imidapril and Cerebrovascular-Disorders

The present study was undertaken to examine the effects of the ACE (angiotensin converting enzyme) inhibitor imidapril, on the brain, when administered after the onset of stroke in a stroke-prone substrain of spontaneously hypertensive rats (SHRSP). Learning deficits and induced lesions in the brain as well as in the kidneys and heart were investigated in detail. SHRSP were divided into two groups with or without salt loading at the age of 4 weeks. The salt loading was performed for 7-9 weeks to increase the incidence of stroke. Within 24 h after the first observation of stroke, animals were subsequently treated with 5 mg/kg imidapril orally once a day or the vehicle for up to the age of 27 weeks. Imidapril attenuated progression of neurological abnormalities such as irritability, hyperkinesia and motor dysfunction, and increased survival rate. In three-panel runway testing, learning deficits did not develop significantly in the imidapril-treated group, and was comparable to that in the non-salt-loaded/non-stroke group. Imidapril reduced oedema formation in the cortex, hippocampus and striatum, and also suppressed lesion formation in the kidneys and heart. Imidapril thus suppressed progression of neurological deficits with loss of learning ability following onset of stroke, and also suppressed formation of oedema in the brain and decreased the number of lesions in other organs. Imidapril-induced reduction of cerebrovascular damage, which presumably occurs in the brain after stroke, may account for the inhibitory effects of imidapril on lesion formation and learning impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Brain Edema; Cerebrovascular Disorders; Imidazoles; Imidazolidines; Kidney; Learning Disabilities; Male; Myocardium; Neurologic Examination; Organ Size; Rats; Rats, Inbred SHR; Survival Rate

To examine chronic changes in mitogen-activated protein (MAP) kinases in cardiac hypertrophy, we determined the activities of two subfamilies of MAP kinases, including extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), in the heart of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) aged 5, 8, 14, and 24 weeks. MAP kinases were determined by using in-gel kinase assay. In both the left and right ventricles of WKY, the activities of ERKs (p44ERK and p42ERK) and JNKs (p46JNK and p55JNK) decreased significantly with age, indicating that aging remarkably downregulated cardiac MAP kinase activities. In SHRSP, left ventricular ERK and JNK activities were already significantly higher at the mild hypertensive phase than they were in the same age of WKY, and they remained higher until development of left ventricular hypertrophy. On the contrary, the right ventricle of SHRSP, which did not exhibit cardiac hypertrophy, had no significant increase in ERK or JNK activities compared with WKY, except for the slight increase in p55JNK in 24-week-old SHRSP. Antihypertensive treatment of SHRSP with imidapril, an angiotensin-converting enzyme inhibitor, decreased the left ventricular JNK activities (P<.01) but did not affect ERK activities, suggesting the contribution of hypertension or the renin-angiotensin system to the increase in JNKs. Our observations provide the first evidence that both ERK and JNK activities are higher in the left ventricle of SHRSP than WKY. However, further study is needed to elucidate the mechanism and the significance of the increased cardiac MAP kinases in SHRSP.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomegaly; Cerebrovascular Disorders; Heart; Hypertension; Imidazoles; Imidazolidines; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Myocardium; Protein Kinases; Rats; Rats, Inbred Strains; Rats, Inbred WKY

Our previous studies showed that imidapril prevented the occurrence of cerebral stroke and ameliorated biochemical parameter changes of renal dysfunction at a dose that did not inhibit the progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). To confirm these findings, a histopathological investigation was conducted on the kidney of salt-loaded (from 11 to 16 weeks of age) SHRSP, which was the subject of the preceding study. Their brains and hearts were also examined. Histopathologically, renal lesions such as fibrinoid necrosis and proliferative arteritis of small calibration arteries, necrotizing glomerulitis and tubular degeneration, and cerebral hemorrhage and slight cardial hypertrophy were observed in salt-loaded control SHRSP. The occurrence of these lesions were prevented in a dose-dependent manner by the administration of imidapril (1 and 2 mg/kg/day). Especially, the preventive effects on the renal lesions were apparently noted. Enalapril also prevented these renal lesions, but its preventive effects were weaker than those of imidapril at the same dose (2 mg/kg/day). It became evident from the results of the present and previous studies that imidapril reduced renal biochemical and histopathological injuries.

Topics: Animals; Antihypertensive Agents; Autopsy; Basilar Artery; Brain; Cerebrovascular Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Heart; Hypertension, Renal; Imidazoles; Imidazolidines; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Microscopy, Fluorescence; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary

Magnetic resonance imaging (MRI) was used to investigate the therapeutic effects of imidapril, a newly synthesized angiotensin converting enzyme (ACE) inhibitor, on cerebral stroke lesions.. Pretreatment with ACE inhibitors is known to prevent stroke in stroke-prone spontaneously hypertensive rats, prolonging their lifespan. Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) were treated with imidapril after the onset of stroke.. M-SHRSP with proved stroke were divided into two groups. One group received 40 mg/kg per day imidapril and the other group was used as a control. For 4 weeks, neurological symptoms were scored daily, and MRI images were taken and scored once a week.. In the control group the MRI score for cerebral lesions increased during the experiment, and seven out of eight control rats died within 17 days. In rats treated with imidapril the major finding was that imidapril rapidly ameliorated the damage to the blood-brain barrier and resolved brain oedema within 1 week. At the same time the neurological symptoms observed after stroke disappeared. Furthermore, none of the rats treated with imidapril showed recurrence of stroke, and their survival rate was improved.. These results suggest that imidapril has therapeutic effects on stroke lesions, as well as prophylactic effects on the recurrence of stroke.

Topics: Animals; Antihypertensive Agents; Behavior, Animal; Blood Pressure; Body Weight; Brain; Cerebrovascular Disorders; Female; Hypertension; Imidazoles; Imidazolidines; Longevity; Magnetic Resonance Imaging; Rats; Rats, Inbred SHR

It has been reported that some angiotensin converting enzyme inhibitors can prevent stroke-prone spontaneously hypertensive rats from stroke at much higher doses than clinical doses used for hypertension therapy. This study was performed to investigate the prophylactic effectiveness of imidapril against stroke in comparison with enalapril.. Salt-loaded stroke-prone spontaneously hypertensive rats were orally given imidapril (0.5, 1, 2, and 5 mg/kg per day), enalapril (2 and 5 mg/kg per day), or hydralazine (5 mg/kg per day). Stroke signs were scored, and blood pressure, protein concentration, and N-acetyl-beta-D-glucosaminidase activity in urine were measured. After 2 weeks of medication, angiotensin converting enzyme activities in the aorta were measured 24 hours after dosing.. In the control group, severe hypertension developed, and all rats died within 12 weeks because of stroke. Imidapril and enalapril dose-dependently decreased the stroke-related mortality, and both agents at 5 mg/kg per day showed excellent prophylaxis, although they did not inhibit hypertensive development. Imidapril at 0.5 mg/kg per day significantly prevented stroke to almost the same extent as enalapril at 2 mg/kg per day or hydralazine at 5 mg/kg per day. Imidapril dose-dependently suppressed the elevation of the two urinary indexes, which was followed by stroke. Imidapril inhibited enzyme activity in the aorta more strongly than did enalapril at the same dose.. Imidapril prevented the incidence of stroke in stroke-prone spontaneously hypertensive rats at a dose of 0.5 mg/kg per day or more by amelioration of kidney dysfunction. Reduction of blood pressure is not necessary, although enzyme inhibition in the vasculature may partly relate to the effect.

Topics: Acetylglucosaminidase; Angiotensin-Converting Enzyme Inhibitors; Animals; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Enalapril; Imidazoles; Imidazolidines; Incidence; Male; Rats; Rats, Inbred SHR

Many of the disorders in urinary, biochemical, and hematological parameters induced by salt-loading in stroke-prone spontaneously hypertensive rats (SHRSP) were significantly ameliorated by chronic treatment with angiotensin converting enzyme inhibitors, imidapril (1 and 2 mg/kg) and enalapril (2 mg/kg). Through the improvement of these parameters, the treatment reduced the incidence of stroke but did not suppress the development of hypertension. These results suggest that the prophylaxis of stroke in SHRSP is probably due to systemic improvement as judged from the parameters of renal functions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Cerebrovascular Disorders; Disease Susceptibility; Electrolytes; Enalapril; Hypertension; Imidazoles; Imidazolidines; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium, Dietary