4 vs. 6.8 ± 0.3 dl · day
1 · 100 g1 body wt in controls).
ETA receptor blockade with
A-127722 significantly reduced MAP (156 ± 8 mmHg) but had no effect
on creatinine clearance of DOCA-salt-treated rats (2.8 ± 0.3 dl · day1 · 100 g1 body wt). Plasma ET-1
levels were significantly raised after DOCA-salt treatment (1.4 ± 0.5 pg/ml vs. 0.4 ± 0.1 pg/ml in controls). A-127722 treatment
increased circulating ET-1 levels in both placebo (2.3 ± 0.5 pg/ml)
and DOCA-salt (5.6 ± 0.7 pg/ml) rats. However, ET-1 mRNA expression
in renal cortical and medullary tissue was not affected by either
A-127722 or DOCA-salt treatments. Thus ETA receptors appear to play a
role in the maintenance and development of DOCA-salt hypertension but
not in the accompanying reduction of renal function.
endothelin; endothelin antagonist; endothelin receptor ; deoxycorticosterone acetate
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