PREVENTATIVE AND THERAPEUTIC EFFECTS OF AE0047 ON RENAL INJURY IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of n itrendipine in stroke-prone spontaneously hypertensive rats (SHRSP). 2 . In the preventative study, drug administration was started before th e appearance of renal injury, such as proteinuria. Treatment for 6 wee ks with AE0047 (1 and 3 mg/kg, p.o.) led to a dose-related reduction i n systolic blood pressure (SBP), Nitrendipine, at doses of 10 and 30 m g/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 gro up, urinary excretion of protein (UproteinV) increased progressively f rom 14 weeks of age for another 6 weeks, AE0047 at both doses maintain ed UproteinV within normal levels throughout the experimental period, However, the elevation of UproteinV was only inhibited in the 30 mg/kg nitrendipine-treated group. Urinary N-acetyl-beta-D-glucosaminide (NA G) activity in the vehicle-treated SHRSP group was elevated, Urinary N AG 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 kidn ey 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 nitren dipine at 30 mg/kg suppressed the development of renal lesions, this e ffect was still weaker than that seen with AE0047 at 1 mg/kg. 5. In th e 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 UproteinV, In the nitrendipin e-treated group, UproteinV tended to decrease but the changes were not significant. 6. Histopathological studies revealed that 3 mg/kg AE004 7 improved renal lesions, such as fibrinoid necrosis, proliferative va sculitis and glomerular lesions, whereas 30 mg/kg nitrendipine did not . 7. Taken together, the results indicate that AE0047 is capable of pr eventing proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore, AE0047 impro ves proteinuria and renal lesions in proteinuria-established SHRSP, Th us, AE0047 may have therapeutic potential in suppressing either the de velopment or the progression of renal disease in hypertensive patients .