Clinical and Investigative Medicine

 

Prevention of stroke with perindopril treatment in stroke-prone spontaneously hypertensive rats

Hong Wang, MSc
Kathleen H. Delaney, DVM, DipPathol
Jacek M. Kwiecien, DVM, PhD
John S. Smeda, PhD
Robert M.K.W. Lee, PhD

Clin Invest Med 1997;20(5):327-338

[résumé]

Mr. Wang and Dr. Lee are with the Smooth Muscle Research Programme and Department of Anaesthesia, and Dr. Delaney is with the Central Animal Facility, Faculty of Health Sciences, McMaster University, Hamilton, Ont.; Dr. Kwiecien is with the Department of Medical Sciences, University of Wisconsin, Madison, Wis.; and Dr. Smeda is with the Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Nfld.

(Original manuscript submitted May 6, 1977; received in revised form July 22, 1977; accepted July 24, 1977)

Reprint requests to: Dr. Robert M.K.W. Lee, Department of Anaesthesia (HSC-4V34), McMaster University, Hamilton ON L8N 3Z5

Contents

Abstract

 Objective: To determine the protective effects of perindopril treatment in the prevention of stroke and the relation between preventive effects and the histopathology of the brain and kidneys in male stroke-prone spontaneously hypertensive rats (SHRSP).

Design: Prospective animal study.

Interventions: Beginning at 6 weeks of age, SHRSP were treated with either distilled water (control) or perindopril for different periods (8, 12 or 24 weeks) and at different dosages (1 or 4 mg/kg per day).

Outcome measures: Regular determination of systolic blood pressure, heart rate and body weight until death; at necropsy, macroscopic and microscopic examinations of the brain and kidneys.

Results: Control SHRSP developed severe hypertension (up to 250 mm Hg) by 11 weeks of age and died of stroke within 14 weeks of age. Treatment with perindopril (4 mg/kg per day for 8 or 12 weeks or either 1 or 4 mg/kg per day for 24 weeks) attenuated the blood pressure rise and prevented stroke. In untreated SHRSP, the last blood pressure measurement before the first stroke sign was significantly higher than in SHRSP of the same age treated with perindopril. Withdrawal of the treatment resulted in a rise in blood pressure in all the treatment groups, to approximately 260 mm Hg within 4 weeks. Most of the rats treated for 8 or 12 weeks died within 10 weeks after withdrawal of treatment, whereas those treated for 24 weeks survived up to 43 weeks of age. Treatment also prevented damage to the brain and kidneys and reduced the severity of lesions in the brain and kidneys after treatment withdrawal.

Conclusion: Treatment of SHRSP with perindopril prevents stroke through the suppression of blood pressure rise and prevention of tissue damage in the brain and the kidneys. Longer treatment decreased the rate of mortality due to stroke after the withdrawal of treatment as well as the severity of lesions in the brain and kidneys.

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Résumé

Objectif : Déterminer les effets protecteurs d'un traitement au perindopril dans la prévention des attaques et le lien entre les effets préventifs et l'histopathologie du cerveau et des reins chez des rats mâles hypertendus spontanément et sujets aux attaques.

Conception : Étude prospective sur des animaux.

Interventions : À compter de l'âge de 6 semaines, on a traité des rats hypertendus spontanément et sujets aux attaques à l'eau distillée (rats témoins) ou au perindopril pendant des périodes différentes (8, 12 ou 24 semaines) et à des doses différentes (1 ou 4 mg/kg par jour).

Mesures des résultats : Détermination régulière de la tension artérielle systolique, de la fréquence cardiaque et de la masse corporelle jusqu'à la mort; au cours de la nécropsie, examen macroscopique et microscopique du cerveau et des reins.

Résultats : Les rats témoins mâles hypertendus spontanément et sujets aux attaques étaient devenus très hypertendus (jusqu'à 250 mm Hg) à l'âge de 11 semaines et sont morts d'une attaque dans les 14 premières semaines de leur vie. Le traitement au perindopril (4 mg/kg par jour pendant 8 ou 12 semaines ou bien 1 ou 4 mg/kg par jour pendant 24 semaines) a atténué l'élévation de la tension artérielle et prévenu l'attaque. Chez des sujets non traités, la dernière mesure de la tension artérielle prise avant le premier signe d'attaque a été beaucoup plus élevée que chez des sujets du même âge traités au perindopril. L'arrêt du traitement a provoqué, chez tous les sujets traités, une élévation de la tension artérielle qui a atteint environ 260 mm Hg dans les 4 semaines. La plupart des rats traités pendant 8 ou 12 semaines sont morts dans les 10 semaines suivant l'arrêt du traitement, tandis que ceux qui ont été traités pendant 24 semaines ont survécu jusqu'à l'âge de 43 semaines. Le traitement a aussi évité les dommages au cerveau et aux reins et réduit la gravité des lésions cérébrales et rénales après l'arrêt.

Conclusion : Le traitement des sujets au perindopril prévient les attaques en évitant l'élévation de la tension artérielle et en prévenant les dommages aux tissus de cerveau et des reins. Des périodes de traitement plus longues ont réduit le taux de mortalité causée par une attaque après l'arrêt du traitement, ainsi que la gravité des lésions cérébrales et rénales.

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Introduction

 Stroke-prone spontaneously hypertensive rats (SHRSP) develop severe hypertension and cerebrovascular lesions, resulting in tissue infarction and severe impairment or death.1 Although hypertension is a major risk factor for cerebrovascular disorder, some studies suggested that angiotensin-converting-enzyme (ACE) inhibitors exert a protective effect independent of their hypotensive effect. Stier and associates reported that enalapril2 or captopril3 improved the survival rate of SHRSP with only a moderate effect on blood pressure. Imidapril has been reported to prevent the incidence of stroke in SHRSP, and it was noted that a reduction of blood pressure was not necessary for this prophylactic effect.4 Recent studies with clentiazem (a calcium antagonist)5 and losartan (an angiotensin II-receptor antagonist)6 also drew the same conclusion, that blood pressure control is not essential for stroke prevention. Most of these studies emphasized the effects of treatment on the blood pressure and survival of the animals. Histopathologic assessment of the brain and kidneys was not carried out.

Feeding SHRSP a Japanese-style animal diet containing 4% sodium chloride and 0.75% potassium produces a very rapid and well-defined onset of stroke.7 The stroke signs usually appear at approximately 11 weeks of age and are characterized by convulsive rhythmic movement of the head and 1 fore limb. Within a few days after the onset of stroke, the rats become less mobile and may show a peculiar "kangaroo" posture, with their rear legs hyperextended at the knees and maintained underneath the body. Most rats die within 2.5 weeks after the first clinical signs of stroke are observed, and a 100% death rate is reached by approximately 20 weeks.7

The main purpose of this study was to investigate the effectiveness of an ACE inhibitor, perindopril, in preventing hypertension and stroke as well as the development of lesions in the brain and kidneys of SHRSP.

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Materials and methods

Rats

SHRSP were bred at McMaster University, Hamilton, Ont. They were derived from rats obtained from Dr. Hiroyuki Ito, Kinki University, Osaka, Japan, in 1983. Male SHRSP were fed a Japanese-style rat diet (Zeigler Brother Inc., Gardner, Pa.) after weaning at 4 weeks of age. The care of these animals was in accordance with the guidelines of the Canadian Council on Animal Care.

Treatment

Several groups of rats were used to conduct the following experiments.

To correlate blood pressure with stroke development, blood pressure measurements were taken every second day, starting at 9 weeks of age, in 12 untreated male SHRSP. These rats were observed closely twice a day, to detect the behaviour signs of stroke, described above.

To study the dose-dependent effect of perindopril on blood pressure and stroke development, 18 male SHRSP were treated with different dosages of perindopril (Servier, France) or distilled water beginning at 6 weeks of age. These rats were divided into 3 groups: 2 groups of 6 rats were given treatment with perindopril (1 or 4 mg/kg per day), and one control group of 6 littermates was given distilled water. Perindopril or distilled water was given by gavage every morning for 24 weeks. The treatment was then discontinued, and the rats were kept under observation for stroke development until they were 43 weeks old, when the experiment was stopped.

To examine the effect of duration of treatment on blood pressure and stroke development, another 27 male SHRSP were treated with perindopril beginning at 6 weeks of age. There were 3 experimental groups: 2 treatment groups were given 4 mg/kg per day of perindopril (12 rats treated for 8 weeks and 15 rats treated for 12 weeks) and a control group consisting of 7 littermates was given distilled water. After 8 or 12 weeks of perindopril treatments, 6 and 10 rats from each treatment group, respectively, were killed ("treatment group") in order to carry out histologic examinations of the brain and kidneys. The remaining rats from the 2 treatment groups were kept under observation until they were 43 weeks old ("treatment/withdrawal group").

In all of the experimental groups, beginning at 6 weeks of age, body weight was measured twice a week until it had reached a steady level, then once weekly. Systolic blood pressure and heart rate were determined weekly by an indirect tail-cuff compression technique 24 hours after treatment by gavage. After withdrawal of treatment, blood pressure and heart rate were measured once a month. The behaviour of the SHRSP was observed daily to detect stroke signs.

Pathology

The animals were killed when we determined that death was imminent on the basis of severe, rapid weight loss, loss of mobility and other clinical signs. Blood samples were taken through a heart puncture while the animals were under general anesthesia for the measurement of serum concentrations of creatinine, urea and albumin.

Brain was examined macroscopically for lesions typically associated with stroke, such as hemorrhage and edema, and then fixed in a universal fixative (4% formaldehyde and 1% glutaraldehyde) by immersion for histology. One kidney from each animal was also fixed in the same universal fixative. Histopathologic examination of the brain and kidney of SHRSP was carried out by one assessor who had no knowledge of the identity of the animals.

The following lesions in the brain were studied in the control and treatment groups: infarction, thrombosis, fibrinoid necrosis of blood vessel wall, microvascular proliferation, perivascular fibrinous exudate or edema, hemorrhage, malacia, rarefaction, cystic structure in neuropil, gliosis and leukocytic infiltration. To quantify these lesions in the brain, each brain was cut into 8 coronal sections of equal thickness. The severity of each type of lesion from these 8 histologic cross-sections was assigned a lesion score according to whether it was mild (1), moderate (2), marked (3) or very severe (4). The "severity score" (S) for each type of lesion per brain was calculated as:
S = (total of the lesion score for each type of lesion per brain / 4 × 8) × 100.
The frequency of each type of brain lesion (F) was calculated as:
F = (total number of each type of lesion) / 11 × 8.
For the assessment of the lesions in the kidneys, from 1 histologic section per kidney, lesions were scored as mild (1), moderate (2) or severe (3), so that for each type of lesion, a percentage severity for each type of lesion was calculated as (lesion score / 3) × 100.

Student's unpaired t-test was used for comparison between 2 experimental groups. Analysis of variance (ANOVA) and Student­Neuman­Keuls test were used for multiple comparison among groups. Differences were considered significant at a p value of less than 0.05.

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Results

Blood pressure and survival rate

In untreated SHRSP, mean systolic blood pressure rose rapidly, reaching 250 mm Hg by 10 weeks of age; all of these SHRSP died of stroke-related complications within 14 weeks. However, beginning at 9 weeks of age, the rate of blood pressure rise varied among individuals. Some rats developed severe hypertension rapidly, their blood pressure rising above 240 mm Hg at an earlier age (9 to 10 weeks), whereas others' blood pressure surpassed 240 mm Hg at a later age (12 to 13 weeks). In some cases, a rapid rise in blood pressure from 210 mm Hg to 290 mm Hg occurred within a few days. There was a significant positive correlation (r = 0.982, p < 0.0001) between the age when stroke developed and the age when blood pressure surpassed 240 mm Hg. The correlation between the age when stroke occurred and lifespan was also significant (r = 0.838, p < 0.001).

Effects of treatment dosages

Perindopril treatment at a dosage of 1 or 4 mg/kg per day for 24 weeks suppressed the blood pressure rise, and blood pressure was maintained around 220 mm Hg beginning at 12 weeks of age (Fig. 1).8 There was no significant difference in blood pressure between the 2 treatment groups receiving different dosages at any time points, whereas significant differences were observed between the treated and control rats at 9 and 10 weeks of age (p < 0.05 and < 0.01, respectively). When the mean systolic blood pressure of control SHRSP before the first stroke sign, which occurred from 9 to 14 weeks of age, was compared with the blood pressure of treated and age-matched SHRSP, there was a significant difference. The mean blood pressure of control SHRSP was 248 (standard error of the mean [SEM] 7) mm Hg, as compared with 207 (SEM 11) mm Hg in the group receiving 4 mg/kg per day of perindopril (p < 0.01) and 204 (SEM 10) mm Hg in the group receiving 1 mg/kg per day (p < 0.005). When treatment was withdrawn at 30 weeks of age, after 24 weeks of treatment, there was a rise in blood pressure to approximately 260 mm Hg in both treatment groups within 4 weeks, and blood pressure was maintained at a similar level in the 2 treatment groups up to 42 weeks of age (Fig. 1).

Perindopril treatment for 24 weeks significantly improved the survival rate of SHRSP (Fig. 2A). Five rats (2 in the 1 mg/kg per day treatment group and 3 in the 4 mg/kg per day treatment group) died during the treatment period (at 22, 24, 26 and 28 weeks of age). However, no behavioral signs of stroke or brain lesions were detected in these animals, and the cause of death was determined to be unrelated to stroke. Autopsy showed that these rats died of complications of Mycoplasma infection. The remaining rats (4 in the 1 mg/kg per day treatment group and 3 in the 4 mg/kg per day treatment group) lived up to 43 weeks of age. Withdrawal of treatment at 30 weeks of age did not result in the death of these animals. They did, however, develop other ailments, including laboured breathing, wheezing, coughing, dehydration, weight loss and lethargy. These clinical signs were associated with Mycoplasma infection, as confirmed by microbiologic culture. Inclusion of antibiotics in the drinking water improved the health of these rats, and they lived up to 43 weeks of age.

Effects of treatment duration

The blood pressure of SHRSP treated with 4 mg/kg per day of perindopril was maintained around 220 mm Hg (Fig. 3). None of the treated SHRSP had stroke during the treatment period, while all of the untreated SHRSP died during this period (Fig. 2). Withdrawal of treatment caused the blood pressure of SHRSP to increase to 260 mm Hg within 6 weeks (Fig. 3). The SHRSP treated for 8 weeks (i.e., from 6 to 14 weeks of age) exhibited typical stroke signs at 18 weeks of age (4 weeks after treatment withdrawal) and died of stroke by 23 weeks of age (Fig. 2B). In the 12-week treatment group (i.e., from 6 to 18 weeks of age), 3 rats (out of 5) had stroke signs between 20 to 22 weeks of age, and died of stroke by 28 weeks. The remaining 2 rats survived but had obvious stroke signs such as convulsive repeated head movements. These signs appeared and disappeared periodically until the rats were 43 weeks old, when the experiment was ended. In the SHRSP treated with perindopril for 24 weeks, which was withdrawn at 30 weeks of age, all survived at least up to 43 weeks of age, when the study was stopped.

Heart rate and body weight

In the untreated SHRSP, body weight began to decline at approximately 12 weeks of age, which coincided with the development of stroke in these animals (Fig. 4). By contrast, the SHRSP treated with perindopril showed steady weight increase, even after withdrawal of the treatment. The only exception was the SHRSP in the 8-week treatment group. At the end of 8-week treatment, the average body weight of SHRSP was 247 (SEM 4) g in the 12 treated rats. Seven weeks after withdrawal, it had dropped to 211 (SEM 11) g in 3 rats, which was significantly different (p < 0.005) from their weight at the end of the 8-week treatment. In the 12-week treatment group, withdrawal of treatment did not result in a decline in body weight, despite the fact that by 28 weeks of age 60% of the animals had died with evidence of stroke.

The heart rate of control and treated SHRSP was between 360 and 390 beats per minute, and there was no significant difference between the control and treated SHRSP, except in the control SHRSP that had stroke: these rats had an increased heart rate (459 [SEM 57] beats per minute) before death within 13 weeks of age.

Pathology of the brain and kidneys

The rats killed just after 8 and 12 weeks of treatment did not have any cerebral hemorrhages when examined during necropsy. In the rats from the 8-week treatment/withdrawal group, the most distinctive lesion was swelling of cerebral hemisphere(s) rather than hemorrhage; hemorrhage was seen in the control rats. In the 24-week treatment/withdrawal group, small cavities filled with a clear fluid were found in the cerebral cortex. These lesions were indicative of previous cerebral tissue infarctions with subsequent lysis and formation of cerebral cysts, which effectively replaced grey matter of the cortex. It was therefore evident that perindopril treatment had prevented stroke during the treatment period and reduced the severity of stroke after withdrawal of treatment.

Histopathologic examination of the brain revealed the absence of lesions in the 8- and 12-week treatment groups. In the untreated and treatment/withdrawal groups, infarcted areas of variable sizes were randomly distributed in the cerebral cortex and the subjacent white matter. Acute, subacute and chronic malacia of grey matter, rarefaction of white matter, and neuronal and glial necrosis and loss were common findings throughout most of the cortex (Fig. 5A). Acute lesions were typified by multifocal hemorrhages, with fibrin deposition around thrombosed blood vessels and occasional perivascular edema (Fig. 5B). In certain areas, there were perivascular, locally diffused infiltrations with neutrophils and macrophages. Subacute and chronic lesions consisted of large vascular thrombi containing multiple small vascular channels lined by hypertrophied endothelial cells, indicative of microvascular recanalization. There were large areas with variably sized cystic structures filled with clear proteinaceous fluid; these were commonly subdivided by strands of fibrous tissue and astrocytic processes (Fig. 5A). These areas contained intense microvascular hyperplasia and gliosis, which consisted of numerous gitter cells, microglia and hyperplastic astrocytes (Fig. 6A). In certain areas, there were numerous scattered macrophages laden with hemosiderin (Fig. 6B).

Overall, the rats from the 8-week treatment/withdrawal group had the greatest severity and frequency of cerebral lesions (Table 1). The severity and frequency of cerebral lesions in the control and 12-week treatment/withdrawal groups were comparable. It should be noted that the rats in the 8- and 12-week treatment/withdrawal groups were much older than those in the control groups. Furthermore, the rats in these 2 groups survived several weeks (2 rats in the 12-week group lived up to 43 weeks) after the development of stroke signs, so the severity of damage would be expected to be worse in these rats than in the control rats, which died within days after the development of stroke signs. Nevertheless, with longer treatment (24 weeks) and after the withdrawal of treatment, the severity of cerebral lesions was less and the frequency was lower than in the control rats and the rats treated for 8 or 12 weeks.

Macroscopically, kidneys from SHRSP given either 8- or 12-week treatment showed normal morphology. In contrast, kidneys from the rats in the control and treatment/withdrawal groups showed pathologic changes, such as a bumpy surface with a mottled white and purple appearance. In some cases, the kidneys were enlarged and edematous, and, in one instance, one of the kidneys was adherent to adjacent tissues and organs.

Histologically, kidneys from the rats in the control and treatment/withdrawal groups exhibited multifocal dilated tubules with poorly differentiated, flattened epithelium containing proteinaceous material (tubulointerstitial lesion). Glomerular lesions ranged from hypercellular to shrunken, with sclerotic wire-loop appearance and flattened epithelium in Bowman's capsule. There was often focal interstitial mononuclear infiltrate. Many arteries had mononuclear infiltrate invading the media, and there was fibrinoid degeneration or necrosis of the blood vessel wall (Table 2).

Treatment of SHRSP with perindopril for 8 or 12 weeks reduced the incidence of fibrinoid necrosis of the blood vessels and tubulointerstitial lesions significantly, but had no effect on the glomerular lesions when compared with control animals (Table 2). After withdrawal of treatment, the severity of all the lesions increased significantly in the 3 treatment/withdrawal groups as compared with the control animals. There was no difference among the 3 treatment/withdrawal groups in the incidence of renal lesions. Perindopril treatment of SHRSP for 8 or 12 weeks significantly attenuated the thickening of the wall in the arterioles at the corticomedullary junction as compared with the 3 treatment/withdrawal groups. Meanwhile, there was no difference in arteriolar thickening between the SHRSP treated with perindopril for 8 or 12 weeks and those in the control group, perhaps because the untreated rats died at an earlier age. After withdrawal of treatment in the 12- and 24-week treatment groups, kidneys from these animals had thicker arteriolar walls than did the kidneys from controls. No significant difference in the thickness of the arteriolar wall was observed between the control animals and the rats from 8-week treatment/withdrawal group. The thickening of the arteriolar wall in the rats from the control and treatment/withdrawal groups was probably related to the longer period of hypertension and the age of these rats.

Hematology

The serum level of creatinine in the untreated SHRSP was in the upper limit of the normal range (Table 3).9 Perindopril treatment at a dosage of 4 mg/kg per day dose for either 8 or 12 weeks significantly reduced the serum level of creatinine (p < 0.05). Withdrawal of the treatment re-established serum creatinine levels at those seen in the untreated SHRSP (Table 3). Similarly, in the SHRSP treated with either 1 or 4 mg/kg per day of perindopril for 24 weeks, the serum level of creatinine at 43 weeks (i.e., 13 weeks after withdrawal of treatment) was similar to that in the untreated SHRSP. The serum level of urea in the control SHRSP was higher than that in normal rats. Perindopril treatment for 8 or 12 weeks significantly lowered the serum urea level to the normal range (p < 0.01 as compared with controls). However, withdrawal of treatment in the 8-, 12- and 24-week treatment groups caused the serum urea level to rise to the level seen in control SHRSP. In contrast, the serum level of albumin was within the normal range in the control, treatment and treatment/withdrawal groups. Since serum albumin levels can be used as an indicator of kidney damage, it appeared that renal damage was more severe in the 8-week treatment/withdrawal group than in the 12-week treatment/withdrawal group, suggesting that a longer treatment had a greater protective effect on the kidneys than a shorter treatment.

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Discussion

Treatment of SHRSP with perindopril is effective in preventing stroke and mortality related to stroke. After an extended period (24 weeks) of treatment with perindopril, the risk of stroke-related mortality after withdrawal of the treatment was significantly reduced. These findings may be relevant to the prevention of stroke in people with essential hypertension through antihypertensive therapy.

Previous studies of SHRSP and antihypertensive treatment with various drugs2­4,6,10,11 concluded that blood pressure was not the only factor involved in stroke development. Studies supporting the hypothesis that stroke can be prevented independent of blood pressure control included treatment with ß-blockers,10,11 ACE inhibitors2­4 and an angiotensin II-receptor antagonist (losartan).6 In contrast, other studies of an ACE inhibitor (cilazapril),12 calcium antagonists,5,13 an angiotensin II-receptor antagonist (losartan)14 and hydralazine12,13 noted a blood pressure normalizing effect and associated prevention of stroke in the SHRSP.

We found that, in untreated SHRSP, stroke development was significantly related to blood pressure and was accelerated when blood pressure surpassed 240 mm Hg. Therefore, a modest suppression of blood pressure by perindopril treatment, to below 240 mm Hg, could have a significant preventive effect. We noticed a transient, rapid increase in blood pressure shortly before stroke development. Such increases often exceeded 70 mm Hg within a few days. Such rapid rises in blood pressure may be particularly important in initiating hemorrhagic stroke in SHRSP and could be missed by less frequent blood pressure measurement, as shown by comparing the results in Fig. 3, when blood pressure of untreated SHRSP was measured less frequently, with those in Fig. 1. The rapid rise in blood pressure in untreated SHRSP compared with treated rats in Fig. 1 was not apparent in Fig. 3. Perindopril treatment may also provide a protective effect through its ability to maintain blood pressure at a steady level below a certain threshold (e.g., 240 mm Hg) during the early developmental period of these animals. Older animals may be able to withstand a higher pressure because of the adaptive structural changes in the cerebral arteries.15

We also found that the protective effect of perindopril depended on the duration of treatment. A longer treatment significantly delayed the onset of stroke after the withdrawal of treatment, and a 24-week treatment prevented stroke-related mortality in all the treated SHRSP up to 43 weeks of age. Treatment of SHRSP with perindopril also has a protective effect on the brain; rats treated for 24 weeks did not develop brain lesions during the treatment period, even in the presence of high blood pressure. After the withdrawal of treatment, the severity and incidence of various types of cerebral lesions were significantly reduced in SHRSP given this longer treatment. Therefore, the prevention of stroke during the treatment period and stroke-related death after the withdrawal of 24-week treatment was probably related to the protective effects of perindopril treatment in preventing these brain lesions. One characteristic of perindopril is that it can cross the blood-brain barrier,16 presumably because of its lipid solubility. There have been reports that brain angiotensin II may play a role in the regulation of blood pressure by its central action.17 The ability of perindopril to penetrate the blood-brain barrier may allow this ACE inhibitor to act on the brain renin-angiotensin system by blocking brain ACE, thus reducing the brain angiotensin II concentration and its central action.

In the kidneys, treatment with perindopril prevented or reduced fibrinoid necrosis of the blood vessels and tubulointerstitial lesions but had no effect on the glomerular lesions. This is probably because the development of these lesions is closely linked to blood pressure, and the blood pressure of the treated SHRSP was still in the hypertensive range (220 mm Hg or higher). This possibility is supported by the observation that, after the withdrawal of treatment, blood pressure increased in these animals and the severity of these renal lesions was also significantly increased. In the spontaneously hypertensive rat (SHR), treatment with perindopril for 12 weeks was effective in permanently preventing hypertension and in increasing the lifespan of these animals.18 Perindopril treatment also reduced the incidence of renal lesions in these rats,18 which is similar to the results we obtained in the SHRSP.

Perindopril treatment also improved renal functions in SHRSP. The increase in serum creatinine and urea levels seen in untreated SHRSP was prevented or attenuated, and this was accompanied by the prevention of stroke in these animals. However, after withdrawal of treatment, renal functions deteriorated to the levels seen in the controls and stroke developed as it had in the untreated SHRSP, although the severity of the stroke was attenuated depending on the duration of treatment. These observations suggested that the renal damage was probably related to the blood pressure rebound after withdrawal of treatment, and the diminished renal function may not be as important in stroke development in SHRSP as some investigators have suggested.19

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Conclusion

Treatment of SHRSP with perindopril was effective in preventing stroke through its effects on blood pressure and on the preservation of brain structure. Perindopril treatment also decreased stroke-related mortality in SHRSP long after treatment withdrawal, showing the long-term benefits of perindopril treatment in this model of hypertension and stroke.

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Acknowledgements

 We thank Servier (France) for its generous supply of perindopril.

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