Renal protective effect of efonidipine hydrochloride (NZ-105), a new calcium antagonist, in spontaneously hypertensive rats

Pergamon

0306-3623(94)00139-1

Gen. Pharmac. Vol. 25, No. 8, pp. 1567-157501994 Copyright ((~ 1994ElsevierScienceLtd Printed in Great Britain.All rights reserved 0306-3623/94$7.00+ 0.00

Renal Protective Effect of Efonidipine Hydrochloride (NZ-105), a New Calcium Antagonist, in Spontaneously Hypertensive Rats C. S H U D O , I Y. M A S U D A , l* H. S U G I T A , ' S. F U R U K A W A , I K. H A Y A S H I , I H. H I R A T A , I S. T A N A K A ' a n d K. T O M I T A 2 tShiraoka Research Station of Biological Science, Nissan Chemical Industries, Lid, 1470 Shiraoka, Minamisaitama, Saitama 349-02, Japan and 2Department of lnternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan lTel: (81)-480-92-2513; Fax: (81)-480-92-2516]

(Received 7 April 1994)

Abstract--l. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increasesof plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

Key Words:NZ-105, calcium antagonist, proteinuria, kidney damage, SHR

INTRODUCTION Hypertension is considered to be the major risk factor that contributes to the progression of renal failure. Aged or uninephrectomized spontaneously hypertensive rats (SHR) have been reported to develop proteinuria and glomerular injury accompanied with the increase of glomerular capillary pressure (Feld et al., 1977; Dworkin and Feiner, 1986). Angiotensinconverting enzyme inhibitors have often been used to improve proteinuria in patients with diabetes meilitus (Parving, 1992). Recently, some calcium antagonists have been suggested to prevent progressive renal failure in animals and humans with chronic renal *To whom all correspondence should be addressed.

disease or hypertension (Luft and Johnston, 1992; Neumayer and Kunzendorf, 1991; Benstein and Dworkin, 1990). Efonidipine hydrochioride (NZ-105) is a new calcium antagonist (Tamura et al., 1991; Masuda et al., 1991; Shudo et aL, 1993a; Muramatsu et al,, 1991). This drug causes a slow-onset and long-lasting hypotensive effect in hypertensive model animals (Masuda et al., 1990). With regard to the effect on the kidney, we have reported that NZ-105 induces a diuretic and natriuretic action which mainly acts at the site beyond the proximal tubulus (Yokoyama et al., 1992). However, the effect of NZ-105 on the kidney damage still remains unknown. Therefore, in the present study, we investigated the renal effect of the long-term administration of NZ-105 in SHR.

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C. SHUDOet al.

1568 MATERIALS AND M E T H O D S

Blood pressure and urinary parameters Male SHR (135-200g) were obtained at 7 weeks old from Hoshino Laboratory Animals (Saitama, Japan) and divided into two groups (ten per group) as follows: the control SHR group and NZ-105treated SHR group. Male Wistar-Kyoto rats (WKY) of the same genetic strain (180-230 g) were used as age-matched control animals. Control SHR and W K Y had free access to a high sodium (0.40%) and potassium (0.75%) diet (SP-diet) and water. The other SHR were given an SP-diet containing 0.075% NZ-105, which was prepared at Funabashi Farms (Chiba, Japan), from 8 weeks old. The systolic blood pressure (SBP) and heart rate were measured by the tail-cuff method (Automatic Monitoring System; UR-5000, U E D A Electronic Works, Ltd, Tokyo, Japan) every 4 weeks. Rats were prewarmed at 36°C for 13 min in a warm box and gently placed in a restraining cage on a heating plate (37°C); they were calmed for 5-15rain before the measurements. To measure the urinary parameters, the urine was collected every 4 weeks. At that time, the rats were placed in metabolic cages individually, and the spontaneous urine was collected for 24 hr. Urinary protein concentration and N-acetyl-fl-glucosaminidase (NAG) activity were determined with a kit purchased from Wako Pure Chemical (Osaka, Japan) and Shionogi (Osaka, Japan), respectively. The creatinine and urea nitrogen concentrations in urine at the last day of the experiment were also determined by each kit (Wako Pure Chemical, Osaka, Japan).

Histological examination The excised kidney and heart were fixed in buffered 10% formalin (Wako Pure Chemical, Osaka, Japan). They were embedded in paraffin and sectioned at a thickness of 4 ttm and stained with hematoxylin and eosin (H.E.). Each section was analyzed histopathologically with a light microscope. A semiquantitative score was used to describe the extent of kidney and heart injuries, ranging from ( - ) to ( + + +).

Statistics The results were presented as the mean + SE and the urinary excretion values except urine volume were expressed per kilogram of body weight. Statistical analysis were performed using one-way analysis of variance followed by Tukey's test for multiple comparison of means. Non-parametric analysis of scores of injuries was performed with the Kruskal-Wallis test, and if significant, it was also performed by Scheffe's method. RESULTS

Body weight and SBP As shown in Fig. !, there was no significant difference in body weight between the two groups of SHR, but the W K Y were heavier than the SHR over t h e experimental period. Food intake in each group was almost maintained at the same level (data not shown). SBP in control SHR increased with age, while the treatment with NZ-105 significantly prevented its elevation (Fig. 2). At 26 weeks old, heart rate in NZ-105-treated SHR was slightly lower than that

Plasma parameters At the end of the experiment, rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and 5 ml of blood was obtained from the vena cava. Plasma renin activity and plasma aldosterone concentration were determined by radioimmunoassay (SRL Co. Ltd, Tokyo, Japan). Plasma creatinine and urea nitrogen were analyzed by means of an auto-analyzer (Hitachi, Model-734). Clearances of creatinine and urea nitrogen (Ccr and Cun) and fractional sodium excretion (FE~a) were estimated from the urinary excretion and the plasma level of creatinine, urea nitrogen and sodium, respectively; Cer (ml/min/kg) = UV x U¢r/Pcr x BW, Cu. (ml/min/kg)= UV x Uun/Pun × BW, FENa (%) = uv

× UN./PN. X Cr.

Organ weights After obtaining the blood sample, the heart, liver and both kidneys were removed and weighed.

(g) (,00-

.I

r

00-

#

#

24

28

300. 2007 8

1

1

20

Age (weeks)

Fig. 1. Changes of body weight in control SHR (©), efonidipine hydrcchloride (NZ-105)-treated SHR (O) and WKY (O) with age. Each point represents the mean + SE of 10 animals. ~ P < 0.05 compared with the corresponding value in WKY.

Renal protective effect of efonidipine

1569

¢mO¢0~)

(mmHg)

$N,

i

#

#

250#

#

~.

#

#*

#,

#,

.#,

#*

.

~IIMP"

2tl0" 150#

IN'

A*

A*

~*

--*

100l0

14

lk

22

26

0"

Age (weeks)

Age (weeks)

Fig. 2. Changes of systolic blood pressure (SBP) in control SHR (©), efonidipine hydrochloride (NZ-105)-treated SHR ( 0 ) and WKY (I-q) with age. Each point represents the mean + SE of 10 animals. *P < 0.05 compared with the corresponding value in SHR control. ~ P < 0.05 compared with the corresponding value in WKY.

Fig. 3. Changes of urinary protein excretion in control SHR (O), efonidipine hydrochloride (NZ-105)-treated SHR ( 0 ) and WKY (I-q) with age. Each point represents the mean _+SE of 10 animals. *P < 0.05 compared with the corresponding value in SHR control. * P < 0.05 compared with the corresponding value in WKY.

Table 1. Effects of efonidipine hydrochloride (NZ-105) on urine volume (UV) and fluid balance 17th week (24 weeks old) Ist day (8 weeks old) 9th week (16 weeks old) UV(ml~ay) balance Group UV (ml/day) balance UV (ml/day) balance 35.3±6.1 0.58±0.07 Control SHR 7.9 ± 0.5 0.30 ± 0.01 19.9 + 2.5 0.52 ± 0.03 14.7±1.4 0.46±0.02 NZ-105-treated SHR 14.6 ± 2.9 0.45 ± 0.03 12.7 ± 1.5 0.46 ±0.03 29.6±4.6 0.56±0.04 WKY 27.8 ± 3.0 0.54 ± 0.03 25.7 ± 3.6 0.53 ± 0.04 Fluid balances (balance) were calculated as follows: UV (ml/day)/water intake (ml/day) Each value represents the mean _+SE of 10 animals.

in control SHR (389.0+9.8 400.9 _ 10.3 beats/min).

beats/min

vs

Urinary parameters Table 1 shows the urinary volume and fluid balance. In W K Y and NZ-105-treated SHR, these were maintained during the experimental period, but in control S H R , urinary volume increased followed by a rise of the fluid balance values. In control SHR, unlike the other two groups, water intake also increased with age (data not shown). Urinary protein excretion markedly elevated from 16 weeks old in control SHR, while that in the NZ-105-treated group was maintained almost at the same level as in W K Y (Fig. 3). At 28 weeks old, the urinary N A G activity in NZ-105-treated S H R was slightly lower than that in control S H R (Fig. 4).

Plasma parameters The plasma renin activity (PRA) and the aldosterone concentration (PAC) in NZ-105-treated S H R were significantly reduced in comparison with control S H R (Fig. 5). As shown in Table 2, the plasma creatinine and urea nitrogen concentrations i n c o n ' trol S H R increased slightly and the long-term administration of NZ-105 lowered their concentrations. The

other plasma parameters affected by NZ-105.

were not

significantly

Clearance and fractional sodium excretion The clearance and fractional sodium excretion

(FENa) were calculated as the index of renal function and the extent of renal tubulus injuries. Creatinine and urea nitrogen clearances were not significantly different between W K Y and control SHR, but they

(U~)

Iit

!iiiiiiiiiiii!ii i:i:i:!:!:i:!:i: ::::::::::::::::::::::

0

Fig. 4. Urinary NAG activity at the last day of the experiment in WKY (open column), control SHR (dot column) and efonidipine hydroehloride (NZ-105),treated SHR (solid column), Each point represents the mean + SE of 10 animals. * P < 0.05 compared with the corresponding value in WKY.

C. SHUDO et al.

1570

(ns/ml/h)

PRA

(win,)

40

PAC

500

~

!i!i!i!iiiiiiii: ....-..

400

• .....

,1,:.:,2.:.:.:.:

ili~!i!i!i!i!i

300

20-

ii!iiiiiiiii!i!i i :i:i:i:i:!:!:!:! ,..............

:Z0~

,o

ililiiiiiii!iill

,o~

...............

]

T

:.:.:.:.:.:.:.:

:~:i:!:!:!:!:i: •........... • "'""'"'"'"

0

Fig. 5. Plasma renin activity (PRA; left graph) and plasma aldosterone concentration (PAC; right graph) at the last day o f the experiment in WKY (open columns), control SHR (dot columns) and efonidipine hydrochloride (NZ-105)-treated SHR (solid columns). Each point represents the mean_+ SE of 9-10 animals. *P < 0.05 compared with the corresponding value in SHR control. # P < 0.05 compared with the corresponding value in WKY.

were h i g h e r in N Z - 1 0 5 - t r e a t e d S H R t h a n in the o t h e r t w o g r o u p s (Table 3). FENa in c o n t r o l S H R h i g h e r t h a n t h o s e in the o t h e r g r o u p s .

was

Histological examination Histological e x a m i n a t i o n o f the k i d n e y in c o n t r o l S H R revealed a large n u m b e r o f glomeruli s h o w i n g swelling a n d hyalinization, renal tubules s h o w i n g d i l a t a t i o n c o n t a i n i n g hyaline casts, a t r o p h y a n d

Organ weights T a b l e 4 s h o w s the weights o f the heart, liver a n d b o t h kidneys. In N Z - 1 0 5 - t r e a t e d S H R , the h e a r t a n d b o t h k i d n e y s w e i g h t s n o r m a l i z e d to b o d y weight were significantly smaller t h a n t h o s e in c o n t r o l S H R . T h e liver w e i g h t s a m o n g S H R g r o u p s did n o t significantly differ.

d e g e n e r a t i o n , a n d arteriolosclerosis were o b s e r v e d (Fig. 6a, b a n d c) a n d t h o s e c h a n g e s were m o r e severe in the j u x t a m e d u l l a r a t h e r t h a n cortex. T w e n t y weeks o f t r e a t m e n t with N Z - 1 0 5 significantly d e c r e a s e d the g l o m e r u l a r histological c h a n g e s (Table 5 a n d Fig. 6d, e). T a b l e

5 s h o w s the scores o f renal

Table 2. Plasma concentrations of various parameters after the chronic treatment of efonidipine hydrochloride (NZ-105) Creatinine Urea nitrogen Total protein Albumin Sodium Potassium Group (mg/dl) (mg/dl) (g/dl) (g/dl) (mEq/l) (mEq/l) Control SHR 0.58±0.06 25.1 ±2.3 5.35±0.11 1.76 ± 0.05~ 143±2.0 3.1 ± 0.1";" NZ-105-treated SHR 0.41 + 0.02* 17.2 ± 0.7* 5.43 + 0.10 1.83 ± 0.03 143 ± 1.3 3.1 ± 0.1";" WKY 0.43 ± 0.02 20.2 ± 0.9 5.46 ± 0.16 1.94 ± 0.04 144 ± 0.3 3.4 ± 0.1 Each value represents the mean ± SE of 10 animals. *P < 0.05 compared with the corresponding values in control SHR. "I'P < 0.05 compared with the corresponding values in WKY. Table 3. Creatinine and urea nitrogen clearances (Ccr and Cu,) and fractional sodium excretion (FEN~)after the chronic treatment of efonidipine hydrochloride (NZ-105)

C~r

Cu.

FEn.

Group (ml/min/kg) (ml/min/kg) (%) Control SHR 5.82 ± 0.45 2.36 ± 0.21 0.94 ± 0.29 NZ-105-treated SHR 6.41 ±0.37 3.17±0.12"? 0.62±0.05 WKY 5.70 ± 0.34 2.36 ± 0.15 0.62 ± 0.02 Each value represents the mean ± SE of 10 animals. *P < 0.05 compared with the corresponding values in control SHR. t P < 0.05 compared with the corresponding values in WKY.

Table 4. Organ weights of 28 week old rats after the chronic treatment of efonidipine hydrochloride (NZ-105) Heart Group

(g)

Control SHR 1.66 ± 0,04"[" NZ-105-treated SHR 1.42 ± 0.02* WKY 1.48 ± 0.03 Each value represents the mean ± SE of 10 animals. with the corresponding values in WKY.

Liver (g/kg)

(g)

Kidney (g/kg)

(g)

(g/kg)

4.76 ± 0.23"I" 12.2 ± 0.49"1" 34.5 ± 0.37"1' 2.63 ± 0.09"1" 7.50 _+0.3 It 3.78 ± 0.07"1" 12.5 ± 0.32"t" 33. I ± 0.60"t 2.45 ± 0.05"1" 6.49 ± 0.09"i" 2.92 ± 0.08 14.9 _+0.64 29.2 ± 0.67 2.89 ± 0.06 5.68 ± 0. I 1 *P < 0.05 compared with the corresponding values in control SHR. t P < 0.05 compared

Fig. 6(a-c)--legend overleaf.

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C. SHUDOet al.

Fig. 6. Histological examination. (a) Many tubules with dilatation containing hyaline casts and some tubules exhibit atrophy and basophilic change in control SHR. H.E. x 80. (b) A glomerulus exhibiting swelling and hyalinization in control SHR. H.E. x 200. (c) Some arterioles exhibit arteriolosclerosis in control SHR. H.E. x200. (d) Few tubules with dilatation containing hyaline casts in efonidipine hydrochioride (NZ-105)-treated SHR. H.E. x80. (e) Some arterioles exhibit arteriolosclerosis in NZ-105-treated SHR. H.E. x 200 damages. As shown in Table 6, the scores of heart damage such as fibrosis, degeneration and arteriolosclerosis were not improved by NZ-105; only hypertrophy was significantly inhibited. DISCUSSION It is well known that renal failure may be the cause or the result of hypertension and a vicious circle is often established. Thus, an important aim of an antihypertensive drug is to prevent renal damage. In

this study, the results indicate that NZ-105 possesses a renal protective effect: NZ-105 (1) inhibited the development of proteinuria in SHR; (2) suppressed the histological changes in the renal glomeruli, tubules and arteriole; and (3) protected the increase in the kidney weight. Although the renal plasma flow (RPF) in hypertensive patients and SHR is generally low, the glomerular filtration rate (GFR) is maintained constant by a renal autoregulation (Feld et aL, 1977; Dworkin and Feiner, 1986), the mechanism of which is considered to be due to a regulation of

Renal protective effect of efonidipine

1573

Table 5. Degree of renal damage after the chronic treatment of efonidipine hydrochloride(NZ-105) Control SHR Finding

-

_

+

++

Glomerulus Swelling and hyalinization Dilatation of Bowman's capsule Thickening of Bowman's wall

2 3 3

3 7 2

5 0 5

0 0 0

Renal tubule Dilatation and hyaline cast Atrophy and degeneration

2 1

I 3

3 1

Stroma Infiltration of inflammatory cells Arterioloselerosis Fibrosis

2 0 2

2 2 7

5 2 1

NZ-105-treated SHR +++

-

_

+

++

0 0 0

10" 10" 10"

0 0 0

0 0 0

0 0 0

4 5

0 0

6* 5*

4 5

0 0

1 6 0

0 0 0

9* 4* 10"

1 6 0

0 0 0

WKY

+++

-

___

+

++

+++

0 0 0

10" 10" 10"

0 0 0

0 0 0

0 0 0

0 0 0

0 0

0 0

10" 9*

0 1

0 0

0 0

0 0

0 0 0

0 0 0

10" I 0* 10"

0 0 0

0 0 0

0 0 0

0 0 0

- , normal; + , slight; + , mild; + + , moderate; + + + , severe. *P < 0.05 compared with the scores in control SHR group. Table 6. Degree of heart damage after the chronic treatment of efonidipine hydrochloride (NZ-105) Control SHR

NZ-105-treated $HR

Finding

-

+

+

+ +

+ + +

Fibrosis Degeneration Hypertrophy Arteriolosclerosis

0 0 I I

8 8 0 4

2 2 6 5

0 0 3 0

0 0 0 0

WKY

-

__.

+

+ +

+ + +

-

+

+

+ +

+ + +

I 2 2* 3

8 7 6 6

1 1 1 1

0 0 1 0

0 0 0 0

6* 6* 5* 10"

4 4 4 0

0 0 I 0

0 0 0 0

0 0 0 0

- , normal; +, slight; + , mild; + + , moderate; + + + , severe. *P < 0.05 compared with the scores in control SHR group.

afferent and efferent arteries. However, when the kidney reaches the limit of renal autoregulation, SBP reaches to intraglomerulus regions and causes proteinuria and renal damage. In our present study, we gave a high sodium and potassium diet (SP-diet) to SHR to accelerate renal damage by hypertension. As a result, a steep increase of proteinuria was observed in control SHR from 16 weeks of age, in contrast to other reports (Feld et al., 1977, 1990; Oizumi et al., 1989) in which proteinuria developed after 30 weeks. The changes of the glomerular permeability associated with the increase of intraglomerular pressure have been reported to be one of the causes for proteinuria (Dworkin and Feiner, 1986; Messina et al., 1987). As shown in Fig. 3, the long-term administration of NZ-105 almost completely inhibited the increase of proteinuria. These findings suggest that NZ-105 lowers the intraglomerular pressure and suppresses glomerular injury, which is consistent with the histological observations showing almost no glomerular injury in NZ105-treated SHR (Table 5). The histological findings also showed that the chronic treatment with NZ-105 significantly inhibited the tubular and arterial injuries, but these inhibitory effects were weaker than those seen in glomeruli. At the end of the experiment, we determined the urinary NAG activity and fractional sodium excretion as a sensitive index of the renal tubular damages (Mansell et al., 1978). Both values in control SHR were higher than those in WKY, and NZ-105 slightly decreased them. Arteriolosclerosis was significantly reduced in NZ-105-treated SHR than control SHR. We have

reported that NZ-105 suppresses the proliferation of rabbit aortic smooth muscle cells (Kitahara et al., submitted; Toyoda et al., 1994). Therefore, the inhibitory effect of NZ-105 on the arterial changes may be due to its direct action. In our study, the kidney weight in NZ-105-treated SHR was lower than that in control SHR. This was in agreement with the effect of NZ-105 administration to SHR for 12 weeks (Shudo et al., 1993b). Feld et al. (1977) have shown that the heart weight in SHR increases with blood pressure. However, increased kidney weight is associated with the development of proteinuria. These findings indicate that the reduction in kidney weight is also one of the results that NZ-105 protected from the development of proteinuria. An increase in plasma creatinine concentration (Per) and a reduction in creatinine clearance (C,) have been reported in SHR (Feld et al., 1977). Although our findings showed that both Per and Cc~ in control SHR did not significantly differ from those in WKY, the chronic treatment with NZ-105 slightly improved each parameter. In addition, the experiment using conscious or anesthetized SHR have shown increases in RPF by NZ-105 (Yokoyama et aL, 1992; Yotsumoto et al., in press). These renal hemodynamic effects may also contribute to the renal protective effect of NZ-105. The SBP in control SHR was higher than that in WKY throughout the experimental period, while the long-term administration of NZ-105 significantly suppressed the elevation of SBP in SHR. Significant correlations were observed between SBP and urinary protein excretion, and between SBP and the extent of

1574

C. Sl-lUOOet al.

glomerular injury (r = 0.79 and 0.76, respectively). Therefore, the reduction in SBP is considered to be a major reason for the inhibition of proteinuria caused by NZ-105. Other calcium antagonists, e.g., felodipine (Nordlander and Havu, 1992), nifedipine (Dworkin et al., 1991) and nitrendipine (Mohacsi and Sonkodi, 1988), also suppressed the proteinuria at doses that lower SBP. However, triple drug therapy consisting of reserpine, hydralazine and hydrochlorothiazide have been reported to significantly aggravate glomerular injury in SHR (Raiji et al., 1985) and rats with reduced renal mass (Lafayette et al., 1992) in spite of the normalization of blood pressure. Moreover, the lack of a renal protective effect of hydralazine (Jarusiripipat et al., 1992) or dihydralazine (Mohacsi and Sonkodi, 1988) has been reported. These findings suggest that the decrease of urinary protein excretion produced by long-term administration of NZ-105 can not solely be explained on the basis of sustained lowering of SBP. NZ-105 causes diuretic and natriuretic effects in conscious SHR during both acute and chronic oral administration (Masuda et al., 1990). In this study, the diuretic effect of NZ-105 was noted only on the first day of treatment. However, the diuretic effect of NZ-105 has been reported to be maintained for 12 weeks in SHR (Yotsumoto et aL, in press). The lack of the diuretic effect in this study was attributed to the loss of fluid balance in control SHR with age. The fluid balance in NZ-105-treated SHR remained constant throughout the experimental period; indicating that NZ-105 has a favorable effect on the kidney. Calcium antagonists increase the PRA accompanied with their hypotensive action. One of the other beneficial effects noted in our study was that PRA was reduced by long-term administration of NZ-105, and this suggests that NZ-105 suppresses the activation of the renin-angiotensin system to compensate for the hypotension. CONCLUSION These findings indicate that the long-term administration of NZ-105 prevented proteinuria and glomerular damage in SHR and that NZ-105 is proposed to have a renal protective effect. The mechanisms involved in this effect were considered to normalization of glomerular pressure, the inhibition of kidney hypertrophy, the improvement of renal function in addition to the lowering of blood pressure. Therefore, NZ-105 may be a useful antihypertensive drug with a renal protective effect.

SUMMARY We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in SHR. SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. In the control SHR (drugfree diet), 24-hr urinary protein excretion increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in WKY, matched control animals, throughout the experimental period. At the end of the treatment period, the histological changes of the kidney were examined by light microscopy. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. Although the kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. In conclusion, NZ-105 is considered to inhibit the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

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