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1 Department of Urology and 3 Department of Medical Engineering and System Cardiology, Kawasaki Medical School, Okayama 701-0192; and 2 Cardiovascular Diseases Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Tsukuba, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We developed a videomicroscope system with a charge-coupled device camera and evaluated it in the investigation of the glomerular microcirculation in normal [Wistar-Kyoto (WKY)], spontaneously hypertensive (SHR), and streptoyotocin-induced diabetic rats (STZ). In WKY, the diameter of the afferent arterioles (Af) was 11.9 ± 0.7 µm and that of the efferent arterioles (Ef) was 8.9 ± 0.7 µm. Af and Ef in each glomerulus could be visualized simultaneously with continuous recording of blood pressure and renal blood flow. In SHR, Af diameter was constricted to ~60% of that in WKY. A dose-dependent dilation of Af and Ef was observed after administration of barnidipine (1-10 µg/kg iv), a calcium channel antagonist, in all three groups. No change was seen in the Af-to-Ef diameter ratio (Af/Ef ratio) in WKY. In SHR, the Af/Ef ratio increased significantly because of the marked dilation of Af after barnidipine administration. In contrast, barnidipine dilated Ef in STZ, causing a significant reduction in the Af/Ef ratio. This system can analyze in vivo glomerular microcirculation and systemic macrocirculation simultaneously, allowing more direct investigation of the characteristics of and acute changes in glomerular microcirculation in pathological animals.
videomicroscope; afferent arteriole; efferent arteriole; glomerular microcirculation; barnidipine hydrochloride
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE GLOMERULAR MICROCIRCULATION regulates glomerular filtration and renal hemodynamics by altering the vascular resistance of afferent arterioles (Af) and efferent arterioles (Ef) (1). Histological cast studies demonstrated Af constriction in spontaneously hypertensive rats (SHR) (7, 16), and this is possibly one cause of the onset of hypertension (19). It has also been reported that a characteristic reduction in Af vascular resistance is seen in streptozotocin-induced diabetic rats (STZ) (28), and it has been confirmed that STZ exhibit hyperfiltration in which the glomerular filtration rate and glomerular hydrostatic pressure increase. Therefore, changes in glomerular microcirculation are a feature of renal and circulatory diseases.
Several experimental methods have been developed to study glomerular microcirculation directly. However, it is difficult to apply the micropuncture method to a spontaneous model (e.g., SHR) because Munich-Wistar rats can be used for direct puncture of Af and Ef near the glomerulus (2). Hydronephrotic rats (10, 22) can be used to investigate the effects of vasoactive substances only in nonfiltering glomeruli. Cast studies can morphologically demonstrate vascular diameter in normal and pathological models but cannot demonstrate acute changes in the glomerular microcirculation (7, 16, 19). Isolated in vitro glomeruli have been used to visualize responses to exogenous stimulation (12, 23) in Af or Ef. Each method has limitations in the direct investigation of in vivo glomerular microcirculation.
We previously developed a needle-probe charge-coupled device (CCD) videomicroscope to observe endocardial microvessels in the beating heart of anesthetized pigs and dogs (9, 24). The tip diameter was 4.5 mm, and spatial resolution was 5 µm. The constrictive action of angiotensin II (25) and angiotensin-converting enzyme inhibitor (18) in the canine glomerular microcirculation was also visualized in a subsequent study. Recently, we developed a pencil-probe CCD videomicroscope to study the glomerular microcirculation in small animals directly, more easily, and under physiological conditions. The newly developed cone-shaped lens allows a tip diameter of 1 mm, magnification of ×520, and spatial resolution of 0.86 µm, permitting each erythrocyte in the glomerulus to be identified.
Using this system, we directly observed systemic hemodynamics and in vivo glomerular microcirculation in anesthetized rats. The characteristics of the glomerular microcirculation in SHR and STZ were demonstrated, and acute changes in glomerular microcirculation were studied after intravenous administration of [3'S]-1-benzyl-3-pyrrolidinyl methyl[4S]-2,6-dimethyl-4-[m-nitrophenyl]-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (barnidipine) (11), a calcium channel antagonist developed by Yamanouchi Pharmaceutical (Tokyo, Japan).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Pencil-probe videomicroscope with a CCD camera.
The experimental system consists of a special-ordered pencil-probe
videomicroscope with a CCD camera (Nihon Kohden, Tokyo, Japan),
micromanipulator, light source (LA- 60Me, Hayashi, Tokyo, Japan),
monitor (PVM-146J, Sony, Tokyo, Japan), videocassette recorder
(VCR; WV-ST1, Sony), and a computer for image analysis (Power Macintosh
G3, Apple Computer, Cupertino, CA) (Fig.
1). The system was modified for renal use
from our previously reported needle-probe CCD videomicroscope system
(9, 24). By employing a corn-shaped lens (optical
magnification = × 13.5, F number = 16.15) without an
interventing relay lens, we were able to reduce the diameter of the tip
to 1 mm. Ample light volume was secured from the xenon light source by
distributing 8 optical fibers around the tip of the lens. The lens was
fitted with a 12.7-mm grayscale CCD image sensor (IK-C41MF, Toshiba,
Tokyo, Japan) at the focal length (200 mm) of the lens. A green filter
to complement red was placed in front of a CCD image sensor to enhance
the contrast on the monitor between vessels and peripheral tissue. The
images formed on the CCD image sensor were converted to grayscale video signals and videotaped on a VCR as a continuous image at 30 frames/s (60 fields/s). The final spatial resolution of the videomicroscope was
confirmed to be 0.86 µm with electrical magnification of ×520. The
scale of the captured video image was 435 × 327 µm on the display, so this system could monitor only one glomerulus in each experimental protocol.
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Experimental protocol. The experimental protocol was approved by the Committee on Animal Research of Kawasaki Medical School. Fourteen-week-old male SHR (n = 7), Wistar-Kyoto rats (WKY) (n = 6), and STZ rats (n = 7), weighing between 250 and 340 g, were used. Diabetes was induced in the STZ group by injection of 55 mg/kg STZ (Sigma, St. Louis, MO) in the tail vein of 12-wk-old WKY, 2 wk before the experiment.
Rats were anesthetized with 100 mg/kg (ip) thiobutabarbital (Wako Chemicals, Osaka, Japan). A polyethylene catheter (PE-50) for measuring blood pressure was inserted in the right femoral artery. The right femoral vein was cannulated with a PE-50 catheter for administration of drugs. The left kidney was exposed via a flank incision and isolated from surrounding tissues. After the left renal artery was detached, a probe (inside diameter 1 mm) for measuring renal blood flow (RBF) was attached to it and connected to an ultrasonic flowmeter (Transonic Systems, Ithaca, NY). The arterial catheter was connected to a pressure transducer (TP-400, Nihon Kohden), and blood pressure was continuously recorded via a polygraph system (RM-6100, Nihon Kohden). Heart rate (HR) was measured by blood pressure pulse wave via a tachometer (AT-601G, Nihon Kohden). RBF was also continuously recorded via a polygraph system. The capsule of the renal cortex was removed, and the renal surface was incised (diameter, 1 mm; depth ~0.5 mm) using a scalpel at an extrarenal (Zondek line) location with little vascular predominance as in nephrolithotomy. The tip of the pencil-probe CCD videomicroscope, which was fixed to a micromanipulator capable of adjusting the coordinates on the X-, Y-, and Z-axes, was then guided diagonally to the inside edge of the excision on the renal surface. Lateral glomeruli from the inside edge of the excision not affected by the excision were observed. Superficial glomeruli in which Af, Ef, and the glomerular outer boundary could be confirmed and in which blood flow was not influenced by surgical insult were used in the experiment. One glomerulus per left kidney per rat was monitored in each protocol. The number of glomeruli and the number of animals is the same, and all parameters were measured in each rat. The direction of blood flow in Af and Ef was determined by first compressing them with the tip of the videomicroscope to lower erythrocyte flow rate. During observation of the glomerular microcirculation, a distance of 20-30 µm was maintained so that the videomicroscope did not inhibit glomerular blood flow. The images of glomeruli were continuously recorded on a VCR. Glomerular microcirculation parameters were analyzed after the end of the experiment. Basal mean blood pressure (MBP), HR, and RBF values were measured before administration of drugs, after hemodynamics and glomerular microcirculation had stabilized. Af and Ef diameters and glomerular size were measured using the glomerular images recorded on videotape at the same time point. Barnidipine (Yamanouchi Pharmaceutical) was dissolved in distilled water and diluted with 0.9% saline. After each parameter was measured, barnidipine (1 µg/kg iv) was administered to the rats. Ten minutes later, hemodynamic and glomerular parameters were remeasured. The dose of barnidipine was increased to 3 µg/kg and then to 10 µg/kg, and each parameter was measured 10 min after each administration. Thiobutabarbital was administered subcutaneously when necessary to maintain a constant level of anesthesia during the experiment.Measurement of arteriolar diameter and glomerular size.
The image at each measurement point was captured as a stack of 3-s,
90-frame images using an image capture board (LG-3, Scion Computer
Service, Frederick, NV) installed in the image analysis computer. One
clear frame not influenced by respiration and heartbeat was selected
from the 90 frames in the captured stacks and analyzed. To measure Af
and Ef diameters, National Institutes of Health (NIH) image software
(NIH, Bethesda, MD) was used to set the measurement position of Af and
Ef near glomeruli (<100 µM) common to each measurement point, and
the change in grayscale was displayed in a direction vertical to the
vascular wall (Fig. 2). The difference in
the grayscale between the peak value and the value of mean noise level
was divided into quarters, and the position with a density one-quarter
higher than the noise level was identified as an inner wall. Yada et
al. (24) have validated this green filter diameter as a
diameter of microvessels by using fluorescein isothiocyanate dextran in
canine subepicardial arterioles. Glomerular size was converted into
square micrometers in the same manner after the border of the glomeruli
was traced and the total number of pixels inside was measured.
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Statistical analysis. All data are expressed as means ± SE. Repeated one-way ANOVA was used for comparison within each group and for comparison of basal values among groups. Two-way ANOVA was used for comparison among groups of the effects of barnidipine on MBP and glomerular size. When ANOVA revealed a significant difference in any of the comparisons, a multiple comparison was performed using Dunnett's test. P < 0.05 was considered to indicate a significant difference.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Typical WKY, SHR, and STZ glomerular images acquired by this
system are shown in Fig. 3. Af, Ef, and
glomeruli in WKY were visualized clearly, and it was possible to
measure hemodynamic values (MBP, HR, and RBF) simultaneously.
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There was no difference between SHR (n = 7) and WKY (n
= 6) in terms of plasma glucose concentration (107 ± 2 and
115 ± 3 mg/dl, respectively), body weight (BW; 308 ± 5 and
324 ± 5 g, respectively), and kidney weight (KW; 0.36 ± 0.01 and 0.32 ± 0.01 g/100 g BW, respectively). Mean values
for the seven SHR showed that basal MBP was ~1.8 times higher,
and Af diameter was ~60% of that of WKY (Table
1). However, there was no
difference in RBF and Ef diameter between the two groups.
Although there was no difference in BW between the STZ (n =
7) group and the other groups, the plasma glucose concentration of STZ
was 
3 times higher than that of WKY (392 ± 3 mg/dl, P
< 0.01 vs. WKY), and KW was also higher (0.52 ± 0.03 g/100
g BW, P < 0.01 vs. WKY). In the seven STZ, there were not
significant increases in RBF and Af diameter compared with WKY (Table
1). There was no difference in MBP and Ef diameter between STZ and WKY.
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Intravenous administration of barnidipine (3 and 10 µg/kg) lowered
MBP dose dependently in WKY (P < 0.01) (Table 1). The maximum dose of barnidipine (10 µg/kg iv) also lowered RBF. Af were
slightly dilated after administration of barnidipine (1 and 3 µg/kg),
and Af diameter after administration of barnidipine (10 µg/kg) was
significantly (P < 0.01) larger than basal Af diameter. Barnidipine (3 and 10 µg/kg) also induced a significant (P
< 0.05, P < 0.01, respectively) dose-dependent
increase in Ef diameter compared with basal Ef diameter. Barnidipine
did not affect the Af-to- Ef diameter ratio (Af/Ef) (Fig.
4).
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Intravenous administration of barnidipine (1, 3, and 10 µg/kg) caused
a dose-dependent reduction in MBP in SHR (Table 1). Barnidipine (1 and
3 µg/kg iv) resulted in a dose-dependent increase in RBF (P
< 0.01), but barnidipine (10 µg/kg iv) decreased RBF (P
< 0.01). Af diameter after administration of barnidipine (3 and
10 µg/kg) increased significantly (P < 0.01) in a
dose-dependent manner compared with the basal measurement. Similarly,
barnidipine (3 and 10 µg/kg iv) also resulted in a significant
(P < 0.05, P < 0.01, respectively)
dose-dependent increase in Ef diameter in SHR. Barnidipine (3 and 10 µg/kg iv) caused an increase in the Af/Ef ratio (Fig. 4). A typical
image of the acute effects of barnidipine on glomerular
microcirculation in SHR is shown in Fig.
5.
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Barnidipine (1, 3, and 10 µg/kg iv) lowered the MBP dose dependently in STZ (Table 1). After administration of the maximum dose (10 µg/kg), RBF decreased and Af were dilated in STZ (P < 0.01). On the other hand, Ef diameter was also increased in STZ after administration of barnidipine (3 µg/kg), and a greater increase was observed in Ef diameter after administration of 10 µg/kg (P < 0.01). The maximum dose of barnidipine (10 µg/kg) resulted in a significant reduction in the Af/Ef ratio (P < 0.01) (Fig. 4).
The percent change from basal values in MBP is shown in Fig.
6. The depressor effect induced by
barnidipine administration was significantly (P < 0.01)
larger in SHR compared with WKY, but no difference was seen between STZ
and WKY (Fig. 6). Barnidipine administration did not produce a change
in glomerular size in WKY. Additionally, there was no difference in the
percent change in glomerular size between SHR and WKY, although it
decreased in STZ compared with WKY (P < 0.05) (Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Using this system, in vivo Af, Ef, and glomeruli were visualized without the use of the hydronephrotic method in WKY, SHR, and STZ. Continuous images of fast-moving erythrocytes in arterioles and intraglomerular capillaries were obtained in this study. The heartbeat caused slight dilation and constriction of glomeruli. Because it is difficult to express the results of our observations of moving images clearly using still images, those data are not included here.
Using the previous system able to measure Af and Ef diameter in vivo, Steinhausen et al. (22) reported that Af and Ef diameters were 7.9 ± 0.5 and 7.7 ± 0.5 µm, respectively, in hydronephrotic rats. Hirata et al. (10) reported Af and Ef diameters of 11.5 ± 0.3 and 10.8 ± 0.2 µm, respectively. Although it should be noted that these studies differed from ours in their use of hydronephrotic rats, the mean Af and Ef diameters found in this study (11.9 ± 0.8 and 8.8 ± 0.7 µm for Af and Ef, respectively) as calculated from still images of six WKY were nearly equivalent to the diameters reported in previous studies.
Basal Af diameter (6.8 ± 1.1 µm) in SHR with developed hypertension was demonstrated to be smaller than that in WKY (11.9 ± 0.8 µm). Enhancement of autoregulatory mechanisms has been reported in SHR, including a myogenic response (14) and a tubuloglomerular feedback response (3). However, there were controversial reports on basal Af tonicity in SHR. One report demonstrated that basal Af diameter in 20-wk-old SHR is significantly smaller than that in WKY of the same age as measured in a cast study (16). Another report using isolated, perfused glomeruli did not show any difference in basal Af diameters between WKYand SHR (13). It is possible that basal vascular tonicity was altered in those in vitro experiments.
This study is, to the authors' knowledge, the first to demonstrate directly the in vivo diameters of Af and Ef near glomeruli in SHR. Af in the filtering glomeruli were constricted in SHR. Although it was previously reported using the in vitro blood-perfused juxtamedullary nephron technique (20) or micropuncture method (27) that the Af diameter in STZ was dilated and the Af vascular resistance was decreased in STZ, this study is the first to provide direct in vivo visualization of Af near filtering glomeruli in diabetic rats. Basal Af diameter was 14.0 ± 1.9 µm in STZ rats. We succeeded in showing significant constriction of Af in SHR (P < 0.05), although Af dilation was not statistically significant in STZ. It is necessary to increase the number of measuring points, number of glomeruli, or number of animals to obtain higher statistical power for the comparison of basal Af and Ef diameters.
In the present experiment, intravenously administered barnidipine lowered MBP and dilated Af and Ef dose dependently in all three animal groups. In general, dihydropyridine-type calcium antagonists act on L-type calcium channels, which are thought to be silent in Ef. However, the vasodilater action of each dihydropyridine-type calcium antagonist on Ef is different (8). Amlodipine dilated angiotensin II-constricted Ef slightly more than nifedipine, and efonidipine dilated both angiotensin II-constricted Af and Ef to the same degree. There were reports that amlodipine inhibited the N-type calcium current (6) and efonidipine inhibited the T-type calcium current (17), and therefore the N- or T-type calcium channel may regulate the tonicity of Ef. Barnidipine also inhibited the N-type calcium current (6). It has been reported that barnidipine dilates Af and Ef in hydronephrotic hypertensive rats (15). Although there is no evidence of the effect of barnidipine on T-type calcium channels, barnidipine possibly dilates Ef mediated by non-L-type voltage-dependent calcium channels. Our results showed that barnidipine dilates Af and Ef in filtering glomeruli.
Dose-dependent Af and Ef dilation occurred after administration of barnidipine (1 and 3 µg/kg iv) in SHR, and RBF increased even though MBP decreased. Af and Ef dilated to a greater degree after administration of barnidipine (10 µg/kg), but RBF decreased. The dilation of the renal microvessels could no longer compensate for the reduction in MBP after the administration of barnidipine (10 µg/kg). We examined these changes directly because our system allows simultaneous observation of MBP, RBF, and Af and Ef diameter.
This system can calculate the Af/Ef ratio in each glomerulus. The Af/Ef ratio is thought to be an important indicator of acute changes in glomerular microcirculation. When systemic blood pressure is constant, an increase in the Af/Ef ratio increases internal glomerular pressure, whereas a decrease lowers it. Barnidipine did not change the basal Af/Ef ratio in WKY at any of the doses used and therefore dilated both Af and Ef to the same degree. However, the Af/Ef ratio in SHR increased dose dependently after barnidipine administration, while in STZ it decreased. MBP was markedly reduced in SHR compared with the other two rat groups. It is possible that the pronounced dilation of Af resulted from a reduction in tonicity attributable to a myogenic response in SHR (21). In addition, the decrease in the Af/Ef ratio after barnidipine administration in STZ rats indicated attenuation of the Af dilatory function. This result is consistent with a report suggesting that Af dilatory dysfunction occurs in diabetic rats, because sodium nitroprusside-induced Af dilation is attenuated in STZ (20). It was possible to show the different characteristics of Af dilatory function in SHR and STZ using the present experimental system.
In this study, barnidipine induced a pronounced hypotensive effect in SHR compared with WKY, but internal glomerular pressure might not decrease, presumably because the Af/Ef ratio increased. It is possible that internal glomerular pressure decreased in STZ because both MBP and the Af/Ef ratio decreased. Several reports on utrastructural studies (26) and isolated rat glomeruli (4, 5) suggest that glomerular volume and internal glomerular pressure are proportionally correlated. Barnidipine induced no change in glomerular size in WKY and SHR in this study, but it reduced the size of glomeruli in STZ. This system cannot presently be used to measure internal glomerular pressure directly, but the acute, relative change in glomerular size was in agreement with the change in internal glomerular pressure inferred from the changes in MBP and the Af/Ef ratio.
This newly developed CCD videomicroscope system allowed us to visualize directly the in vivo glomerular microcirculation in anesthetized rats, and acute changes in glomerular microcirculation and changes in systemic macrocirculation simultaneously. Moreover, it is possible to investigate the characteristics of glomerular microcirculation in pathological animals. Therefore, this system is useful for elucidating the pathophysiology in many pathological models and investigating the acute effects of drugs on the glomerular microcirculation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Yamamoto, Dept. of Urology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 31 December 2000; accepted in final form 30 April 2001.
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REFERENCES |
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.01 vs. basal
values in each experimental group. Af/Ef, ratio of afferent arteriole
diameters to efferent arteriole diameters.
