359s
Clfnical Science (1982) 63,359s-362s
‘Structural autoregulation’ of the pregIomerular/postglomerular
resistance ratio and hence of glomerular filtration rate in the
clipped (low pressure) kidney in two-kidney, one-clip
renal hypertension
GUNNAR G d T H B E R G AND B J d R N FOLKOW
Department of Physiology. Universiw of Gcteborg, Sweden
Summary
1. The chronically clipped left kidneys of
two-kidney, one-clip renal hypertensive rats
(duration >4 weeks) showed a 45% decrease in
organ weight compared with left kidneys from
age-matched normotensive
Wistar
rats
(0.59 f 0.09 vs 1.12 f 0.05 g).
2. These ‘low-pressure’ kidneys exhibited at
maximal vasodilatation a 4096 decrease in total
renal vascular resistance per unit kidney weight, a
reduction in the preglomerular/postglomerular
resistance ratio (filtration curve displaced
markedly to the left of the control), though
combined with some decrease in maximal
glomerular filtration capacity.
3. Thus the vascular bed of chronically clipped low-pressure kidneys displays a ‘downward‘
structural autoregulation, which by lowering of
the total renal vascular resistance and the
preglomerular/postglomerular resistance ratio
serves to maintain blood flow and to increase
filtration pressure thereby raising the filtration
fraction.
Key
words:
experimental hypertension,
glomerular filtration capacity, kidney, resistance,
structural autoregulation.
Abbreviations: NC, Wistar normotensive (rat);
RH, renal hypertensive (rat).
Introduction
The kidneys serve as one of the most important
long-term regulators of arterial pressure, which is
Correspondence: Dr Gunnar Gothberg, Department of Physiology, University of Giiteborg, Box
3303 1, S-40033 Goteborg, Sweden.
considerably dependent on, among other things,
the salt-volume balance [ll. The renal excretory
function is based on the glomerular filtration
process, determined by glomerular permeability,
effective filtration pressure and glomerular blood
supply, which all are ultimately based on how the
renal vascular bed is structurally designed.
Spontaneously hypertensive rats have already in
early established hypertension developed an
efficient resetting of the renal ‘long-term barostat
function’ by an increase in the preglomerular/
postglomerular resistance ratio. This is mainly
due to an adaptive structural increase of the
preglomerular resistance [2, 31 only moderately
increasing total renal vascular resistance. In the
two-kidney, one-clip renal hypertensive (RH) rats
the kidney exposed to high pressure showed an
important increase in total renal vascular resistance, although the preglomerular/postglomerular resistance ratio was largely unchanged [41, indicating a mechanism which here
prohibits this kidney from being structurally reset
to an increased perfusion pressure. The reason
for this could be the demand for increased
glomerular filtration in this untouched kidney
when that in the clipped one is more or less
drastically reduced. In any case, with an unchanged preglomerular/postglomerular resistance ratio the effective filtration pressure in the
untouched high pressure kidney of RH rats is
raised compared with that in normotensive
control kidneys, perhaps indicative of the more
potent postglomerular effect of angiotensin [51.
The aim of the present study was to explore
how the clipped kidney, exposed to a prolonged
reduction in perfusion pressure, structurally
adapts its vascular bed to sustain renal function.
360s
G. Gothberg and B . Folkow
Methods
Hypertension was induced in Wistar normotensive (NC) rats by placing a silver clip around
the left renal artery ([61; two-kidney, one-clip RH
rats). Four weeks after clipping mean arterial
pressure (MAP) was measured intra-arterially in
the conscious rats. Rats with blood pressure
above 150 mmHg were included in the study. In
each experiment a pair of kidneys from R H rats
and age-matched NC rats were isolated and
perfused in parallel after careful decapsulation of
the kidneys (for preparation details, see [31).
To evaluate the true total vascular resistance at
maximal dilatation the mineral oil kerosene was
used 171. This eliminates the disturbing passive
autoregulation caused by filtration and consequent tubular distension [ 81. Pressure-flow
relationships were determined in these pairs of
oil-perfused kidneys. Total renal vascular resistance per unit wet kidney weight at maximal
dilatation was defined at a perfusion pressure of
100 mmHg. For determination of the relationship between perfusion pressure and glomerular
filtration rate (PA-GFR) the two kidneys were
perfused with oxygenated 2% dextran-Tyrode
solution, containing sodium nitroprusside (08
mmol/l) to achieve maximal vasodilatation. Urine
formation was continuously measured by sensitive weighing devices and GFR was determined
spectrophotometrically from the concentrations
of Cr-EDTA in perfusate and urine. Filtration
values were expressed in relation to unit dry
kidney weight, to avoid artifacts caused by
different extents of oedema formation in the
perfused kidneys. Values of G F R and perfusion
pressure (PA)were then analysed for each rat by
linear regression. In this way the slope of the
‘filtration curve’ which reflects the maximal
glomerular filtration capacity, and its intercept
with the pressure axis (‘starting point’), were
defined. Here starting point reflects the preglomerular/postglomerular resistance ratio, and
the higher this ratio the more to the right on the
pressure axis is the starting point placed.
Values are presented as means k SEM. Statistical evaluations were made by paired design
I-test or Student’s group comparison t-test.
Differences were considered as significant at P
values < 0.05.
Results
Mean arterial pressure was 188 ? 5 and 108 t 2
mmHg (P< 0-001), and left ventricle mass per
100 g body wt. was 0.27 t 0.02 vs 0.18 f 0.01
g ( P <0.001) for RH and NC rats ( n = 15)
respectively. Wet kidney weights in the kerosene
perfusion studies (n = 6) were 0.59 2 0.09 for
the clipped R H rat kidneys and 1.12 & 0-05 g
(P< 0.01) for the left NC ones; the right kidneys
weighed 1.38 & 0.14 in R H rats and 1.11 k 0.05
g (P> 0.05) in NC rats.
Total renal vascular resistance at maximal
dilatation and at 100 mmHg perfusion pressure
during kerosene perfusion was 2.3 ? 0.1 for the
clipped ‘low-pressure’ RH rat kidneys and
3.8 f 0.5 for the left NC rat kidneys (P< 0.05).
The right, ‘high-pressure’ RH rat kidneys had a
total renal flow resistance of 5.7 ? 1.1. All values
are given per g of kidney wet weight.
The relationships between PAand GFR (n = 9)
showed that filtration in the clipped kidney
started at 21 t 3 mmHg, and in the left control
kidney at 40 t 5 mmHg (P< 0.02). The slopes
of these filtration curves were 1.2 & 0.2 vs
2.2 t 0.2 ml x min-’ x 100 mmHg-’ per g of
kidney dry weight in the clipped and control
kidneys respectively (P< 0.02).
Results are shown in Fig. 1.
Discussion
In this study it was found that the clipped,
‘low-pressure’ kidney in RH rats structurally
adapts to this underperfusion, first by regression
in tissue mass, perhaps to adapt to the actual
level of blood flow, second by a decrease of the
structurally determined resistance to flow per unit
kidney weight (in other words structural autoregulation of the renal vascular bed to hypotension). Total flow at 100 mmHg (kerosene
perfusion) for the left kidneys of RH and NC
rats, per 100 g body weight (RH rats weighed
300 g and NC rats 340 g), was about 9 ml in both
RH and NC rats. Also the right, high-pressure
RH kidney, like the right NC kidney, showed a
total renal flow of about 9 ml, calculated in this
way.
It could then be argued that the renal vascular
bed may stay unchanged, and that it is the renal
tissue alone that adapts its mass. This is,
however, not the case, because the preglomerular/postglomerular resistance ratio is
greatly reduced in the clipped, hypotensive
kidney, compared with the NC and right RH
kidneys. Thus the glomerular filtration, that is
dependent on the preglomerular/postglomerular
resistance ratio, showed a clear resetting downwards to suit a lowered perfusion pressure,
shifting the PA-GFR relationship of the ‘lowpressure kidney’ almost 20 mmHg to the left of
that of NC kidneys. However, there was simultaneously a decrease in maximal glomerular
Structural autoregulation of renal vessels
361s
50
la1
40
T
5
x
5
-Y
3c
2
DI,
.-C
E
-
2c
kidney
01
10
C
80
100
FIG. 1. (a) Average relationships (&SEM) between arterial perfusion pressure (PA)and flow of
kerosene (per g wet kidney weight) in isolated, maximally vasodilated kidneys. Renal resistance to
flow, calculated as mmHg x min x g x ml-’ at PA= 100 mmHg, was for RH rat left-clipped
‘low-pressure’ kidneys 2.3 f 0-1, for NC rat left kidneys 3.8 & 0.5 and for RH rat right ‘highpressure’ kidneys 5.7 & 1-1. *P < 0.05. (b) Average relationship ( ~ S E M )between PAand GFR
during perfusion with 2% dextran-Tyrode solution. Here dry kidney weights were used to avoid
artifact weight changes due to oedema formation. The slope of the PA-GFR relationship reflects
the filtration capacity, and was for RH rat clipped ‘low-pressure’ kidneys clearly lower (P < 0.02)
than for NC rat left kidneys. The intercept of the ‘filtration slopes’ with the pressure axis (‘starting
point’, SP) reflects the preglomerular/postglomerularresistance ratio and was 21 & 3 mmHg for
the RC clipped kidneys and 40 & 5 mmHg (P < 0.05) for the NC left kidneys. The more to the
right SP is placed, the higher is the structurally set preglomerular/postglomerular resistance ratio.
filtration capacity in the chronically clipped
low-pressure kidney, indicating that these adaptive structural changes of the resistance vessels
are for some reason associated with a decrease in
glomerular performance. The reason for this is
unclear, and it might be due to glomerular
capillary deterioration obtained early after
clipping, when the kidney is often really underperfused in relation to tissue mass. However, it is
probably also due to a reduced tissue compliance
in the clipped R H kidney, since the tissue
pressure could be deduced t o increase much more
rapidly with increasing G F R in the clipped
kidneys than in the controls.
Acknowledgment
This study was supported by grants from the
Swedish Medical Research Council (no. 00016)
and by AB Hassle, Molndal.
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