Perindopril treatment in the prevention of stroke in experimental animals
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OBJECTIVE: To determine the effect of perindopril treatment and treatment withdrawal in the prevention of stroke in male stroke-prone spontaneously hypertensive rats (SPSHR). DESIGN: After weaning at 4 weeks of age, male SPSHR were given a Japanese-style rat diet which induces stroke in these animals. Beginning at 6 weeks of age, SPSHR were treated with either distilled water (control) or different daily dosages of perindopril (1 or 4 mg/kg) by gavage for 24 weeks followed by treatment withdrawal. Additional subgroups were treated with the 4 mg/kg dose for different durations (B, 12 or 24 weeks) before treatment withdrawal. Treatment effects on blood pressure, heart rate and body weight were studied during the treatment period and after the withdrawal of the treatment. Myogenic and mechanical properties of the middle cerebral arteries were studied in control SPSHR that had developed stroke, in treated SPSHR at the end of the treatment period, and at certain intervals after the withdrawal of the treatment. METHODS: Systolic blood pressure, heart rate and body weight of control and treated SPSHR were determined at regular intervals before, during and after the treatment withdrawal periods until they died from stroke, or until 42 or 43 weeks of age when the study was terminated. Functional studies of the cerebral arteries were carried out using a pressurized artery system. At necropsy, macroscopic and microscopic examinations were made of the kidneys and brain. RESULTS: Untreated SPSHR usually died of stroke-related complications by 14 weeks of age. The middle cerebral arteries from these animals had lost their ability to contract in response to pressure increase. Chronic treatment of SPSHR with perindopril when initiated at 6 weeks of age attenuated the sharp blood pressure rise, and prevented the development of stroke during the treatment period. This was associated with the preservation of the myogenic response of the middle cerebral arteries to pressure increase, and the prevention of tissue damage in the kidneys and brain. After withdrawal of the treatment, SPSHR treated for a longer period (12 or 24 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent loss of myogenic response in the middle cerebral arteries was associated with the development of stroke and death in these treatment withdrawal groups. CONCLUSION: Chronic treatment with perindopril is beneficial for the prevention of stroke in SPSHR, through the preservation of the myogenic response properties of the cerebral arteries, and the attenuation of tissue damage in the brain and kidneys.