The angiotensin AT₁ receptor antagonist CV-11974 regulates cerebral blood flow and brain angiotensin AT₁ receptor expression

We studied cerebral blood flow autoregulation by laser Doppler flowmetry, and expression of brain angiotensin II AT₁ receptors by quantitative autoradiography, after administration of an angiotensin AT₁ receptor antagonist, CV-11974 (Candesartan, 0.5 or 1.0 mg/kg·day) for two weeks via subcutaneously implanted osmotic pumps in adult normotensive Wistar Kyoto and spontaneously hypertensive male rats (SHR). In SHR, the autoregulation curve was shifted towards higher blood pressures, when compared with that of normotensive Wistar Kyoto rats. Administration of CV-11974 shifted the autoregulation curve toward lower blood pressures in both Wistar Kyoto and SHR, partially normalizing the autoregulation curve in SHR. CV- 11974 treatment markedly decreased the expression of AT₁ receptors in Wistar Kyoto rats, both in areas outside the blood brain barrier (subfornical organ, 95 % decrease) and inside the blood brain barrier (nucleus of the tractus solitarius, 87 % decrease, and paraventricular nucleus, 96 % decrease). Our results demonstrate that blockade of AT₁ receptors tends to normalize the shift to higher pressures in the autoregulation curve of genetically hypertensive rats, and has a profound modulatory role in brain angiotensin II AT₁ receptors.