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Morphology of norepinephrine-induced acute renal failure in the dog.

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THE ANATOMICAL RECORD 214:341-347(1986)
Morphology of Norepinephrine-lnduced Acute
Renal Failure in the Dog
RUTH ELLEN BULGER, THOMAS J. BURKE, ROBERT E. CRONIN,
ROBERT W. SCHRIER, AND DENNIS C. DOBYAN
Renal Research Laboratory, The University of Texas Health Science Center, Graduate School
of Biomedical Sciences at Houston, Houston, T X 77030 (R.E.B., D.C.D.), The Department of
Medicine, University of Colorado Health Sciences Center, Denver. CO 80220 (TJ.B., R. W.S.),
and The Department of Internal Medicine, Veteran’s Administration Medical Center at
Dallas, Dallas, TX 75216 (R.E.C.)
ABSTRACT
The 40-minute infusion of norepinephrine (NE) into the renal artery
of dogs produces a reversible ischemic model of acute renal failure. While the
physiology of this model has been extensively studied, no complete description of the
pathology exists. This study uses light microscopy and transmission electron microscopy to describe and quantitate the structural and ultrastructural changes which
occur in the kidneys of dogs 1, 3, and 24 hours after the intrarenal infusion of 0.75
mgkg/minute of NE. One hour after a 40-minute NE infusion the majority of
convoluted and straight proximal tubules showed apical blebs, loss of brush border,
microvillar whorl formation, and mitochondria1 condensation and high-amplitude
swelling with flocculent densities. Necrotic cells were occasionally seen at 1 hour.
The injury was progressive after 3 hours and by 24 hours animals had either
complete or partial patchy necrosis of all regions of the proximal tubule. The
percentages of injured and necrotic proximal tubules in outer, mid-, and inner
cortical regions are presented. We conclude that the extent and pattern of injury
seen after NE infusion differs significantly from the renal artery clamping model of
ischemia.
The infusion of norepinephrine (NE) (0.75 pgkgiminUte) into the renal artery of dogs for 40 minutes produces
a reversible model of acute renal failure. Although the
pathophysiology of this model has been extensively studied (Cronin et al., 1978a,b; Schrier et al., 1978; Burke et
al., 1980, 1982; Patak et al., 1979; de Torrente et al.,
1978),a complete description of the pattern and progression of renal injury caused by this treatment has not
been made. This report concentrates on the renal injury
caused by norepinephrine infusion and compares it to
the injury previously described in the renal pedicle
clamp model of rat (Glaumann and Trump, 1975; Glaumann et al., 1975; Venkatachalam et al., 1978, 1981).
MATERIALS AND METHODS
Experiments were performed on seven mongrel dogs
of both sexes weighing 22-32 kg. Food was withheld for
18 hours and water was allowed ad libitum. Anesthesia
was induced with intravenous sodium pentobarbital (25
mgkg). The animals were intubated and ventilated with
a Harvard respirator. Light anesthesia was maintained
by the intermittent administration of additional small
doses of pentobarbital. Catheters were placed in both
ureters and renal veins, and the left renal artery was
isolated for placement of a n electromagnetic flow probe
(Carolina Medical Electronics, Inc., King, NC). During
dissection, care was taken to prevent damage to the
renal nerves. After control clearance determinations, an
angiographic catheter, French 7-8 (Cordis Corporation,
Miami, FL), was introduced into a femoral artery and
0 1986 ALAN R. LISS, INC
manually guided into one renal artery. The catheter was
positioned in the main renal artery while avoiding obstruction of blood flow. Streaming of the injected NE in
the renal artery did not appear to occur since the fall in
renal blood flow (RBF) to zero following the NE infusion
was rapid and complete within approximately 10-30
seconds. For the %hour studies, the catheter was placed
by using fluoroscopy and dye injection. During the procedure, arterial blood pressure was measured from a
brachial artery catheter with a Statham transducer
(Statham Instruments, Inc., Oxnard, CAI. Surgical fluid
losses were replaced with isotonic saline. Since these
animals were used for studying the pathophysiology of
this model, physiological parameters were measured as
described elsewhere (Burke et al., 1984). Clearance of
inulin and para-aminohippuric acid were measured by
standard techniques. PAH clearances were corrected for
extraction. Total plasma protein was measured by the
Technicon autoanalyzer method. Plasma and urine osmolality determinations were made by using an osmometer (Advanced Instruments, Needham Heights, MA).
The experiments were begun after a 60-minute equilibration period and control clearance collections. Norepinephrine (0.75 pg/kg/minute) was infused into one renal
artery for 40 minutes. At the conclusion of the infusion
Received J u n e 25, 1985; accepted October 23, 1985.
Address reprint requests to Dr. Ruth Ellen Bulger, Renal Research
Laboratory, The University of Texas Medical School, Room 7.242
MSMB, P.O. Box 20708, Houston, TX 77225.
342
R.E. BULGER ET AL.
Fig. 1. Light micrograph showing the kidney from a dog subjected to
norepinephrine (NE) infusion, Note the patchy cortical necrosis (arrows). Hematoxylin and eosin, x 130.
Fig. 2. Light micrograph showing the kidney from a dog subjected to
NE infusion. Note the extensive necrosis involving all of the proximal
tubules. Hematoxylin and esoin, x 110.
period the catheter was withdrawn and the kidneys
were subsequently fixed at 1, 3, and 24 hours after
completion of the norepinephrine infusion.
For the fixation process, loose ligature snares were
placed above and below a short segment of aorta that
included both renal arteries. One-half-strength Karnovsky’s fixative (1965)buffered with potassium phosphate
.
was perfused into this aortic segment through a 16gauge needle, with a monitored perfusion pressure
maintained equal to or slightly greater than mean arterial pressure. When the solution was flowing well, the
ligature snares were tightened, maximizing flow of fixative to the renal arteries. The renal veins were then
cut to allow free flow of fixative out of the kidneys. A
total of 300-400 ml of fixative was used in each animal.
Pieces of kidney from each animal were embedded in
paraffin according to routine histologic methods. Sections 5 pm thick were cut and stained with hematoxylin
and eosin for light microscopic analysis.
Tissue for transmission electron microscopy was
minced and washed in 0.2 M phosphate buffer, pH 7.4,
for 1hour. The tissue was then postfixed in 2% osmium
tetroxide buffered in 0.1 M s-collidine (pH 7.2-7.4) for 1
hour a t room temperature, stained en bloc with uranyl
acetate in veronal acetate buffer at pH 5.0, dehydrated
in a graded series of alcohols, treated with propylene
oxide, and embedded in epoxy resin. Ultrathin sections
were cut on Sorvall MT-2 or LKB I11 ultramicrotomes,
stained sequentially in 7.5% uranyl magnesium acetate
and 0.15% lead citrate, and examined with a Siemens
102 or a Philips 200 transmission electron microscope.
Semithin epoxy sections (0.5-1.0 pm thick) also were
cut, stained with toluidine blue, and viewed with a light
microscope.
QUANTITATION OF STRUCTURAL ALTERATIONS
Paraffin sections of kidney were used for the quantitative analysis of injury. In each kidney, five areas each
from the outer cortex, the midcortex, and the inner
cortex were utilized. The data from each region was then
combined to give a single value for each. Tubular injury
was evaluated in the proximal tubule, the major site of
injury along the nephron. By using a Leitz-Wetzlar overhead projecting microscope, each area was first centered
a t low-power magnification and then the high-power
objective was positioned for viewing the field a t random,
without moving the specimen stage to avoid bias of the
chosen area. The image was projected upon a screen
containing 144 points. The cell or structure lying under
or nearest each point was classified by one observer
(R.E.B.) without the observer having prior knowledge of
the treatment of the specimen being examined. Each of
the counted proximal tubular cells was assigned to one
of the following categories: 1)normal or indistinguish-
NOREPINEPHRINE-INDUCED ACUTE RENAL FAILURE IN DOGS
able from controls, 2) injured when the cell shape was
obviously altered to a low cuboidal or squamous type or
revealed extensive apical vesiculation or vacuolization
in addition to the loss of brush border but had no evidence of necrosis, or 3) necrosis when the cell showed
irreversible damage such as loss of membrane integrity,
or loss of nuclear staining, or had been shed into the
lumen. All values reported represent mean & standard
error of the mean. This method, a modification of the
point-counting method described by Weibel (19791, has
been used extensively in our laboratory to quantitate
renal structural changes (Eknoyan et al., 1982; Dobyan
and Bulger, 1984).
RESULTS
General comments
Some glomeruli in both the infused and contralateral
kidneys of several of the dogs exhibited diffuse hypercellularity. There were abundant neutrophilic polymorphonuclear leukocytes seen in both the control and
experimental kidneys. The contralateral kidneys, however, failed to show any significant degree of acute cellular injury. The changes observed were similar
regardless of the sex of the animal under investigation.
In some animals, casts and calcified material could be
seen in a few of the tubular lumens in the renal medulla
of the experimental kidney. The proximal tubule, both
convoluted and straight portions, was the most consistently damaged region of the nephron (Figs. 1, 2). The
morphometric analysis of normal, injured, and necrotic
proximal tubule cells in the outer, mid-, and cortical
regions of the kidney at 3 and 24 hours after norepinephrine infusion is summarized in Table 1. The extent of
injury was similar in all three regions of the cortex with
damage occurring in both convoluted and straight portions of the proximal tubule. Renal tubular injury in the
S2 regions within the straight portion of the proximal
tubule could be easily quantitated; however, the cells of
the S3 segment were more predisposed to sectioning
damage so injury in this latter segment could not be
reliably quantitated a t the 1-and 3-hour time intervals.
Glomeruli did not show extensive alterations (Cronin et
al., 1978).
The amount of variation in the extent of injury among
the animals was striking. In some animals, almost all of
the proximal tubules were involved while in others there
was little evidence of renal injury (Figs. 1, 2). In some
instances, the major injury occurred in the proximal
convolutions while in others it was localized to primarily
the straight part of the proximal tubule. Renal lobules
also frequently reacted differently with one having all
proximal tubules injured while the adjacent lobule
showed little evidence of damage. A layer of less injured
tubules was also noted next to the renal capsule and
surrounding thin-walled veins in the cortex.
In this study, the contralateral kidney (noninfused) in
each dog served as a control. These kidneys showed
morphological features consistent with and indistinguishable from those of untreated mongrel dogs (Bulger
et al., 1980).Both the 3- and 24-hour NE-infused kidneys
had significantly greater tubular injury and necrosis
compared to contralateral controls ( P < .001; Student’s
t-test).
343
Stages of injury
Injured proximal tubular cells tended to follow a definite progression through stages described as reversible
injury to necrosis. These changes were similar to those
described previously by Trump e t al. (1980)for the renal
pedicle clamp model of ischemia. At 3 hours, paraffin
sections showed mainly early changes such as apical
blebbing (Fig. 3). The earliest changes seen by transmission microscopy involved distortions of the brush border
with large cytoplasmic blebs being released into the
lumens (Fig. 4). These blebs were generally free of
formed organelles and sometimes appeared paler than
the cytosolic density. Loss in the number and length of
microvilli on the proximal tubular cells, simplification
in cell shape, rounding of the mitochondria (Fig. 51, and
clumping of nuclear chromatin characterized these early
changes (Fig. 6). Intracristal swelling was not prominent. Red blood cells were seen within the interstitium
(Fig. 6). The next alterations included vesiculation of
the cytoplasm, which was especially prominent apically,
a n early stage of matrical swelling of some of the mitochondria (Fig. 7) and dilation of the lumens of the endoplasmic reticulum (Fig. 8). A few of these mitochondria
contained indistinct matrical densities (Fig. 9). The nuclei appeared more condensed a t this stage and the cells
continued to simplify in shape. Some lateral cytoplasmic
extensions extended out from the less injured cells to
cover areas of the basal lamina which had already been
denuded.
The next stage was characterized by a decrease in
cytoplasmic density, increased membrane vesiculation,
and the presence of some mitochondria which had
undergone high-amplitude swelling heralded the beginning of the transition to cell death (Fig. 9). Cells showing
high-amplitude swelling of the mitochondria, marked
discontinuities in the plasmalemma, membrane whorls,
and a marked loss in cytosolic and nuclear density
marked the conversion to necrotic debris (Figs. 9, 10).
One-hour post norepinephrine
The injury involved proximal tubules. The lumina contained material which appeared to be derived from blebbing of the proximal tubular cells. The proximal tubules
in the outer stripe appeared to be obstructed with this
material. The microvilli of the injured proximal tubules
were distorted and disorganized. The apical cytoplasm
in some proximal tubules displayed membrane vesiculation. Nuclear clumping was present. Aggregates of
smooth endoplasmic reticulum were present. Although
the majority of the injury was early and appeared to be
of a reversible nature, some cells had progressed to a
degree that injury was even identifiable in H & E sections. Occasional cells were necrotic, being characterized by mitochondria1 swelling with flocculent matrical
densities.
Three hours after norepinephrineinfusion
Over half of the proximal tubules from outer, mid-,
and inner cortex now demonstrated marked injury (see
Table 1).A few necrotic cells were present at this time
as well. The proximal tubules appeared expanded and
filled with pink staining material. Some hyaline casts
were present distally.
Fig. 3.Light micrograph showing early changes in proximal tubules
from dogs receiving an infusion of NE. The lumens are occluded with
numerous cytoplasmic blebs. Hematoxylin and eosin, X 400.
Fig. 5. Transmission electron micrograph showing the early proximal tubule alterations after NE infusion. There is loss in the number
of microvilli on the apical surface and the cells are simplified in shape.
~4,000.
Fig. 4.Transmission electron micrograph showing the early proximal tubule alterations after NE infusion. Note the large cytoplasmic
bleb (B) which is present within the lumen. The brush border (BB) is
markedly distorted. ~ 5 , 2 0 0 .
Fig. 6.Transmission electron micrograph showing the early proximal tubule alterations after NE infusion. There is marked cytoplasmic
vesiculation and clumping of the nuclear chromatin. A red blood cell
has extravasated into the interstitium (arrow). ~ 4 ,5 0 0 .
Fig. 7. Transmission electron micrograph showing early changes i n
the proximal tubule. There is loss of brush border, a simplification i n
the shape of the cell, increased cytoplasmic vesiculation, and early
matrical swelling in the mitochondria. ~ 5 , 6 0 0 .
Fig. 8 . Transmission electron micrograph showing t h e markedly
dilated endoplasmic reticulum in proximal tubule cells after NE infusion. ~ 6 , 4 0 0 .
Fig. 9. Transmission electron micrograph showing proximal tubule
cells in various stages of reversible and irreversible cell injury. The
cell a t the top of the micrograph shows clumping of the nuclear chromatin and increased vesiculation. The center cell shows more severe
injury and marked mitochondria1 swelling is apparent (arrows). The
cell in t h e lowcr portion of the micrograph demonstrates frank necrosis. There is dissolution of the cclular membranes and the mitochondria contain numerous flocculent densities. ~ 2 , 8 0 0 .
Fig. 10. Transmission electron micrograph showing necrotic debris
within the lumen o f t h e proximal tubule after NE infusion. Note the
swollen mitochondria containing flocculent densities (MI and the membrane whorls (MW). ~ 7 , 2 0 0 .
346
R.E. BULGER ET AL.
TABLE 1. Morphological analysis of normal, injured, and necrotic proximal tubules in norepinephrine-induced
acute renal failure in the dog'
Outer cortex (a)
Normal
NE3 3 hours'
Postinfusion
(N = 4)
NE3 24 hours
Postinfusion
42
rt8
41
+24
Injured
Necrotic
Normal
Midcortex (%)
Injured
Necrotic
Normal
Inner cortex (%I
Injured
Necrotic
53
+8
5
+2
34
60
15
+7
6
*3
43
+6
+6
2
rt1
30
29
23
+20
33
38
*9
29
*23
37
+21
42
+8
+ 17
+ 10
55
21
'Values are means f SEM. Control dog kidneys exhibited less than 1%proximal tubule injury.
'The 3-hour postinfusion quantitation has been previously reported (Burke et al., 1984).
3NE = Norepinephrine.
24 hours after norepinephrine infusion
Twenty-four hours after norepinephrine infusion, the
amount of necrosis had increased as had the total number of tubules characterized by injury plus necrosis (Table 1). All zones of the cortex were equally involved.
Hyaline casts were prominent in the lumen of distal
nephron segments. Prominent margination of white
blood cells was seen in the veins. Numerous red blood
cells were seen within the cortical interstitium.
DISCUSSION
Although certain morphological changes have been
mentioned in various studies (Cronin et al., 1978a;
Schrier et al., 1978; Baehler et al., 1980; Cox et al., 1974)
a complete description of the pattern and extent of injury has not been previously published. It is clear, however, that the ischemic injury seen after NE infusion
differs markedly in distribution from the location described in the renal pedicle clamp model which has been
carefully studied for the rat kidney (Glaumann and
Trump, 1975; Glaumann et al., 1975a,b; Venkatachalam
et al., 1978, 1981).With the renal clamp model in the
rat, tubular injury occurs preferentially within the proximal pars recta.
The production of acute renal failure (ARF) by the
administration of NE has been described in several different species with varying doses and time intervals.
Cox et al. (1974) induced irreversible ARF in dogs with
a 2-hour infusion which was characterized by extensive
tubular necrosis, principally involving the proximal convoluted tubules. They noted widespread loss or distortion of glomerular foot processes. The authors proposed
that these glomerular changes were important in the
decreased glomerular filtration rate found in this model.
A subsequent study (Bulger et al., 1980) of the morphological changes seen in the glomerulus after the 2-hour
NE infusion period noted only a slight increase in abnormal areas of podocytes but failed to find the extensive
podocyte alterations reported by Cox et al. (1974).
Cronin et al. (197813) produced a reversible model of
acute renal failure in which norepinephrine was infused
intrarenally for 40 minutes a t a dose of 0.75 pglkgl
minute. The 40-minute norepinephrine infusion model
has been carefully studied in elucidating the mechanisms involved in the production and maintenance
phases of acute renal failure in the dog (Cronin et al.,
1978a,b; Schrier et al., 1978; Burke et al., 1980, 1982;
Patak et al., 1979; de Torrente et al., 1978).In the study
of Cronin et al. (1978a), glomeruli of 37 of 39 animals
appeared to have fairly normal structure while the proximal tubules were injured. In two other animals, more
severe lesions characterized by necrosis of both proximal
and distal tubules as well as glomerular changes similar
to those reported by Cox et al. (1974) were seen. This
reversible infusion model is useful since it demonstrates
many of the characteristics seen in human acute renal
failure such as a disproportionate decrease in glomerular filtration rate when compared to changes in renal
blood flow, a decrease in the urine-to-plasma osmolality
and creatinine ratios, a n increase in the urine sodium
concentration, and a reversible course of azotemia.
Normal glomeruli were described after a n 80-minute
infusion of norepinephrine in dogs by Baehler et al.
(1980). Taguma et al. (1980) has described a model of
norepinephrine administration in which the length of
the infusion was 30, 60, or 120 minutes in unilaterally
nephrectomized dogs. In the early time periods studied
in this model, blebs were released from injured proximal
tubules and lodged in lumina of the tubules distally and
suggested a pathogenetic role of tubular obstruction. No
prominent glomerular foot process fusion was seen with
any duration of infusion.
Similar norepinephrine infusion studies were accomplished in rats by Steinhausen et al. (1978) and Conger
et al. (1981). Tubules were flattened, dilated, and contained occasional casts. Glomeruli were described as
normal after 90 minutes of NE infusion in the latter
study.
In the present 40-minute NE model the stages of tubule cell injury were similar to those described by Glaumann and Trump (1975), Glaumann et al. (1975),
Donohoe et al. (1980), and Venkatachalam et al. (1978,
1981)for the renal clamp model. Intracristal swelling of
mitochondria was never a prominent feature; however,
early changes in luminal cell contours with apical blebbing were seen. The location of NE-induced injury did
not show a preferential location to the proximal pars
recta and was variable in degree and location. The injury occasionally could affect one lobule of the kidney
while sparing a n adjacent one. In some kidneys, more
injury was seen in the proximal convolutions while in
others the injury centered on the proximal pars recta.
The injury was more prominent in superficial nephrons
in some instances while in others it was more prominent
near the medulla. On average, however, the proximal
tubules in all cortical regions of the kidney seemed to be
involved to a similar degree (see Table 1).These differences between dogs and rats could relate in part to the
NOREPINEPHRINE-INDUCED ACUTE RENAL FAILURE IN DOGS
heterogeneous state of the mongrel dogs studied wherein
age and previous medical and nutritional factors were
unknown. This varying pattern of distribution correlates with the original description “remarkable patchy
areas of renal ischemia” in humans by Oliver et al.
(1951). It should be noted, however that necrosis of the
more distal regions of the nephron, as reported by Oliver
et al. (1951) for human ischemic acute renal failure,
occurs with less frequency in experimental models and
is generally seen only in the more severely injured kidneys (Cox et al., 1974; Cronin et al., 1978a). The norepinephrine model also differs from human acute renal
failure because less cellular necrosis is evident in the
human kidneys (Solez et al., 1979). One reason for this
difference may be the fact that human biopsies are frequently taken several days after the initiating insult, as
opposed to the immediate observation in the experimental model, and hence may reflect the reparative processes as well.
As discussed above,.the majority of the studies of norepinephrine-induced injury clearly descibe no or minimal changes to the glomerular podocytes (Cronin et al.,
1978a; Bulger et al., 1980; Taguma et al., 1980; Conger
et al., 1981; Schrier et al., 1978; Baehler et al., 1980)
unless severe irreversible damage has been sustained
by the kidney as appears to be the case in the study of
Cox et al. (1974) and with two of the 39 animals studied
by Cronin et al. (1978a). In these instances, the podocyte
changes may result from other factors such as proteinuria and not be the underlying cause of the decreased
glomerular filtration rate seen in acute renal failure.
On the basis of this and other morphologic studies (Taguma et al., 1980; Cronin et al., 1978a; Steinhausen et
al., 1978; Baehler et al., 1980) it appears that the primary morphologic changes are injury and necrosis of the
proximal tubules, which leads to nephron obstruction
from cellular debris. Such tubular obstruction has been
documented by the studies of Burke et al. (1980). The
protective effect of agents which bring about increased
osmolar excretion (Burke et al., 1980, 1983; Patak et al.,
1979; Schrier et al., 1979; de Torrente et al., 1978) may
be, a t least in part, a consequence of their ability to
reduce tubular obstruction.
In summary, the intrarenal infusion of norepinephrine
to dogs produces a reproducible model of reversible acute
renal failure. The extent and pattern of injury differ
significantly from the renal artery clamping model of
ischemia.
ACKNOWLEDGMENTS
The authors wish to thank Ms. Lena Wallach for her
excellent secretarial assistance.
This study was supported in part by National Institutes of Health grants 5-R01-AM-26134,AM-25151, and
AM-19928.
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