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.
Email: *igbe.ighodaro@uniben.edu
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.
Copyright © 2012 SciRes. PP
Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
d Medullary Circulations of Anesthetized Rabbits,”
Hypertension, Vol. 42, No. 2, 2003, pp. 200-205.
doi:10.1161/01.HYP.0000083341.64034.00
[20] S. Y. Chou, J. G. Porush and P. F. Faubert, “Renal Me-
dullary Circulation: Hormonal Control,” Kidney Inter-
national, Vol. 37, No. 1, 1990, pp. 1-13.
doi:10.1038/ki.1990.1
[21] D. S. A. Majid, M. Godfrey and L. G. Navar, “Pressure
Natriuresis and Renal Medullary Blood Flow in Dogs,”
Hypertension, Vol. 29, No. 4, 1997, pp. 1051-1057.
doi:10.1161/01.HYP.29.4.1051
[22] S. A. Omoro, D. S. A. Majid, S. S. El-Dahr and L. G.
Navar, “Kinin Influences on Renal Regional Blood Flow
Responses to Angiotensin-Converting Enzyme Inhibition
in Dogs,” American Journal of Physiology Renal Physi-
ology, Vol. 276, No. 2, 1999, pp. F271-F277.
[23] N. Parekh, L. Dobrowolski, A. P. Zou and M. Stein-
hausen, “Nitric Oxide Modulates Angiotensin II- and
Norepinephrine-Dependent Vasoconstriction in Rat Kid-
ney,” American Journal of Physiology Regulatory Inter-
grative and Comparative Physiology, Vol. 270, 1996, pp.
R630-R635.
[24] R. G. Evans, G. BergstroÈm and A. J. Lawrence, “Effects
of the Vasopressin V1 Agonist [Phe2,Ile3,Orn8]-Vaso-
pressin on Regional Kidney Perfusion and Renal Excre-
tory Function in Anesthetized Rabbits,” Journal of Car-
diovascular Pharmacology Vol. 32, No. 4, 1998, pp. 571-
581. doi:10.1097/00005344-199810000-00009
Copyright © 2012 SciRes. PP
Differential Effects of Angiotensin II on Intra-Renal Hemodynamics in Rats;
Contribution of Prostanoids, NO and K+ Channels
Copyright © 2012 SciRes. PP
396
[25] L. G. Navar, B. L. Harrison, J. D. Imig, et al., “Role of
AT1 Receptor in Target Organ Disease: A Functional
Perspective,” American Journal of Hypertension, Vol. 13,
No. 1, 2000, pp. 45S-54S.
doi:10.1016/S0895-7061(99)00248-4
[26] R. G. Evans, G. A. Head, G. A. Eppel, S. L. Burke and N.
W. Rajapakse, “Frontiers in Research Series: Neural,
Hormonal and Renal Interactions in Long-term Blood
Pressure Control II: Angiotensin II and neurohumoral
Control of the Renal Medullary Circulation,” Clinical and
Experimental Pharmacology and Physiology, Vol. 37, No.
2, 2010, pp. 58-69.
doi:10.1111/j.1440-1681.2009.05233.x
[27] P. A. Ortiz, N. J. Hong, D. Wang and J. L. Garvin, “Gene
Transfer of eNOS to the Thick Ascending Limb of
eNOS-KO Mice Restores the Effects of L-Arginine on
NaCl Absorption,” Hypertension, Vol. 42, No. 4, 2003,
pp. 674-679. doi:10.1161/01.HYP.0000085561.00001.81
[28] H. M. Siragy and R. M. Carey, “The Subtype-2 (AT2)
Angiotensin Receptor Regulates Renal Cyclic Guanosine
3,5-Monophosphate and AT1 Receptor-Mediated Pros-
taglandin E2 Production in Conscious Rats,” Journal of
Clinical Investigation, Vol. 97, No. 8, 1996, pp. 1978-
1982. doi:10.1172/JCI118630
[29] M. D. Breyer and R. M. Breyer, “Prostanglandin E Re-
captors and the Kidney,” American Journal of Physiology,
Renal Physiology, Vol. 279, No. 1, 2000, pp. F12- F23.
[30] A. Yared, V. Kon and I. Ichikawa, “Mechanism of Pres-
ervation of Glomerular Perfusion and Filtration during
Acute Extracellular Volume Depletion: Importance of In-
trarenal Vasopressin Prostaglandin Interaction for Pro-
tecting Kidneys from Constrictor Action of Vasopressin,”
Journal of Clinical Investigation, Vol. 75, No. 5, 1985, pp.
1477-1487. doi:10.1172/JCI111851
[31] F. G. Knox and J. P. Granger, “Control of Sodium Excre-
tion: An Integrative Approach,” In: E. E. Windhager, Ed.,
Renal Physiology, Oxford University Press, New York,
1992.
[32] J. Sadowski, E. Kompanowska-Jezierska, L. Dobrowolski,
A. Walkowska and B. Badzynska, “Simultaneous Re-
cording of Tissue Ion Content and Blood Flow in Rat
Renal Medulla: Evidence on Interdependence,” American
Journal of Physiology Renal Physiology, Vol. 273, No. 4,
1997, pp. F658-F662.
[33] E. Kompanowska-Jezierska, A. Walkowska and J. Sadowski,
“Exaggerated Volume Expansion Natriuresis in Rats Pre-
loaded with Hypertonic Saline: A Paradoxical Enhance-
ment by Inhibition of Prostaglandin Synthesis,” Acta Physi-
ologica Scandinavica, Vol. 167, No. 3, 1999, pp. 189-194.
doi:10.1046/j.1365-201x.1999.00604.x
[34] H. G. Klieber and J. Daut, “A Glibenclamide-Sensitive
Potassium Conductance in Terminal Arterioles Isolated
from Guinea Pig Heart,” Cardiovascular Research, Vol.
28, No. 6, 1994, pp. 823-830. doi:10.1093/cvr/28.6.823
[35] S. M. Gardiner, P. A. Kemp, J. E. March, B. Fallgren and
T. Bennett, “Effects of Glibenclamide on the Regional
Haemodynamic Actions of α-Trinositol and Its Influence
on Responses to Vasodilators in Conscious Rats,” British
Journal of Pharmacology, Vol. 117, No. 3, 1996, pp. 507-
515. doi:10.1111/j.1476-5381.1996.tb15219.x
[36] A. L. Salzman, A. Vromen, A. Denenberg and C. Szabo,
“KATP-Channel Inhibition Improves Hemodynamics and
Cellular Energetics in Hemorrhagic Shock,” American
Journal of Physiology Heart Circulation Physiology, Vol.
272, No. 2, 1997, pp. H688-H694.
[37] T. Mimuro, T. Kawata, T. Onuki, S. Hashimoto, K. Tsu-
chiya, H. Nihei and T. Koike, “The Attenuated Effect of
ATP-Sensitive K+ Channel Opener Pinacidil on Renal
Haemodynamics in Spontaneously Hypertensive Rats,”
European Journal of Pharmacology, Vol. 358, No. 2,
1998, pp. 153-160. doi:10.1016/S0014-2999(98)00573-1
[38] C. Cao, W. Lee-Kwon, E. P. Silldorff and T. L. Pallone,
“KATP-Channel Conductance of Descending Vasa Recta
Pericytes,” American Journal of Physiology Renal Physi-
ology, Vol. 289, No. 6, 2005, pp. F1235-F1245.
doi:10.1152/ajprenal.00111.2005
[39] M. DeGasparo, K. J. Catt and T. Inagami, “International
Union of Pharmacology XXIII. The Angiotensin II Re-
ceptors,” Pharmacological Reviews, Vol. 52, No. 3, 2000,
pp. 415-472.
[40] H. Matsubara, T. Sugaya, S. Murasawa, Y. Nozawa, Y.
Mori and H. Masaki, “Tissue-Specific Expression Of
Human Angiotensin II AT1 and AT2 Receptors and Cel-
lular Localization of Subtype mRNAs in Adult Human
Renal Cortex Using in Situ Hybridization,” Nephron, Vol.
80, No. 1, 1998, pp. 25-34. doi:10.1159/000045121
[41] L. M. Duke, R. E. Widdop, M. M. Kett and R. G. Evans
“AT2 Receptors Mediate Tonic Renal Medullary Vaso-
constriction in Renovascular Hypertension,” British Jour-
nal of Pharmacology, Vol. 144, No. 4, 2005, pp. 486-492.
doi:10.1038/sj.bjp.0706036
[42] R. E. Widdop, E. S. Jones, R. E. Hannan and T. A. Gas-
pari, “Angiotensin AT2 Receptors: Cardiovascular Hope
or Hype?” British Journal of Pharmacology, Vol. 140,
No. 5, 2003, pp. 809-824. doi:10.1038/sj.bjp.0705448