1. The present study was designed to investigate the preventative and
therapeutic effects of
AE0047 on renal injury compared with those of
nitrendipine in
stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the preventative study,
drug administration was started before the appearance of renal injury, such as
proteinuria. Treatment for 6 weeks with
AE0047 (1 and 3 mg/kg, p.o.) led to a dose-related reduction in systolic blood pressure (SBP).
Nitrendipine, at doses of 10 and 30 mg/kg, also lowered SBP to a similar degree to that seen with
AE0047 at 1 and 3 mg/kg, respectively. 3. In the vehicle-administered SHRSP group, urinary excretion of
protein (Uprotein V) increased progressively from 14 weeks of age for another 6 weeks.
AE0047 at both doses maintained Uprotein V within normal levels throughout the experimental period. However, the elevation of Uprotein V was only inhibited in the 30 mg/kg
nitrendipine-treated group. Urinary N-acetyl-beta-D-glucosaminide (NAG) activity in the vehicle-treated SHRSP group was elevated. Urinary NAG activity remained at a low level only in AE0047-treated groups. 4. Histopathological examination revealed severe lesions (i.e. fibrinoid
necrosis, proliferative
vasculitis and glomerular lesions) of the kidney in SHRSP.
AE0047 treatment at each dose attenuated the development of renal lesions in SHRSP. In contrast,
nitrendipine,
at 10 mg/kg, was ineffective against the development of renal lesions. Although
nitrendipine at 30 mg/kg suppressed the development of renal lesions, this effect was still weaker than that seen with
AE0047 at 1 mg/kg. 5. In the therapeutic study, drugs were administered to 17-week-old SHRSP with moderate renal damage for 10 days. Treatment with
AE0047 (1 and 3 mg/kg) produced dose-dependent decreases in Uprotein V. In the
nitrendipine-treated group, Uprotein V tended to decrease but the changes were not significant. 6. Histopathological studies revealed that 3 mg/kg
AE0047 improved renal lesions, such as fibrinoid
necrosis, proliferative
vasculitis and glomerular lesions, whereas 30 mg/kg
nitrendipine did not. 7. Taken together, the results indicate that
AE0047 is capable of preventing
proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore,
AE0047 improves
proteinuria and renal lesions in
proteinuria-established SHRSP. Thus,
AE0047 may have therapeutic potential in suppressing either the development or the progression of renal disease in hypertensive patients.