EFFECT OF ACUTE AND CHRONIC TREATMENT WITH THE ANGIOTENSIN-II SUBTYPE-1 RECEPTOR ANTAGONIST EXP-3174 ON BAROREFLEX FUNCTION IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

Objective: To determine whether the angiotensin II subtype 1 (AT(1)) r eceptor antagonist EXP 3174 can modify the baroreceptor-heart rate ref lex in conscious rats. Design: EXP 3174 was given acutely, both periph erally and centrally, as well as chronically to spontaneously hyperten sive rats (SHR), and baroreflex function was then examined. Methods: B aroreceptor reflex activity was assessed by constructing sigmoidal mea n arterial pressure (MAP)-heart rate curves after injection of presser (phenylephrine) and depressor (sodium nitroprusside) agents. Barorefl ex testing was performed before and after intravenous (1 mg/kg) and in tracerebroventricular (1 mu g) administration of EXP 3174 in separate groups of conscious SHR and Wistar-Kyoto (WKY) rats. EXP 3174 was also given subcutaneously for 15 days (5 mg/kg per day) in SHR, and barore ceptor reflex activity was assessed approximately 24 h later. Results: EXP 3174 lowered MAP after acute peripheral administration in SHR and , to a lesser extent, WKY rats. MAP was not altered after central admi nistration of EXP 3174 in either group. Baroreceptor reflex function w as not significantly modified after acute peripheral or central inject ion of the AT(1) receptor antagonist in SHR or WKY rats. In contrast, chronic treatment of SHR with EXP 3174 markedly decreased MAP compared with vehicle-treated SHR. Moreover, the MAP-heart rate curve was shif ted leftwards together with an enhancement of reflex bradycardia, such that baroreflex function was restored to the level observed in untrea ted WKY rats. Conclusion: Chronic, but not acute, administration of EX P 3174 normalized baroreflex function in SHR. This facilitation of bar oreflex function might contribute to the greater antihypertensive effe ct observed after chronic administration of EXP 3174 in SHR.