Renal vasoconstrictor action of angiotensin II (Ang II) is exaggerated in the spontaneously hypertensive rat (SHR) before development of hypertension. We have recently demonstrated that in the rabbit afferent arteriole (Af-Art) activation of the AT2 receptor causes vasodilation, which modulates the vasoconstrictor action of Ang II mediated by the AT1 receptor. In this study, we tested the hypothesis that vasoconstrictor action of Ang II is exaggerated in SHR Af-Arts due to an impaired function of the AT2 receptor before development of hypertension. Af-Arts were microdissected from the superficial cortex of 4- to 5-week-old SHR or age-matched Wistar Kyoto rats (WKY), and perfused at 60 mm Hg in vitro. Ang II (10–11 to 10–8 M) decreased the luminal diameter of Af-Arts of both strains in a dose-dependent manner. However, the constriction was stronger in SHR; at 10–10 M, the diameter decreased by 34 ± 4% in SHR (n = 6) compared to 18 ± 3% in WKY (n = 6; p < 0.01). Pretreatment with PD123319 (PD), an AT2 receptor antagonist, significantly augmented Ang II-induced constriction in WKY but not SHR Af-Arts; at 10–10 M, the diameter now decreased by 41 ± 5 and 37 ± 1% in SHR (n = 6) and WKY (n = 6), respectively. Thus, blockade of the AT2 receptor abolished the difference in Ang II action on Af-Arts between strains. Moreover, with the AT1 receptor blockade Ang II caused dose-dependent dilation of preconstricted Af-Arts only in WKY (27 ± 5% at 10–8 M, n = 5), and the dilation was abolished by simultaneous treatment with PD. In contrast, no such dilation was observed in SHR Af-Arts. These results suggest that activation of the AT2 receptor modulates AT1 receptor vasoconstriction in WKY Af-Arts, while impaired modulatory function of AT2 receptor may play a role in the exaggerated vasoconstrictor action of Ang II on the Af-Art of prehypertensive SHR.

1.
Harrap SB, Merwe WMV, Griffin SA, Macpherson F, Lever AF: Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension 1990;16:603–614.
2.
Harrap SB, Doyle AE: Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat. Clin Sci 1988;74:63–69.
3.
Guidi E, Hollenberg NK: Differential pressor and renal vascular reactivity to angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 1987;9:591–597.
4.
Arendshorst WJ, Chatziantoniu C, Daniels FH: Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension. Kidney Int 1990;38(suppl 30):S92–S96.
5.
Kawashima K, Shiono K, Sokabe H: Variation of plasma and kidney renin activities among substrains of spontaneously hypertensive rats. Clin Exp Hypertens 1980;22:229–245.
6.
Berecek KH, Schwertschlag U, Gross F: Alterations in renal vascular resistance and reactivity in spontaneous hypertensive of rats. Am J Physiol 1980;238:H287–H293.
7.
Dilley JR, Stier CT, Arendshorst WJ: Abnormalities in glomerular function in rats developing spontaneous hypertension. Am J Physiol 1984;246:F12–F20.
8.
Beierwaltes WH, Arendshorst WJ, Klemmer PJ: Electrolyte and water balance in young spontaneously hypertensive rats. Hypertension 1982;4:908–915.
9.
Arima S, Endo Y, Yaoita H, Omata K, Tsunoda K, Takeuchi K, Abe K, Ito S: Possible role of P450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 1997;100:2816–2823.
10.
Ito S, Juncos LA, Carretero OA: Pressure-induced constriction of the afferent arteriole of spontaneously hypertensive rats. Hypertension 1992;19(suppl 2):II-164–II-167.
11.
Ito S, Johnson CS, Carretero OA: Modulation of angiotensin II-induced vasoconstriction by endothelium-derived relaxing factor in the isolated microperfused rabbit afferent arteriole. J Clin Invest 1991;87:1656–1663.
12.
Arima S, Ito S, Omata K, Takeuchi K, Abe K: High glucose augments angiotensin II action by inhibiting NO synthesis in in vitro microperfused rabbit afferent arterioles. Kidney Int 1995;48:683–689.
13.
Masari D, Bottani S, Whitebread S, Gaspero M, Levens N: Renal actions of the selective angiotensin AT2 receptor ligands CGP 42112 B and PD 123319 in the sodium-depleted rat. Eur J Pharmacol 1993;249:85–93.
14.
Berchler V, Jones PW, Levens NR, Gaspero M, Bottari S: Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul Pept 1993;44:207–213.
15.
Shibouta Y, Inada Y, Ojima M, Wada T, Noda M, Sanada T, Kubo K, Kohara Y, Naka T, Nishikawa K: Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2′-(1H-terazol--5-yl) biphenyl-4-yl]methyl]-1H-benzimida- zole-7-carboxylic acid (CV11974), and its prodrug, (±)-1-(cyclohexyloxycarbonyloxy)-ethyl-2-ethoxy-1-[[2′(1H-tetrazol-5-yl)biphenyl- 4-yl]-methyl]-1H-benzimidazole-7-carboxylate (TCV116). J Pharmacol Exp Ther 1993;266:114–120.
16.
Arima S, Ren Y, Juncos LA, Carretero OA, Ito S: Glomerular prostaglandins modulate vascular reactivity of the downstream efferent arterioles. Kidney Int 1994;45:650–658.
17.
Edwards RM: Response of isolated renal arterioles to acetylcholine, dopamine, and bradykinin. Am J Physiol 1985;248:F183–F189.
18.
Ito S, Carretero OA: Impaired response to acetylcholine despite intact endothelium-derived relaxing factor/nitric oxide in isolated microperfused afferent arterioles of the spontaneously hypertensive rat. J Cardiovasc Pharmacol 1992;20(suppl 12):S187–S189.
19.
Edwards RM: Effects of prostaglandins on vasoconstrictor action in isolated renal arterioles. Am J Physiol 1985;248:F779–F784.
20.
Ruan X, Wagner C, Chatziantoniou C, Kurtz A, Arendshorst WJ: Regulation of angiotensin II receptor AT1 subtypes in renal afferent arterioles during chronic changes in sodium diet. J Clin Invest 1997;99:1072–1081.
21.
Ichiki T, Kanbayashi Y, Inagami T: Differential inducibility of angiotensin II AT2 receptor between SHR and WKY vascular smooth muscle cells. Kidney Int 1996;49(suppl 55):S14–S17.
22.
Goto M, Mukoyama M, Suga S, Matsumoto T, Nakagawa M, Ishibashi R, Kasahara M, Sugawara A, Tanaka I, Nakao K: Growth-dependent induction of angiotensin II type 2 receptor in rat mesangial cells. Hypertesnion 1997;30:358–362.
23.
Omata K, Abraham NG, Schwartzman ML: Renal cytochrome P-450 arachidonic acids metabolism: Localization and hormonal regulation in SHR. Am J Physiol 1992;262:F591–F599.
24.
Madhum ZT, Goldthwait DA, McKay D, Hopfer U, Douglas JG: An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. J Clin Invest 1991;88:456–461.
25.
Jacobs LS, Douglas JG: Angiotensin II type 2 receptor subtype mediates phospholipase A2-dependent signaling in rabbit proximal tubular epithelial cells. Hypertension 1996;28:663–668.
26.
Zou AP, Imig JD, Kaldunski M, Ortiz de Montellano PR, Shi Z, Roman RJ: Inhibition of renal vascular 20-HETE production impairs autoregulation of renal blood flow. Am J Physiol 1994;266:F275–F282.
27.
Imig JD, Falck JR, Gebremedhin D, Harder DR, Roman RJ: Elevated renovascular tone in young spontaneously hypertensive rats. Role of cytochrome P-450. Hypertension 1993;22:357–364.
28.
Gebremedhin D, Ma YH, Imig JD, Harder DR, Roman RJ: Role of cytochrome P-450 in elevating renal vascular tone in spontaneously hypertensive rats. J Vasc Res 1993;30:53–60.
29.
Chatziantoniou C, Arendshorst WJ: Impaired ability of prostaglandins to buffer renal vasoconstriction in genetically hypertensive rats. Am J Physiol 1992;263:F573–F580.
30.
Jackson EK, Herzer WA: Angiotensin II/prostaglandin I2 interactions in spontaneously hypertensive rats. Hypertension 1993;22:688–698.
31.
Konieczkowski M, Dunn MJ, Stork JE, Hassid A: Glomerular synthesis of prostaglandins and thromboxane in spontaneously hypertensive rats. Hypertension 1983;5:446–452.
32.
Siragy HM, Carey RM: The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3′, 5′-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats. J Clin Invest 1996;97:1978–1982.
33.
Ito S, Arima S, Ren YL, Juncos LA, Carretero OA: Endothelium-derived relaxing factor/nitric oxide modulates angiotensin II action in the isolated microperfused rabbit afferent but not efferent arteriole. J Clin Invest 1993;91:2012–2019.
34.
Gohlke P, Pees C, Unger T: AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 1998;31:349–355.
35.
Seyedi N, Xu X, Nasjletti A, Hintze TH: Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension 1995;26:164–170.
36.
Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD: Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205–251.
37.
Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BLM, Inagami T: Effects on blood pressure and exploratory behavior of mice lacking angiotensin II type-2 receptor. Nature 1995;377:748–750.
38.
Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK: Behavioral and cardiovascular effects of disrupting the angiotensin II type-2 receptor gene in mice. Nature 1995;377:744–747.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.