EFFECTS OF A SELECTIVE ENDOTHELIN A-RECEPTOR ANTAGONIST, BQ-123, IN SALT-LOADED STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. We examined the effects of a selective endothelin A (ET(A))-recepto r antagonist, BQ-123, on the development of hypertension and organ dam age in stroke-prone spontaneously hypertensive rats (SHRSP) given 1% N aCl for 6 weeks. 2. BQ-123 at doses of 0.7, 2.1 and 7.1 mg/day was con tinuously administered for 6 weeks to 8 week old salt-loaded SHRSP, wh o were given water containing 1% NaCl for the following 6 weeks, via a subcutaneous osmotic minipump. 3. Development of high blood pressure was accelerated in salt-loaded SHRSP compared with that in non-salt-lo aded SHRSP. After 6 weeks of salt-loading, incidence of cerebral infar ction, renal sclerosis and renal fibrosis were greater in salt-loaded than non-salt-loaded SHRSP. 4. BQ-123 attenuated the age-related rise in blood pressure in a dose-dependent manner. The effect coincided wit h reduction in the incidence of cerebral infarction and prevention of renal sclerosis and fibrosis. Kidney function was improved as observed by an increase in glomerular filtration rate and decreases in urinary protein excretion, blood urea nitrogen and fractional sodium excretio n. Furthermore, BQ-123 prevented increases in the heart weight/bodywei ght ratio and aortic wall thickness in salt-loaded SHRSP. 5. These res ults suggest that endogenous endothelin-1 (ET-1) and ET(A)-receptors m aybe, at least in part, involved in the pathogenesis of hypertension a nd organ damage in salt-loaded SHRSP.