Early-onset but not late-onset endothelin-A-receptor blockade can modulatehypertension, cerebral edema, and proteinuria in stroke-prone hypertensiverats

The ability of endothelin receptor blockade to prevent and to treat establi shed cerebral and renal injury was explored in salt-loaded stroke-prone spo ntaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist A127722. SHRSP were subjected to 1% NaCl intake. The start of t reatment 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 T-2-weighted magnetic resonance imaging. In untreated c ontrol animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset A127722 treatment increased median surv ival 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 i n the 70-mg/kg treatment group developed hemorrhages in the basal ganglia s hortly 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 hypert ension, cerebral edema, and proteinuria was prevented in SHRSP when A127722 treatment was initiated at the start of salt-loading. However, A127722 tre atment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the devel opment of increased blood pressure and initiation of organ damage but parti cipates minimally in established malignant hypertension and progression of target-organ damage.