Pharmacology & Pharmacy, 2012, 3, 388-396
http://dx.doi.org/10.4236/pp.2012.34052 Published Online October 2012 (http://www.SciRP.org/journal/pp)
1
Differential Effects of Angiotensin II on Intra-Renal
Hemodynamics in Rats; Contribution of Prostanoids, NO
and K+ Channels
Ighodaro Igbe1*, Eric K. I. Omogbai1, Adebayo O. Oyekan2
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Benin, Benin City, Nigeria; 2Center for Cardio-
vascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, USA.
Received May 22nd, 2012; revised June 24th, 2012; accepted July 15th, 2012
ABSTRACT
Many agents are known to cause qualitative and quantitative differences in intrarenal blood flow. This study tested the
hypothesis that angiotensin II (AII) evokes a differential effect on cortical (CBF) and medullary blood flow (MBF) and
that AT2 receptor mediates AII-induced increase in renal MBF by mechanisms related to nitric oxide (NO) and
prostanoids. AII (100, 300 and 1000 µg/kg/min) increased mean arterial blood pressure (MABP) by 24% ± 7% (p <
0.05); decreased CBF by 30% ± 2% (p < 0.05); but increased MBF by 21% ± 8% (p < 0.05). Indomethacin (5 mg/kg),
enhanced AII effects on MABP by 154% ± 26% (p < 0.05), MBF by 141% ± 46% but decreased CBF by 74% ± 54% (p <
0.05) indicating the involvement of dilator prostanoids in the systemic and medullary circulation but constrictor
prostanoids in the cortex. NG nitro-L-arginine (L-NNA), an inhibitor of NO synthase (100 mg/L in drinking water) en-
hanced AII effects on MABP (169 ± 75, p < 0.05) and decreased CBF (107% ± 50%, p < 0.05) but blunted the effects
of AII on MBF (150% ± 21%, p < 0.05). 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; 2 mg/kg), a guanylyl
cyclase inhibitor, enhanced AII effects on MABP (118% ± 32% , p < 0.05) and decreased CBF(85% ± 47% , p < 0.05)
but blunted the effects of AII on MBF (96% ± 15%, p < 0.05). However, glibenclamide (20 µg/kg), a KATP channel
blocker, did not affect intra-renal hemodynamics elicited by AII. Blockade of AT2 receptors with PD123319 (50
µg/kg/min) did not change basal or AII-induced changes MABP or CBF but blunted AII-induced increase in MBF by
60% ± 11% (p < 0.05). CGP42112 (10 µg/kg/min), an AT2 receptor agonist, elicited a reduction in MABP and increases
in CBF and MBF that were abolished or attenuated by PD123319. These findings demonstrate that AII elicited differen-
tial changes in intrarenal blood flow; an AT1-mediated reduction in CBF but an AT2-mediated increase in MBF. The
AT2 receptor-mediated increase in MBF involves guanylase cyclase, NO and dilator prostanoids but not KATP channels.
Keywords: Angiotensin II; Hemodynamics; Medullary Blood Flow; AT2 Receptors; Prostanoids
1. Introduction
The intrarenal vasculature can respond to neural and a
variety of humoral stimuli with vasodilatation or vaso-
constriction, resulting in increased or decreased perfusion
of renal tissue, respectively [1]. Such responses may
have more serious functional consequences within the
medulla than in the cortex. This is of major physiological
and pathophysiological importance as the medulla is
widely viewed as having a crucial role in maintaining
body fluid homeostasis and in the control of arterial pres-
sure [2].
The renin-angiotensin system is a coordinated hormonal
cascade important to the regulation of renal sodium ex-
cretion and blood pressure. The major effector peptide,
angiotensin II (AII), binds to two major receptors; AT1
and AT2. While the majority of AII actions are mediated
via the AT1 receptor, evidence has accumulated that the
AT2 receptor opposes the AT1 receptor, especially by
inducing vasodilation instead of vasoconstriction and
may be important in the regulation of blood pressure and
renal function by counterbalancing the vasoconstrictor
and antinatriuretic actions of AT1 receptors [3]. However,
the roles of AT1 and AT2 receptors in regulating regional
kidney perfusion remain unclear. In rats and rabbits,
infusions of AII reduced total renal blood flow (RBF)
and cortical blood flow but have a lesser effect on
medullary blood flow [4,5]. AII can even increase MBF,
especially when administered as a bolus [1,6]. Many
studies have demonstrated that the medullary vasculature
was poorly sensitive to the vasoconstrictor effects of AII
*Corresponding author.

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
389
compared with the cortical circulation [4,7,8]. A study [9]
has shown that AII induced a potent vasoconstriction of
isolated medullary vasa recta in Sprague-Dawley rats, a
response also observed in conscious rats [10]. Conversely,
other studies have shown that the systemic infusion of
AII increased papillary blood flow in young Sprague-
Dawley and Wistar rats [11] by increasing local medullary
synthesis of vasodilator agents such as prostaglandins,
nitric oxide (NO), or kinins.
Nitric oxide (NO) synthase and/or cyclooxygenase
(COX) blockade can enhance AII-induced reductions in
medullary blood flow (MBF) and abolish AII-induced
increases in MBF, both of which are chiefly AT1 mediated
[12-14]. However, the contributions of AT2 receptors to
these effects have received little attention, even though
they are expressed in vessels that might contribute to
MBF control (e.g., afferent arterioles and vasa recta). In a
routine experiment to address the effects of AII in the rat,
we noticed a differential effect on CBF and MBF and
this led us to characterize these effects. We hypothesized
that AII evokes a differential effect on intrarenal hemo-
dynamics by an AT1-mediated cortical vasoconstriction
but AT2 receptor-mediated increase in renal medullary
blood flow. To test this hypothesis, mean arterial blood
pressure (MABP), MBF and CBF responses to graded
doses of AII were determined in the presence of indo-
methacin, Nω-nitro-L-arginine, ODQ (1H-[1,2,4] oxadia-
zolo[4,3,-a]quinoxalin-1-one), or glibenclamide. In addi-
tion, we characterized the increase in MBF using
CGP42112, a highly selective AT2 agonist, and PD123319,
an AT2 antagonist.
2. Materials and Methods
2.1. Drugs and Chemicals
Nω-nitro-L-arginine (L-NNA;Sigma-Aldrich, St. Louis,
MO) and indomethacin (Sigma-Aldrich, St. Louis, MO)
were dissolved in 0.1 M NaHCO3, and pH was adjusted
to 7.0 - 7.2. Glibenclamide (Sigma-Aldrich, St. Louis,
MO) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ; Sigma-Aldrich, St. Louis, MO) were prepared in
dimethylsulfoxide (DMSO) as stock solutions of 0.1 M,
from which aliquots were diluted in normal saline for
intravenous administration. Angiotensin II (Sigma-Aldrich),
CGP42112 (21st Century Biochemicals, USA) and
PD123319 (a gift from Park Davis, USA) were dissolved
in normal saline (0.9% NaCl). All agents were kept on
ice during the experiments.
Female Sprague-Dawley rats (230 - 290 g body wt;
Harlan Sprague Dawley, Houston, TX) were maintained
on standard rat food (Purina Chow; Purina, St Louis, MO)
and allowed ad libitum access to water and food until the
beginning of the experiments. The study protocol was
approved by the Animal Care and Use Committee of
Texas Southern University.
2.2. Surgical Preparation
Animals were anesthetised with thiobutabarbital (Inactin),
100 mg/kg ip (Sigma-Aldrich) and placed on a heated
surgical table to maintain body temperature at 37˚C.
The tail vein was cannulated with a 25-gauge butterfly
needle (Vacutainer, Becton and Dickson) for infusion or
administration of drugs. The trachea was isolated and a
polyethylene catheter (PE-250) was placed in the tra-
chea for spontaneous ventilation. A polyethylene catheter
(PE-50) was placed in the left carotid artery to monitor
the blood pressure. Mean arterial blood pressure (MABP)
was measured with a pressure transducer (model BLPR2,
World Precision Instruments, Sarasota, FL) to a signal
manifold (Transbridge, model TBM-4, World Precision
Instrument, Sarasota, FL) and recorded on a data acqui-
sition system (model DI720, DataQ Instruments, Akron,
OH). The left kidney was exposed by an abdominal in-
cision, intrarenal blood flow was measured simulta-
neously by laser-Doppler (LD) flowmeter (system 5000,
version 1.20, Periflux, Stockholm, Sweden) via a surface
probe (model PF 407) to measure CBF or an optical fiber
LD probe (model PF 402) fixed to a micromanipulator
and placed in the medulla (5 mm below the kidney sur-
face) to measure MBF. CBF and MBF were recorded as
perfusion units (PU).
2.3. Experimental Protocol
After surgery and placing of probes for recording regional
blood flows, a 30- to 45-min equilibration period was
allowed. AII was administered by an infusion pump
(Model 100, SP 100i syringe pump, WPI, USA) at graded
doses of 100, 300 and 1000 ng/kg/min. These graded
doses were administered cumulatively. The effects on
MABP, CBF and MBF were determined in the presence
of indomethacin, a COX inhibitor (10 mg/kg iv; n = 6)
[15], L-NNA, Nω-nitro-L-arginine, a NO synthase in-
hibitor (100 mg/L in drinking water for 2 days; n = 6)
[16], ODQ, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-
one, a guanylase cyclase inhibitor (2 mg/kg iv; n = 5)
[17], glibenclamide, a KATP channel blocker (20 µg/kg, iv)
[18]; or their respective vehicles: 0.1 M NaHCO3 for
L-NNA and indomethacin, 5% DMSO for glibenclamide
and ODQ and normal saline for AII. Data obtained from
rats treated with 5% DMSO and 0.1 M NaHCO3 were not
different from those obtained from rats treated with
normal saline; hence, data from both groups were pooled
to represent control data for all the treatment groups.
Another set of experiments to characterize the possible
mechanisms involved in AII-induced increase in MBF

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
390
was carried out. MABP, MBF and CBF responses to
graded doses of AII were determined in the presence of
CGP42114, an AT2 receptor agonist and PD123319, an
AT2 receptor antagonist. Animals were anesthetized and
the left carotid artery cannulated for MABP determination
while intrarenal blood flow was measured simultaneously
by a laser-Doppler (LD) flow meter. After recording
baseline values, the effects of CGP42114 (10 µg/kg/min;
n = 5) were evaluated on MABP, CBF and MBF at
intervals of 5, 10, 15 and 20 min. After infusion was
stopped, a 30 min interval was allowed for the values to
return to baseline. PD123319, an AT2 receptor antagonist
was infused at 50 µg/kg/min [19] for 10 min before
CGP42112 (10 µg/kg/min) was infused concurrently and
the antagonistic effect of PD123319 was determined at
intervals of 5, 10, 15 and 20 min. Doses of all agents
used were those reported in the literature to produce sig-
nificant desired effects.
2.4. Statistical Analysis
All data were expressed as mean ± SEM. Changes in
systemic and renal hemodynamics were expressed as
absolute values and changes from baseline. The effects of
a particular agent were analysed using a two-way ANOVA
followed by Tukey’s multiple comparison test when
appropriate. Statistical analysis was performed using Graph
Pad Prism V. 4.01 where p < 0.05 was considered sta-
tistically significant.
3. Results
3.1. Effect of Angiotensin II Infusion on Systemic
and Renal Haemodynamics
Figure 1(a) shows a representative tracing illustrating the
differential effect of AII on systemic and renal haemody-
namics. AII (300 and 1000 ng/kg/min) increased mean
arterial blood pressure (MABP) and medullary blood
flow (MBF) while decreasing renal cortical blood flow
(CBF) in a dose related manner. AII (300 and 1000
ng/kg/min) increased mean arterial blood pressure (MABP)
by 24 ± 5, and 47 ± 7 mmHg; decreased renal cortical
blood flow (CBF) by –202 ± 69 and –98 ± 81 perfusion
units (PU), but increased medullary blood flow (MBF)
by 17 ± 09 and 53 ± 14 PU respectively.
3.2. Effect of Angiotensin II Infusion on Systemic
and Renal Haemodynamics in the Presence
of Indomethacin, L-NNA, ODQ and
Glibenclamide
Figure 2 illustrates that AII (100, 300 and 1000 ng/kg/min)
dose-dependently increased MABP by 13 ± 4, 22 ± 6,
and 49 ± 8 mmHg, respectively; decreased CBF by –116 ±
(a)

(b)
Figure 1. (a) Tracing showing the differential effects of an-
giotensin II (AII) on systemic (MABP) and renal hemody-
namics (CBF & MBF). MABP = mean arterial blood pres-
sure, MBF = medullary blood flow, CBF = cortical blood
flow; (b) Graphical illustration showing the differential
effects of angiotensin II (AII) on systemic (MABP) and re-
nal hemodynamics (CBF & MBF). (*p < 0.05 vs 300
ng/kg/min of AII).

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
391
(a)
(b)
(c)
Figure 2. Effect of acute angiotensin II infusion on systemic
(a) and renal (b), (c) haemodynamics in the presence of
indomethacin, L-NNA, ODQ or glibenclamide (*p < 0.05,
**p < 0.01 vs Control).
42, –204 ± 83 and –96 ± 67 perfusion units (PU), re-
spectively but increased MBF by 18 ± 10 and 52 ± 15 PU
respectively. Indomethacin (10 mg/kg) enhanced AII-
induced increase in MABP by 154% ± 26% (p < 0.05),
decreased CBF by 74% ± 54% (p < 0.05) and increased
AII-induced increase in MBF by 141% ± 46% (p < 0.05)
indicating that vasodilator prostaglandins may be con-
tributing to the increase in MBF while the vasocon-
strictor prostaglandins may be contributing to the in-
crease in MABP or decrease in CBF elicited by AII. NG
nitro-L-arginine (L-NNA; 100 mg/L in drinking water
for 2 days) enhanced AII-induced increase in MABP by
169 ± 75 (p < 0.05) and decrease in CBF by 107 ± 50 (p <
0.05) but blunted the effects of AII on MBF by 150 ± 21
(p < 0.05). ODQ, a soluble guanylyl cyclase (sGC; 2
mg/kg) inhibitor, enhanced AII-induced increase in
MABP by 118% ± 32% (p < 0.05) and decrease in CBF
by 85% ± 47% (p < 0.05) but blunted the effects of AII
on MBF by 96% ± 15% (p < 0.05). This indicates that
NO and activation sGC contribute to the AII-induced
increase in MBF or decrease in CBF. However, in the
presence of glibenclamide there were no significant changes
in AII-induced increase in MABP and MBF or decrease
in CBF as compared to the control, thus indicating that
ATP channels are not involved in AII-induced increase
in MBF.
K
3.3. Effect of Angiotensin II Infusion on Systemic
and Renal Haemodynamics as Affected by
AT2 Receptor Antagonism
The involvement of AT2 receptors in AII-induced changes
in intrarenal haemodynamics, AII (100, 300 and 1000
ng/kg/min) was infused in the presence of PD123319, an
AT2 receptor antagonist. PD123319 (50 µg/kg/min) did
not change basal or AII-induced changes BP or CBF.
However, PD123319 blunted AII-induced increase in
MBF by 60% ± 11% (p < 0.05) (Figures 3 and 4) indi-
cating the involvement of AT2 receptors in AII-induced
increase in MBF.
3.4. Effect of CGP42112 Alone and in
Combination with PD123319 on Basal
Systemic and Renal Haemodynamics
As an additional evidence to support that activation of
AT2 receptor was responsible for AII-mediated increase
in MBF, the effects of CGP42112, an AT2 receptor agonist,
was tested on basal systemic and renal haemo-dynamics
in the presence or absence of PD123319. Figure 5
(a)
(b)

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
392
illustrates that CGP42112 decreased basal MABP, in-
creased basal medullary perfusion and CBF in a time-
dependent manner. PD123319, AT2 receptor antagonist,
attenuated CGP42112-induced decrease in MABP by
121% ± 13% (p < 0.05), and CGP42112 induced increase
in CBF by 142% ± 3% (p < 0.01). CGP42112-induced
increase in basal MBF was also blunted by PD123319 by
67% ± 6%. These data imply that AT2 receptor activation
accounts for the increase renal MBF by AII.
4. Discussion
(c)
There is still considerable controversy regarding the rela-
tive effects of angiotensin II on CBF and MBF in
anaesthetized animals perhaps reflecting a species de
pendency. Thus, studies in dogs indicated that both
Figure 3. Effect of PD123319 on basal systemic (a) and re-
nal (b), (c) haemodynamics. 0 min represents basal values
while 10 min represents values obtained after infusion of
PD 123319 (50 µg/kg/min) for 10 min.
(a)
(b)
(c)
Figure 4. Effect of acute angiotensin II infusion on systemic (a) and renal (b), (c) haemodynamics in the presence of
PD123319 (*p < 0.05 vs control). Control animals were infused with normal saline (1 mL/h).

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
393
(a)
(b)
(c)
Figure 5. Effect of CGP42112 (10 µg/kg/min) alone and in combination with PD123319 (50 µg/kg/min) on basal systemic (a)
renal (b), (c) haemodynamics (*p < 0.05, **p < 0.01 vs CGP42112 + PD123319).
exogenous and endogenous angiotensin II profoundly in-
crease MBF, even at levels that have little impact on
CBF [20,22]. In contrast, in most studies in anaesthetized
rats and rabbits, intravenous or renal arterial infusion of
angiotensin II significantly decreased CBF but not MBF
[11,23,24].
In the present study, we tested the hypothesis that AII
evokes a differential effect on intrarenal hemodynamics
and that the AT2 receptor mediates the increase in the
renal medullary blood flow during acute AII infusion in
rats. Infusion of AII increased MABP and MBF dose
dependently with associated decrease in CBF. The pressor
and renal cortical vasoconstriction is a result of the
vasoconstrictive effect of AII [25] probably mediated
through AT1 receptors. Several studies have shown the
paradoxical increase in MBF with AII bolus dose [1,19].
AII-induced vasodilatation, as seen in the medulla, could
also have been indirect, being dependent on stimulation
on the biosynthesis and/or release of vasodilator agents,
such as prostaglandins, kinins or NO [26]. In order to
determine which of the vasodilatory agents was involved
in AII-induced increase in MBF, we examined the effect

Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
394
of AII infusion in the presence of indomethacin, a COX
inhibitor, L-NNA, a NO synthase inhibitor, ODQ, a sGC
inhibitor or glibenclamide, a KATP channels blocker.
LNNA or ODQ enhanced AII-induced increase in MABP
and decrease in CBF but remarkably inhibited AII-
induced increase in MBF. This is in agreement with the
studies that showed that inhibition of NO synthesis
prevented an increase in perfusion of the medulla after
AII [14,27]. NO acts through the stimulation of sGC,
with subsequent formation of cyclic GMP. These findings
implicate NO involvement via sGC in the increase in
MBF induced by AII. These data are in agreement with
previous studies [14,27,28]. The rate of synthesis and
tissue concentration of prostaglandins is much higher in
the medulla compared with the cortex, and AII stimulates
prostaglandin synthesis via AT1 receptors [28]. Prosta-
glandin E2 (PGE2) is a major renal cyclooxygenase me-
tabolite of arachidonate that modulates renal hemody-
namics and salt and water excretion [29]. The main-
tenance of normal renal blood flow and function during
physiological stress is especially dependent on endoge-
nous prostaglandin synthesis [30] buffering the vasocon-
strictor effects of AII, catecholamines, and vasopressin in
the kidney thereby preserving normal renal function.
Contrary to previous reports showing a tonic vasodilator
influence of prostaglandins on the medullary circulation
[31-33] inhibition of prostaglandins by indomethacin in
this study enhanced AII-induced increase in MBF. This
result suggests that vasodilator prostaglandins may be
contributing to the increase in MBF while the vasocon-
strictor prostaglandins may be contributing to the in-
crease in MABP or decrease in CBF elicited by AII.
KATP channel regulation of vasoactivity in vascular
beds has been documented and infusion of glibenclamide,
a KATP into rats induced mesenteric, skeletal muscle, and
renal vasoconstriction [34,35]. In vivo, KATP channel
inhibition also increases resistance to blood flow in
mesentery [36], renal cortex and medulla [32,37]. Pre-
vious studies demonstrated that high concentrations of
AII inhibit KATP in the renal medulla [38] and infusions of
KATP channel inhibitors have been shown to decrease
MBF [15,32]. In the present studies, inhibition of KATP
channels with glibenclamide did not significantly change
AII-mediated effects on systemic and renal hemodynamics.
AII acts at two main receptor subtypes: AT1 and AT2
receptors. AT1 receptors are responsible for mediating
most of the known actions of AII, including vasocon-
striction [39]. Moreover, a role for the AT2 receptor in
opposing the actions of AT1 receptor stimulation has
been implicated in growth and cardiovascular function
[39-41]. In the kidney, infusions of AII reduce total renal
blood flow (RBF) and cortical perfusion measured by
laser Doppler flowmetry in rats and rabbits [41]. How-
ever, medullary perfusion is relatively insensitive to the
vasoconstrictor effects of AII under most experimental
conditions [1,23]. The explanation for these observations
seems to be that, although AT1-receptor activation causes
vasoconstriction within vascular elements controlling
MBF, it can also cause vasodilatation by release of nitric
oxide and/or prostaglandins [5]. The contributions of
AT2 receptors to the control of MBF are less clear.
However, recent studies in anaesthetised rabbits suggest
that AT2-receptor activation counteracts AT1-mediated
vasodilatation in the renal medulla, as the AT2 antagonist
PD123319 revealed dose-dependent increases in Medul-
lary Laser Doppler Flux (MLDF) during renal arterial in-
fusion of AII [19] implying an AT2-mediated medullary
vasoconstriction but AT1-mediated vasodilation in the
rabbit. This observation is at odds with the current study
and contrary to the conventional view that AT2 receptors
mediate vasodilatation [42]. In our studies, blockade of
AT2 receptors with PD123319 attenuated AII-induced
increase in MBF, suggesting that the increase in MBF
was AT2 receptor mediated. These data were further con-
firmed by infusion of CGP41112, an AT2 receptor agonist
in the absence and presence of PD123319 to determine
the effect of AT2 receptor on basal MABP, CBF and
MBF. PD123319 had no detectable effect on resting
systemic or renal hemodynamics. Thus, AT2 receptors
did not appear to contribute greatly to the control of
resting MBF in anesthetized rats under these experimental
conditions. Activation of AT2 receptor by CGP41112
decreased basal MABP while increasing CBF and MBF.
These responses were attenuated by PD123319, con-
firming that AT2 receptor is not only involved in in-
creasing MBF but also appears to be involved in the
increase in CBF and decrease in MABP. These data are
at odds with studies that showed that the increased me-
dullary perfusion was AT1 receptor-mediated [1,6,19] in
rats.
In conclusion, AII evoked differential effects on intra-
renal haemodynamics in the rat evoking cortical vaso-
constriction but medullary vasodilation. AT2 re-ceptor
appears to mediate AII-induced increase in MBF by me-
chanisms involving guanylase cyclase, nitric oxide and
dilator prostanoids but not KATP channels.
5. Acknowledgements
This study was supported by National Institutes of Health
grant HL03674. The facilities of the RCMI program at
Texas Southern University were used for this study.
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