CLIN. AND EXPER.THEORY AND PRACTICE, A9(2&3), 409413 (1987) PREVENTION OF RENAL DAMAGE AND DECREASE OF URINARY KININS EXCRETION BY CHRONIC TREA"TS WITH ENALAPRIL AND CAPTOPRIL IN STROKEPRONE SPONTANEOUSLY HYPERTENSIVE RATS Koichiro Kawashima, Takushi X. Watanabe*, Hirofumi Sokabe* and Ken Saito** Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Departments of *Pharmacology and **Pathology, Jichi Medical School, Tochigiken, Japan. Key words: Renal Damage SH3SP Captopri 1 Ena 1 apr i 1 Kinins INTRODUCTION: The antihypertensive mechanism of converting enzyme inhibitors (CEI) has not been completely established yet (1). It has been suggested that accumulation of hypotensive vasodilator kinins in the kidney in addition to the reduced formation of angiotensin (ANG) I1 could also contribute to the antihypertensive effect of CEI (2). The strokeprone spontaneously hypertensive (SHRSP) rat is an excellent model for the study on antihypertensive effect of CEI because its extremely high blood pressure depends partly on the activated reninangiotensin (RA) system (3) and its responsiveness to CEI has been well confirmed in our previous studies (46). We have observed that enalapril tends to decrease urinary kinins excretion (UKINV) in SHRSP rats in the shortterm study (6). To investigate further the possible involvement of renal kinins in the antihypertensive effect of CEI, we studied effects of chronic treatments with enalapril and captopril on blood pressure, UKINV and renal damage in SHRSP rats. MATERIALS AND METHODS: Urine and the kidney samples sere obtained from 14 to 15weekold male SHRSP rats used in the previous study 40 9 Copyright 0 1987 by Marcel Dekker, Inc.
W K 3 v) W 41 0 mmhg 300 250 K n n 0 4 m 200 4 a I SHRSP KAWASHIMA ET AL. p (5) 7 l 0 H20 L L m 5ml/kg. PO (10) **! (10) 5 0 enalapril 10mg/kg, PO (10) A captopril 30mg/kg, PO (10) E I I 1 I I I I I 1 t 1 I I 0 1 2 3 4 5 6 7 8 9 1 0 1 1 w k FIG. 1. Effects of enalapril and captopril on blood pressure in SHRSP rats. Treatments were started at 14 to 15 weeks of age. Values are mean 5 S.E.M. *P < 0.05, **P < 0.01, compared to the control. (5). Rats were treated with orally administered either water as control, enalapril (10 mg/kg), or captopril (30 mg/kg) once daily for 11 weeks. Food and water were offered ad libitum. Blood pressure was determined indirectly by tailcuff method (5). At the end of the treatment, direct mean blood pressure (MBP) was monitored through the indwelling aortic catheter (3). On the 3rd day, and during the 5th and 10th week of the treatment, rats were placed in individual metabolism cages with water and powdered rat food offered ad libitum. Twentyfourhr urine sample was collected into a graduated cylinder containing 100 p1 of 6 N HC1. UKINV was determined by a radioimmunoassay (7) * Histological study on the kidney was performed on the 4 vm sections stained with hematoxylineosin or Elasticavan Giesen. The severity of renal damage was graded from 0 to 3 according to the following criteria: grade 0, no discernible vascular lesion; grade 1, a few vascular lesions without remarkable parenchymal
PREVENTION OF RENAL DAMAGE 41 1 1 1 Hz0 5ml/kg, PO enalaprii captopril lomg/kg, PO 30mg/kg, PO ** ** 1 wk 5wk lowk FIG. 2. Effects of enalapril and captopril on urinary kinins excretion. Values are mean 2 S.E.M. Data of the 1st week were obtained on the 3rd day of the treatment. **P < 0.01, compared to the control. destruction; grade 2, scattered vascular lesions with focal parenchymal destruction; grade 3, disseminated vascular lesions with remarkable parenchymal destruction. RESULTS: In enalapril and captopril treated groups, a rapid and significant decrease of blood pressure from about 250 to around 200 mmhg was observed soon after the beginning of the treatment (FIG. 1) (5). Although blood pressure in the drug treated groups tended to return gradually towards the pretreatment level during the treatment, it was significantly lower than that in the control group at almost all the points of the determination.
41 2 KAWASHIMA ET AL. TABLE 1 Effects of chronic treatments with enalapril and captopril on the severity of renal damage in adult SHRSP rats Severity of renal damage Treat men t mean 2 S.E.M. of Grade: 0 1 2 3 severity grade Enalapril 4 4 2 0 0.8 2 0.3** (10 mgkg per day) Captopril 1 4 4 1 1.5 2 0.3** (30 mg/kg per day) Figures indicate number of rats.?data of rats died before completion of the experiments were included. **P < 0.01, compared to the control. Criteria for severity grade of the renal damage are shown in the section of MATERIALS AND METHODS. Urine volume (W) in the control group increased significantly during the 5th and 10th week of the treatment ( 5). A positive correlation was observed between W and MBP (r = 0.724). As early as on the 3rd day of the treatment, U K ~ ~ in V drug treated groups tended to decrease. Marked decreases in UKINV in the drug treated groups were observed during the 5th and 10th week of the treatment (P < 0.01) (FIG. 2). A positive correlation was found between ~ I N V and W during the 10th week of the treatment (r = 0.812). Severe vascular lesions and remarkable parenchymal destruction were observed in the control group. The value for renal damage in the control group was significantly higher than those in groups treated with CEI (P < 0.01) (TABLE 1). The severity of renal damage positively well correlated with the MBP (r = 0.896), and with W (r = 0.746). DISCUSSION: Chronic treatments with enalapril and captopril produced significant reductions of blood pressure and UK~NV, and prevented renal damage in adult SHRSP rats. UKINV tended to decrease soon after the beginning of the treatment and was significantly decreased during the chronic treatment with CEI. These results are consistent with the previous study (6). Thus, these data do not support the hypothesis of possible additional involvement of renal kinins in the antihypertensive effect of CEI. In the SHRSP with activated RA system (3), enalapril and captopril appear to
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