(Hypertension. 1999;33:137-144.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats
From the Departments of Nephrology (E.L.A.B., H.A.K., J.A.J.) and Pathology (R.G., G.H.J.), University Hospital Utrecht; and the Department of In vivo NMR (E.L.A.B., K.N.), Bijvoet Center, Utrecht University, The Netherlands.
Correspondence to Jaap A. Joles, DVM, PhD, Department of Nephrology and Hypertension (F03.226), Utrecht University Hospital, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail nephrology.gdl{at}pobox.ruu.nl
Abstract—The ability of endothelin receptor blockade to prevent and to treat established cerebral and renal injury was explored in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist A127722. SHRSP were subjected to 1% NaCl intake. The start of treatment with A127722 (35 and 70 mg · kg-1 · d-1, respectively) was either synchronized with salt loading or initiated after the first observation of cerebral edema with T2-weighted magnetic resonance imaging. In untreated control animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset A127722 treatment increased median survival to 233 days (range, 92 to 407 days; P<0.05 versus controls) with 35 mg/kg and to 124 days (range, 97 to 169 days; P<0.05 versus control) with 70 mg/kg. The development of cerebral edema was prevented, and systolic blood pressure and proteinuria were dose-dependently reduced. However, all rats in the 70-mg/kg treatment group developed hemorrhages in the basal ganglia shortly before death. Late-onset A127722 treatment failed to affect survival, systolic blood pressure, or proteinuria. Nevertheless, cerebral edema was reduced but not as well as in early-onset treatment. Development of hypertension, cerebral edema, and proteinuria was prevented in SHRSP when A127722 treatment was initiated at the start of salt-loading. However, A127722 treatment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the development of increased blood pressure and initiation of organ damage but participates minimally in established malignant hypertension and progression of target-organ damage.
Key Words: edema, cerebral • rats, inbred strains • magnetic resonance imaging • endothelin • receptors, endothelin • proteinuria
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