153
Enhanced Myogenic Responsiveness of Renal
Interlobular Arteries in Spontaneously
Hypertensive Rats
Koichi Hayashi, Murray Epstein, and Rodger Loutzenhiser
We recently demonstrated that the interlobular artery (ILA) constricts in response to elevating
renal arterial pressure (RAP), suggesting that the ILA contributes to renal autoregulation. In
the present study, we examined the segmental myogenic responsiveness of the ILA in kidneys
from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The tapered
nature of the ILA allowed us to characterize the regional responsiveness, using the basal
diameter to define segments as either proximal (greater than 60 fim), intermediate (40-60
pim), or distal (less than 40 pm). At 80 mm Hg, segmental diameters were similar in WKY and
SHR arteries (proximal, 76.0±3.1 versus 71.6±3.5 /un; intermediate, 48.2±1.4 versus 48.1±1.7
/im; distal, 30.7±0.9 versus 27.9±13 Aim for WKY and SHR, respectively). In both strains,
intermediate and distal segments exhibited graded reductions in diameter as RAP was elevated,
whereas proximal segments did not Pressure-induced decrements in the diameters of distal
ILA segments were similar in WKY (-24±2%) and SHR (-20±2%;p>0.1). The intermediate
ILA of SHR exhibited an augmented myogenic responsiveness, constricting at lower RAP levels
and exhibiting greater maximal decrements in diameter at 180 mm Hg (i.e., - 1 9 ±2% and
-12±2% for SHR and WKY, respectively; p<0.05). Nifedipine (1.0 fiM) reduced pressureinduced vasoconstriction of intermediate and distal ILA segments by 56 ±11% and 79 ±7%,
respectively, in WKY. In contrast, nifedipine completely abolished pressure responses of both
segments in SHR kidneys, suggesting a greater involvement of calcium channels in mediating
myogenic vasoconstriction of the HA in SHR. In concert, these observations indicate an
augmented myogenic reactivity of the intermediate HA segment in SHR and suggest that this
adaptation reflects an enhanced activity of calcium channels. (Hypertension 1992; 19:153-160)
S
ustained hypertension alters the renal excretory response to pressure1 and renal autoregulation.2 We have previously demonstrated
that myogenic afferent arteriolar vasoconstriction is
reset to higher renal arterial pressure (RAP) levels in
spontaneously hypertensive rats (SHR).3 Although
the afferent arteriole is primarily responsible for both
acute4-5 and chronic6'7 adaptations to elevated RAP,
the interlobular artery (ILA) may also contribute to
renal autoregulation.8'9 The involvement of the ILA
in chronic adaptations of the renal vasculature to
hypertension has not been previously examined.
From the Nephrology Section and Research Services, Veterans
Administration Medical Center, and the Division of Nephrology,
University of Miami, School of Medicine, Miami, Fla.
Supported by grants from the Department of Veterans Affairs.
R.L. is an Established Investigator of the American Heart
Association.
Address for correspondence: Rodger Loutzenhiser, PhD, Nephrology Section (111C1), Veterans Administration Medical Center, 1201 N.W. 16th Street, Miami, FL 33125.
Received January 12, 1990; accepted in revised form October
17, 1991.
The diameter of the ILA decreases as the vessel
courses from its origin at the arcuate artery to
superficial cortical regions. The tapered characteristic of the ILA contributes to a substantial pressure
gradient along its length8'9 and may influence its
responsiveness to pressure. Luminal pressure measured at the distal, superficial segment is lower than
that measured within the aorta8 and is partially,
albeit not perfectly, autoregulated.9 Thus, it is possible that the ILA exhibits regional differences in its
response to pressure. However, segmental myogenic
responses of this vessel have not been previously
characterized. Furthermore, the myogenic reactivity
of this vessel in normotensive and hypertensive animals has not been compared.
In the present study, segmental responses of the
ILA to acute elevations in RAP were studied in in
vitro perfused hydronephrotic kidneys isolated from
normotensive rats (Wistar-Kyoto) and SHR. The
effects of the nifedipine on myogenic vasoconstriction of the ILA were also assessed to determine the
role of potential dependent calcium channels mediating in this response.
154
Hypertension
Vol 19, No 2 February 1992
Methods
Animal Preparation
Male Wistar-Kyoto (WKY) and stroke-prone SHR
(body weight, 120-150 g; Charles River Breeding
Laboratories, Wilmington, Mass.) were used as donors of hydronephrotic kidneys. The right ureter was
ligated under methoxyflurane (Pitman-Moore, Washington Crossing, N.J.) anesthesia in 6-week-old animals. After 8-10 weeks of chronic unilateral hydronephrosis, when tubular atrophy of the right kidney
had progressed to a stage that allowed direct microscopic visualization of the renal microvessels,10 the
kidneys were excised and perfused in vitro as described below.
On the day of the perfusion study, systolic blood
pressures of the conscious donor animals were measured by tail-cuff sphygmomanometry (model KN210-1, Natume, Tokyo). Data were obtained from the
mean of at least five measurements.
Perfusion of Hydronephrotic Kidneys
Donor animals were anesthetized with methoxyflurane. The renal artery of the hydronephrotic kidney
was cannulated as described previously.3'11-14 An
infusion of warm oxygenated media was initiated
during the cannulation procedure. The hydronephrotic kidney was excised and perfused on the stage
of an inverted microscope (model K, Nikon, Tokyo)
modified to accommodate a heated chamber with a
thin glass viewing port on the bottom surface. Kidneys were allowed to equilibrate for at least 30
minutes before initiating the experimental protocols.
The kidneys were perfused with a cell-free artificial medium consisting of a Krebs-Ringer bicarbonate buffer containing 5 mM D-glucose, 7.5% bovine
serum albumin (Bovuminar, Armour Pharmaceutical
Co., Kankakee, 111.), and a complement of amino
acids as detailed previously.15 The perfusate was
saturated with 95% Oj-5% CO2 and the pH was
adjusted to 7.4.
The apparatus used to study the hydronephrotic
kidneys in vitro is described in detail in previous
publications.1113 Kidneys receive media from a pressurized reservoir. The perfusion pressure, monitored
at the level of the renal artery, is altered by adjusting
a back-pressure-type regulator (model 10BP, Fairchild Industrial Products Co., Winston-Salem, N.C.)
controlling the exit of gas from the media reservoir.
ILA diameters were measured by computer-assisted
image processing as detailed previously.3-11-13-14
Video images of the renal microcirculation were
recorded on videocassette and later transmitted to an
IBM-AT computer equipped with a video acquisition
and display board (model FVG-128, Datacube, Peabody, Mass.). Vessel diameters were estimated from
the mean distance between parallel edges of the
selected vascular segments. Vessel segments approximately 50 ^,m in length were analyzed. Diameters
were measured at 2-4-second intervals for at least 1
DMal: <40fim
:40-60ffm
Proximal: > 60fnn
Arcuata Artery
FIGURE 1. Schematic diagram of the interlobular artery
(ILA). The ILA is tapered along its length with greatest
diameter near the arcuate artery (proximal segment) and the
smallest diameter at the terminal portion (distal segment).
minute at each RAP. Thus, each diameter was obtained by averaging 15-30 individual measurements.
Experimental Protocols
Renal microvascular responses were observed as
RAP was elevated in 20-mm Hg increments from 80
mm Hg to a maximum of 180 mm Hg. Vessels from
13 WKY and 13 SHR kidneys were studied. To
define the regional variations in the responses of the
ILA, vessels with diameters in the ranges of 10-30
fim, 30-40 yum, 40-50 nm, 50-60 ^m, 60-80 fim,
and greater than 80 fim were grouped for analysis.
This analysis indicated that small vessels with basal
diameters less than 40 fim responded similarly to
pressure. Furthermore, the largest ILA segments
(greater than 60 fim) were uniformly unresponsive to
elevated pressure (see below). Therefore, to facilitate further analysis, ILAs were classified as either
proximal (greater than 60 fim), intermediate (40-60
fim), or distal (less than 40 ^.m) in all subsequent
analyses (see Figure 1). The range of basal diameters
of the ILAs was similar in WKY (20.7-119.5 fim) and
SHR (17.2-93.7 fim).
In an additional series of experiments, the ability
of nifedipine to inhibit pressure responses of the ILA
was examined in both WKY (n=6) and SHR (n = 10)
kidneys. Initially, ILA diameters were determined at
the RAPs of 80-180 mmHg in the absence of
nifedipine. Nifedipine was then administered at a
concentration of 1.0 fiM, a dose previously found to
completely inhibit myogenic responses of the afferent
arteriole.3 After a 10-minute equilibration period,
the responses of the same regions of the ILAs were
reassessed in the presence of the calcium antagonist.
Statistics
All data are expressed as the mean±SEM. Data
were analyzed by one-way analysis of variance followed when appropriate by application of Student's t
test. Changes within experimental groups were subjected to paired analysis. For multiple comparisons
within data groups, a value of N*P<0.05 (where TV
Hayashi et al
Proximal
I nt©fTT>0tfflt8
Myogenic Responses of Interlobular Arteries
Distal
155
o Decrease
0 -1
In
" 10 -j
Diameter
-10-
-20 (%Ch«n9«)
-20—I
-30 -I
I
200-,
20
1
I
40
60
80
100
Basal Diameter (microns)
3(1501.10050 -
FIGURE 2. Representative tracings illustrate segmental differences in myogenic reactivity of an interlobular artery (ILA)
from a Wistar-Kyoto kidney. As renal arterial pressure (RAP)
was increased, the diameter of the proximal segment did not
change (left), whereas the intermediate (middle) and distal
(right) ILA segments vasoconstricted markedly. Data are
plotted as percent changes from basal diameter (Le., at 80
mmHg).
represents the number of comparisons) was considered to indicate statistically significant differences.
Results
Segmental Heterogeneity of the Response of the
Interiobular Artery to Pressure
On the day of study, systolic blood pressures of
conscious donor animals were 139 ±1 mm Hg («=13)
in WKY and 205±5 mmHg (n = 13) in SHR
QxO.001).
Myogenic responsiveness of the ILA exhibited
segmental heterogeneity in both WKY and SHR.
Figure 2 illustrates representative tracings obtained
from an ILA of WKY. To facilitate a comparison of
the responses of the three segments, data are expressed as the percent change from basal diameter
(i.e., at 80 mm Hg). As depicted, the larger ILA
segment (63.8 pm, proximal) maintained its diameter
but did not constrict as RAP was increased. In
contrast, elevation of RAP elicited vasoconstriction
in the two smaller segments. Increasing RAP to 180
mm Hg decreased the diameters of the intermediate
and distal segments by 12% (from 50.2 to 44.0 jtm)
and 22% (from 32.1 to 25.2 ^m), respectively.
To delineate regional differences in the responses
of the ILA to pressure, vessel segments were grouped
according to their diameters at 80 mm Hg. The
results of this analysis are summarized in Figure 3.
The decrement in vessel diameter elicited by raising
RAP from 80 to 180 mmHg is expressed as the
percent change and is plotted as a function of basal
diameter. As illustrated, the response of the ILA to
pressure increased as basal diameter decreased, suggesting an increase in myogenic reactivity along the
FIGURE 3. Line graph shows segmental responsiveness of the
interlobular artery (ILA) to pressure in Wistar-Kyoto (o) and
spontaneously hypertensive rats (•). Responses of ILA segments observed when renal arterial pressure is elevated from 80
to 180 mm Hg are presented as mean ± SEM of percent change
in vessel diameters. Basal vessel diameters (yjn, mean±SEM)
are measured at 80 mm Hg.
length of the vessel. In WKY, ILA segments smaller
than 40 fj,m exhibited prominent vasoconstriction
(10-30 fim, -24.9 + 2.6%, n = 12; 30-40 p.m,
-23.0±2.1%, n=19), whereas smaller decreases in
vessel diameter were observed in larger caliber segments (40-50 fim, -12.6±3.3%, n = 10; 50-60 pm,
-12.6+3.2%, n=7; 60-80 nm, -8.4±3.4%, n=9;
greater than 80 ^m, -6.6±4.1%, n=5). In SHR,
prominent vasoconstriction was observed in vessels
with basal diameters ranging from 10 to 60 ^.m (10-30
tun, -21.1+2.0%, H=14; 30-40 fim, -19.5±3.2%,
n=9; 40-50 /xm, -19.5±3.2%, n=9; 50-60
-21.2±3.4%, n=8). Segments greater than 60
in diameter did not constrict in response to pressure
elevation (60-80 /xm, -1.4±1.3%, n=8; greater than
80 p-m, -1.7±3.7%, n=3) in SHR. Based on these
results, ILA segments were categorized as either
proximal (greater than 60 fim), intermediate (40-60
^m), or distal (less than 40 ^m) in subsequent
analyses.
Figure 4 summarizes pressure responses of proximal
ILA segments in WKY and SHR kidneys. At 80
mm Hg, the proximal ILA diameters in SHR (71.6±3.5
fim, n=6) did not differ significantly from that of WKY
(76.0±3.1 pm, n=W,p>05). Increasing RAP to 180
mmHg tended to reduce proximal ILA diameters
slightly, however, significant changes in vessel diameters were not attained in either strain (WKY, 71.2+4.5
fim,p>0.05; SHR, 70.7+3.8 fim,p>0A).
Pressure responses of intermediate ILA segments
are summarized in Figure 5. Responsiveness of the
intermediate segment to pressure was enhanced in
kidneys from SHR. Basal diameters of the intermediate ILA were identical in WKY (48.2 ±1.4 /im,
n = l l ) and SHR (48.1 ±1.7 jun,n = 14,/»0.5). At 180
mm Hg, the diameters of intermediate ILAs from
SHR kidneys tended to be smaller than those of
WKY kidneys (38.7±1.6 ^m and 42.5±1.2 urn, respectively,/? =0.08). When these data were expressed
156
Hypertension
Vol 19, No 2 February 1992
Distal Segment
Proximal Segment
80 - i
32
-
a c
5 o 27
22 - 1
65 - 1
80
100 120 140 160 180
80
Renal Arterial Pressure (mm Hg)
FIGURE 4. Line graph shows effects of elevating renal
arterial pressure (RAP) on proximal interiobuiar artery (ILA)
diameters in Wistar-Kyoto (o) (n=10) and spontaneously
hypertensive rats ( • ) (n=6). Vessel diameters (mean±SEM)
did not change significantly in response to elevated RAP
(compared with diameter at 80 mm Hg) in either strain.
as the percent changes from the basal diameter, the
vasoconstriction of intermediate segments in SHR
(-19.3±2.4%) was found to be significantly greater
than that of WKY (-11.5+2.4%, p<0.05). Furthermore, the intermediate segment of SHR exhibited a
lower threshold response, manifesting significant vasoconstriction at 100 mm Hg (46.7±1.6 fim,
p<0.005). In WKY, significant vasoconstriction of
Intermediate segment
48 - i
2 E
38 - 1
I
80
i
I
I
I
I
100 120 140 160 180
Renal Arterial Pressure (mm Hg)
FIGURE 5. Line graph shows effects of elevating renal
arterial pressure (RAP) on diameters of intermediate interiobuiar artery (ILA) segments in Wistar-Kyoto (WKY) (n=ll)
and spontaneously hypertensive rats (SHR) (n=14). As RAP
was elevated, the intermediate ILA diameters decreased progressively in SHR ( • ) and WKY (o> Intermediate ILA
segment of SHR manifested an enhanced response when
compared with that of WKY. Results are mean±SEM.
*p<0.01 vs. diameter at 80 mm Hg.
100 120 140 160 180
Renal Arterial Pressure (mm Hg)
FIGURE 6. Line graph shows effects of elevated renal arterial
pressure (RAP) on diameters of the distal interiobuiar artery
(ILA) segment in Wistar-Kyoto (o) (n=28) and spontaneously hypertensive rats (•) (n=21). Diameters of the distal
ILA segment decreased in a similar fashion as RAP was
raised. Results are mean±SEM. *p<0.01 vs. diameter at 80
mmHg.
the intermediate ILA was not attained until RAP was
elevated to 140 mm Hg (44.1 ±1.3 iim,p<Q.0\).
Figure 6 summarizes the vasoconstrictor responses
to pressure of distal ILA segments in WKY and SHR
kidneys. Basal diameters of this segment in SHR
(27.9±1.3 /im, n=2l) did not differ from that in
WKY (30.7 ±0.9 Aim, n=28,p>0.05). Similarly, at all
levels of RAP, the vasoconstrictor responses did not
differ between the two strains (p>0.l). Thus, in both
WKY and SHR, significant vasoconstriction was observed at 100 mm Hg (WKY, 28.9 ±1.0 fim,p< 0.001;
SHR, 26.7±1.2 /xm,/?<0.001), and further increases
in RAP elicited pressure-dependent vasoconstriction
of this segment. At 180 mm Hg, the diameters of the
distal segment were 23.5+1.0 Aim in WKY (/?<0.001)
and 22.4±1.1 fim in SHR (p<0.001), corresponding
to 23.6±1.8% and 19.9±1.7% decrements from the
basal diameter, respectively (p>0.1). Thus, the distal
segment of the ILA exhibited identical pressure
responsiveness in the two strains.
To further facilitate comparison of the segmental
myogenic responsiveness of the ILA in WKY and SHR,
data from proximal, intermediate, and distal segments
in kidneys from each strain are expressed as percent
changes from the basal diameter in Figure 7. Distal
LLA segments constricted prominently in both strains,
whereas proximal LLA segments did not exhibit significant vasoconstriction in either strain. The response of
the intermediate segment clearly differed in WKY
and SHR kidneys. In WKY, the response of the
intermediate ILA segment was significantly less than
that of the distal segment (120 mm Hg, -4.5±2.1%
versus -13.0±1.4%,p<0.005; 140 mm Hg, -8.1±2.4%
versus -17.6 + 1.7%, /?<0.005; 160 mmHg,
-10.4±2.7% versus -21.1±1.9%, /?<0.005; 180
mmHg, -11.5±2.4% versus -23.6±1.8%,/7<0.001;
intermediate and distal segments, respectively). In
Hayashi et al
Myogenic Responses of Interlobular Arteries
WKY
o
157
SHR
-
Prox
Prox
~ -10
a
-\
Inter
I
If'0
35
£ -20 H
Dtat
-30 - 1
-30 - 1
I
I
80
I
I
I
I
1
100 120 140 160 180
I
I
I
I
I
80 100 120 140 160 180
Reno) Arterial Pressure (mm Hg)
Renal Arterial Pressure (mm Hg)
FIGURE 7. Line graphs show comparison of the segmental myogenic responsiveness in Wistar-Kyoto (WKY) (left panel) and
spontaneously hypertensive rat (SHR) (right panel) kidneys. In both strains, the distal interlobular artery segment (Dist; A)
vasoconstricted markedly, whereas the diameters of the proximal segment (Prox; m) decreased only modestly. In WKY, the responses
of the intermediate segment (Inter, o) were less than those of the distal segment (left panel). In SHR, the responses of the
intermediate segments were greatly augmented (right panel). Thus, in SHR the magnitude of myogenic vasoconstriction of the
intermediate segment was identical to that of the distal segment. Results are mean±SEM.
contrast, the responses of the intermediate ILA from
SHR kidneys was identical to that of the distal
segment at every level of RAP (p>0.l).
Effects of Nifedipine on Pressure-Induced Interlobular
Artery Vasoconstriction
The effects of nifedipine on myogenic responses of
intermediate and distal ILA segments were assessed
by measuring the responses before and after adminis-
Intermediate Segment
WKY
Distal Segment
SHR
WKY
So
#NHMIplne
SHR
" N ^ ^ Nifedipine
% "S" -10 •
II
es
"S--10
E o)
I & -20-I
Control
2 5
•
Control
Q
£
O
-20-30
J
Control
80100120140160180
80100120140160180
Renal Arterial Pressure (mm Hg)
FIGURE 8. Line graphs show effects of1.0 tiM nifedipine on
the pressure-induced vasoconstriction of the intermediate interlobular artery (ILA) segments in Wistar-Kyoto (WKY) (left
panel) and spontaneously hypertensive rat (right panel)
kidneys. In WKY, nifedipine greatly attenuated myogenic
responses; however, the intermediate ILA vasoconstricted
significantly in the presence of the calcium antagonist. In
contrast, nifedipine completely abolished myogenic vasoconstriction in SHR. *Points at which diameters differed
(p<0.01) compared with basal diameter. fPoints at which
responses (percent change) differed between nifedipine and
control (p<0.05). Data are mean±SEM of percent change.
Open symbols, control; closed symbols, nifedipine.
- 3 0 •>
80100120140160180
80100120140160180
Renal Arterial Pressure (mm Hg)
FIGURE 9. Line graphs show effects of nifedipine on the
pressure-induced vasoconstriction of distal interlobular artery
segments in Wistar-Kyoto (WKY) (left panel) and spontaneously hypertensive rats (SHR) (right panel). Administration of
1 fiM nifedipine partially prevented the pressure-induced
vasoconstriction of this segment in WKY. In contrast, nifedipine completely inhibited the pressure response in SHR kidneys. *Points at which diameters differed (p<0.01) compared
with basal diameter. fPoints at which responses (percent
change) differed between nifedipine and control (p<0.05).
Data are mean±SEM of percent change. Open symbols,
control; closed symbols, nifedipine.
158
Hypertension
Vol 19, No 2 February 1992
tration of the calcium antagonist in WKY and SHR
kidneys. The results of these studies are summarized
in Figures 8 and 9. In WKY, nifedipine only partially
inhibited myogenic responses in each segment. Thus,
elevating RAP from 80 to 180 mmHg elicited a
14.4 ±2.7% decrement in the intermediate ILA diameter (i.e., from 50.0±1.5 to 43.0±2.2 yon, p<0.001,
n=l2, Figure 8, left panel). After 1 fiM nffedipine,
this vessel exhibited a partial response, manifesting a
4.6±1.2% decrement in diameter at 180 mm Hg (i.e.,
from 49.6±1.4 to 47.4±1.6 /xm,p<0.005). This corresponds to a 56±11% inhibition of myogenic vasoconstriction of the intermediate ILA in WKY kidneys.
The distal ILA segment constricted by 27.6±2.4% at
180 mmHg (i.e., from 31.2+2.0 to 22.6±1.7 urn,
/?<0.001, n=9) in the absence of nifedipine and by
6.0±2.2% in the presence of nifedipine (Figure 9),
corresponding to a 79 ±7% inhibition of myogenic
responsiveness in this segment.
The intermediate ILA segment in SHR exhibited an
enhanced response to nifedipine (Figure 8, right panel). In the absence of nifedipine, the intermediate ILA
segment manifested a 20.1 ±2.7% decrement in diameter at 180 mmHg (from 45.8±2.0 to 36.6+1.9 jan,
/?<0.001, n=l). After nifedipine administration, increasing RAP resulted in a passive distention of this
segment, increasing diameter to 120±9% (i.e., from
45.7+2.1 fim at 80 mm Hg to 47.0±2.0 /im at 180
mmHg, p=0.08, n=7). Thus, nifedipine completely
inhibited myogenic vasoconstriction of this segment.
Myogenic vasoconstriction of the distal ILA segment
was also inhibited by nifedipine in kidneys from SHR.
In the absence of nifedipine, the distal ILA exhibited
a 73.1±2.1% decrease in diameter (i.e., from 30.3+1.9
to 23.1±1.7 ^m,p<0.001, n=8) in kidneys from SHR
(Figure 9). After nifedipine administration, the diameter of distal ILA segments did not change in response
to elevation of RAP, exhibiting neither a decrease nor
a passive distention (Figure 9).
Discussion
Renal vascular resistance (RVR) is increased in
both human and experimental hypertension.6-7'16'17
To the extent that vasodilators reverse the increased
RVR associated with hypertension, the increase in
resistance may be viewed as reflecting a functional
adaptation of the renal circulation.16"18 Afferent
arteriolar resistance is a principal determinant of
RVR19 and is elevated in hypertensive animals.6'720
The contribution of the ILA to altered renal hemodynamics in hypertension has not been fully defined.
The ILA, originating at the arcuate artery near the
corticomedullary junction and terminating at the superficial cortex, is anatomically well suited to regulate the
arterial pressure gradient within the renal cortex. The
ELA is tapered along its length, varying in diameter
from more than 90 jim near the arcuate artery to less
than 30 fim at the terminal segment. Intraluminal
pressure at the proximal portion is directly related to
systemic blood pressure,21 whereas that within the
distal segment is partially autoregulated.8-9 The seg-
mental responsiveness of the ILA to pressure, however,
has not been previously examined. Furthermore, the
effects of hypertension on the myogenic responsiveness
of this vessel have not been investigated.
Segmental Differences in Pressure Response of
Interiobular Artery in Spontaneously
Hypertensive Rats
The present study clearly demonstrates that myogenic reactivity of the ILA exhibits a regional heterogeneity, increasing in magnitude from proximal to
distal segments (Figure 2). Although we cannot
ascertain fully the mechanisms responsible for the
variation in myogenic reactivity along the ILA, it is
likely that vessel diameter itself is a contributing
factor. At increased pressures, myogenic vasoconstriction would be opposed by an increased distending force exerted on the vessel wall. Since wall
tension directly relates to vessel diameter (LaPlace:
wall tension=pressure x radius), the distending force,
countervailing the myogenic constrictor response,
would be greater in larger vessels.
The role of the HA in maintaining renal autoregulation has not been established. Previous investigators have suggested that this vessel contributes to
RVR.8-9-22 T0nder and Aukland8 observed the intraluminal pressure of the ILA in the outer cortex to be
substantially less than that of the aorta. Similarly,
Kallskog et al9 demonstrated that changes in renal
perfusion pressure result in much smaller changes in
the pressure within the superficial segment of the ILA.
Although the major contribution of the afferent arteriole is clearly acknowledged, these findings indicate
that the ILA also contributes importantly to autoregulatory responses. Previous studies have not determined the relative contributions of myogenic responses of proximal versus distal segments of the ILA.
Our current findings indicate that the distal and
intermediate segments of the ILA contribute more to
autoregulation than the proximal portion of this vessel.
Altered Pressure Response of the Interiobular Artery in
Spontaneously Hypertensive Rats
Hypertension is associated with alterations in the
renal response to pressure, including a shift in renal
autoregulation.2 In previous studies with the isolated
perfused hydronephrotic kidney, we demonstrated
that pressure-induced afferent arteriolar vasoconstriction is reset to higher pressure levels in SHR.3 In the
present study, alterations in the myogenic responsiveness of the intermediate segment of the ILA were
observed to occur in this same model. In contrast to
the afferent arteriole, however, myogenic responses of
intermediate ILA segments were enhanced, exhibiting
both a lower threshold pressure (Figure 5) and a
greater maxima] response (Figure 7). Thus, the nature
of the adaptations of the afferent arteriole and ILA in
SHR exhibits opposite characteristics. Furthermore,
the adaptive changes in myogenic reactivity of the ILA
were restricted to the intermediate segment of this
Hayashi et al Myogenic Responses of Interlobular Arteries
vessel: distal and proximal ILA segments responded
similarly in SHR and WKY.
The reasons for the differing adaptive responses of
the intermediate ILA and afferent arteriole of SHR
cannot be discerned from the present study. An
enhanced vasoconstriction of the ILA could conceivably reduce the increment in transmural pressure
sensed by downstream afferent arterioles, thereby
resulting in a shift in afferent arteriolar responses to
higher renal arterial pressures. Although this formulation remains a possibility, we did not observe
alterations of pressure-induced afferent arteriolar
responses to be restricted to those vessels arising
downstream from the intermediate ELA. Furthermore, the response of RVR to pressure was also
shifted to higher pressures in SHR, suggesting a
correlation with the altered responsiveness of the
afferent arteriole.3 Thus, we do not believe that the
shift in afferent arteriolar responsiveness is due to
increased ILA vasoconstriction. Rather, we suggest
that the altered responsiveness of the intermediate
ILA and afferent arteriole in SHR reflects different
functional adaptations of these two vessel types to
hypertension.
Our current observations of the actions of nifedipine support the view that differing mechanisms may
underlie the adaptations of the ILA and afferent
arteriole in SHR. We previously demonstrated that
nifedipine has identical effects on myogenic vasoconstriction of afferent arterioles in WKY and SHR,
completely abolishing afferent arteriolar responses in
both strains at 1.0 jtM and exhibiting an identical
IQo.3 In contrast, however, the effects of nifedipine
on myogenic responses of the ILA differed in SHR
and WKY. At 1.0 jtM, nifedipine only partially
inhibited myogenic vasoconstriction of the ILA in
WKY kidneys but completely eliminated the pressure
responses in SHR. This finding suggests an alteration
in excitation-contraction coupling of the ILA in
SHR. Since afferent arteriolar responses to nifedipine were identical in WKY and SHR,3 it follows that
differing cellular mechanisms underlie the adaptations of these two vessel types to hypertension.
The observation that 1.0 fiM nifedipine inhibited
myogenic ILA responses to a greater extent in SHR
than WKY suggests an augmented calcium channel
activity in the ILA of this strain. Although we have no
direct evidence to support this interpretation, it is of
interest that Hermsmeyer and Rusch23-24 observed
smooth muscle cells cultured from SHR to exhibit a
greater ratio of L-type versus T-type calcium channels than cells cultured from WKY, suggesting an
alteration in calcium channel expression in vascular
smooth muscle of this strain. Studies by Steele and
Challoner-Hue25 also suggest that preglomerular resistance vessels of SHR kidneys exhibit alterations in
calcium channel activity; they observed that isolated
perfused kidneys from SHR manifested an exaggerated response of glomerular filtration rate to administration of verapamil in comparison with kidneys
isolated from WKY. These authors suggested that
159
the renal vasculature of the SHR exhibits an enhanced calcium channel activity. The present observations support and extend these interpretations and
suggest that the ILA represents a potential site of
augmented calcium channel activity in the SHR.
Finally, the adaptation of the intermediate ILA
segment in SHR kidneys may be relevant to the
pattern of pathological findings in kidneys from this
hypertensive model. In SHR kidneys, glomerular
injury is most prevalent in juxtamedullary nephrons,
whereas pathological changes are much less apparent
in superficial glomeruli.26-27 In addition, Feld et al26
demonstrated that urinary protein excretion is elevated in SHR, whereas albumin clearance in superficial nephrons appears normal, suggesting that proteinuria derives mainly from juxtamedullary
nephrons. Furthermore, the distribution of the glomerular injury in SHR also corresponds to differences in intrarenal hemodynamics. Juxtamedullary
glomeruli manifest a higher single nephron glomerular filtration rate in SHR than in WKY,28 presumably due to elevated glomerular capillary pressure. In
contrast, in superficial glomeruli both glomerular
capillary pressure and single nephron glomerular
filtration rate are similar in SHR and WKY,6>7 indicating an increased preglomerular resistance in SHR.
Previously, it has been assumed that an increased
afferent arteriolar resistance alone prevented an
increase in superficial glomerular capillary pressure
in SHR kidneys.6-7'20 The results of the present study
indicate that the intermediate ILA segment exhibits
an augmented myogenic response that may also
contribute to the increased preglomerular resistance,
especially of superficial glomeruli. It is tempting to
speculate that the enhanced vasoconstriction of the
intermediate ILA acts in concert with afferent arteriolar vasoconstriction to prevent or attenuate elevated glomerular capillary pressure in superficial
nephrons. This postulate concerning the possible
pathophysiological consequences of the myogenic
response of the ILA is offered with a number of
caveats. We have not demonstrated that the augmented ILA vasoconstriction reduces the pressure
within downstream vessels nor have we shown that
the altered ILA responses occur to a similar extent in
nonhydronephrotic kidneys. Gearly, further studies
are required to establish the role of the ILA in
regulating the arterial pressure gradient within the
renal cortex.
In conclusion, the present study demonstrates that
myogenic reactivity of the ILA to pressure varies along
the length of the vessel, with greater responses occurring in the more distal segments. In SHR, the myogenic responsiveness of the intermediate ILA segment
is markedly augmented, suggesting an adaptation in
this hypertensive model that could differentially influence pressures in superficial and juxtamedullary nephrons. Finally, pressure-induced contractions of the
ILA from SHR were inhibited by 1.0 /AM nifedipine to
a greater extent than those of WKY rats, suggesting
that the enhanced myogenic reactivity of this vessel
160
Hypertension
Vol 19, No 2 February 1992
reflects an alteration in calcium channel activity associated with the hypertensive state.
Acknowledgment
We gratefully acknowledge the contribution of
Hayley Forster in the statistical analysis of these data
and preparation of the manuscript.
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KEY WORDS • arteries • vasoconstriction • microcirculation •
essential hypertension • calcium channel bloclters • ion channels
• spontaneously hypertensive rats