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)) receptor antagonist EXP 3174 can modify the baroreceptor-heart rate reflex in conscious rats. Design: EXP 3174 was given acutely, both peripherally and centrally, as well as chronically to spontaneously hypertensive rats (SHR), and baroreflex function was then examined. Methods: Baroreceptor reflex activity was assessed by constructing sigmoidal mean arterial pressure (MAP)-heart rate curves after injection of presser (phenylephrine) and depressor (sodium nitroprusside) agents. Baroreflex testing was performed before and after intravenous (1 mg/kg) and intracerebroventricular (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 baroreceptor 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 administration of EXP 3174 in either group. Baroreceptor reflex function was not significantly modified after acute peripheral or central injection 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 shifted leftwards together with an enhancement of reflex bradycardia, such that baroreflex function was restored to the level observed in untreated WKY rats. Conclusion: Chronic, but not acute, administration of EXP 3174 normalized baroreflex function in SHR. This facilitation of baroreflex function might contribute to the greater antihypertensive effect observed after chronic administration of EXP 3174 in SHR.