Effects of long-term treatment with the calcium antagonist AE0047 on cerebrovascular autoregulation and hypertrophy in spontaneously hypertensive rats

Chronic hypertension is associated with structural and functional changes in the cerebrovascular bed, which influence cerebral circulation and its autoregulation. We examined whether or not long-term treatment of spontaneously hypertensive rats (SHRs) with the new calcium antagonist AE0047 would reverse structural changes in the cerebral vasculature and normalize the elevated lower blood pressure (BP) limit of the cerebral blood flow (CBF) autoregulation. Treating 6-month-old SHRs with a diet containing either 0.013 or 0.04% AE0047 for 8 weeks reduced BP and, at the higher dose, maintained BP at a level similar to that of age-matched Wistar-Kyoto (WKY) rats. At the end of the treatment period, CBF was measured by using the hydrogen-clearance method, and the lower limit of the autoregulation curve was estimated by repeated CBF measurement with stepwise reduction of BP through bleeding. This limit was significantly higher in untreated SHRs than in WKY rats (111 +/- 8 vs. 60 +/- 8 mm Hg). AE0047 caused a significant and dose-dependent shift in the elevated lower BP limit, which decreased to 83 +/- 9 and 75 +/- 6 mm Hg at the low and high dose, respectively. In perfusion-fixed proximal, intermediate, and distal portions of the middle cerebral artery, media thickness/external diameter (M/ED) ratios were significantly greater in untreated SHRs than in WKY rats. In AE0047-treated animals, M/ED ratios in all portions tended to be reduced halfway between those for untreated SHRs and those for WKY rats, but with no statistical significance. These results suggest that long-term treatment of patients with hypertension with AE0047 will normalize the autoregulatory threshold while preserving CBF and thereby improve tolerance to BP reduction, but the potential to ameliorate structural alterations may be small.