Effect of Angiotensin II Type 1 Receptor Blockade on Conduit Artery Tone in Subtotally Nephrectomized Rats

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Abstract

Background: Angiotensin II type 1 (AT1) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT1 blockade on conduit artery function in renal failure is unknown. Methods: The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT1 receptors quantified using autoradiography. Results: NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [125I]-Sar1,Ile8-angiotensin II binding to renal AT1 receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca2+-activated K+ channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K+ channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K+ channel agonist, was impaired in untreated but not in losartan-treated NX rats. Conclusion: Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K+ channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT1 blockade confers functional benefits to large arteries in renal failure.

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Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.

A Hürlimann, M Krayenbuhl, U Brunner … (1995)

Uremic small-artery disease with medial calcification and intimal hyperplasia can lead to life-threatening skin necrosis or acral gangrene. It is a distinct complication of chronic renal failure that must be differentiated from soft-tissue calcification. An increased calcium-phosphate product and secondary hyperparathyroidism are the main underlying conditions. The benefit of parathyroidectomy is controversial. This article is based on a literature search to determine prognostic factors and, in particular, the benefit of parathyroidectomy. The literature on uremic small-artery disease (so-called calciphylaxis) was reviewed (full data set: 104 cases, including five of our own). The therapeutic benefit of parathyroidectomy and the relation between prognostic predictors (localization, dialysis, and transplant) and outcome were analyzed. The relation between diabetes and acral gangrene was also examined. Further epidemiologic data on the reviewed group of patients were established. Thirty-eight of 58 patients who underwent parathyroidectomy survived compared with 13 of 37 patients who did not undergo parathyroidectomy (p = 0.007, n = 95). Forty of 53 patients with distal localization of necrosis survived compared with 11 of 42 patients with proximal pattern (p < 0.00001; n = 95). Dialysis and kidney transplantation followed by immunosuppression showed no relation to disease outcome. No association was found between diabetes and acral gangrene (p = 0.50). Uremic small-artery disease is a distinct complication of chronic renal failure. Its recognition and early diagnosis should allow more effective treatment. In our retrospective study parathyroidectomy was significantly related to survival. Only a randomized, controlled, prospective trial (parathyroidectomy vs conservative treatment of secondary hyperparathyroidism) can establish the value of parathyroidectomy in uremic small-artery disease.

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Angiotensin II inhibits rat arterial KATP channels by inhibiting steady-state protein kinase A activity and activating protein kinase Ce.

Y Hayabuchi, Peter S W Davies, Nicholas Standen (2001)

We used whole-cell patch clamp to investigate steady-state activation of ATP-sensitive K+ channels (KATP) of rat arterial smooth muscle by protein kinase A (PKA) and the pathway by which angiotensin II (Ang II) inhibits these channels. Rp-cAMPS, an inhibitor of PKA, did not affect KATP currents activated by pinacidil when the intracellular solution contained 0.1 mM ATP. However, when ATP was increased to 1.0 mM, inhibition of PKA reduced KATP current, while the phosphatase inhibitor calyculin A caused a small increase in current. Ang II (100 nM) inhibited KATP current activated by the K+ channel opener pinacidil. The degree of inhibition was greater with 1.0 mM than with 0.1 mM intracellular ATP. The effect of Ang II was abolished by the AT1 receptor antagonist losartan. The inhibition of KATP currents by Ang II was abolished by a combination of PKA inhibitor peptide 5-24 (5 microM) and PKC inhibitor peptide 19-27 (100 microM), while either alone caused only partial block of the effect. In the presence of PKA inhibitor peptide, the inhibitory effect of Ang II was unaffected by the PKC inhibitor Go 6976, which is selective for Ca2+-dependent isoforms of PKC, but was abolished by a selective peptide inhibitor of the translocation of the epsilon isoform of PKC. Our results indicate that KATP channels are activated by steady-state phosphorylation by PKA at normal intracellular ATP levels, and that Ang II inhibits the channels both through activation of PKCepsilon and inhibition of PKA.

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AT1 receptor blockade improves vasorelaxation in experimental renal failure.

Olli Vuolteenaho, Heikki Ruskoaho, Jarkko Kalliovalkama … (2003)

It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8-week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6-fold after nephrectomy, and ventricular synthesis of atrial and B-type natriuretic peptides was increased 2.2-fold and 1.7-fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium-mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium-activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham-operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate-sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodeling: Wall-to-lumen ratio was increased without change in wall cross-sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin-angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.

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Author and article information

Journal

Journal ID (publisher-id): NEP

Journal ID (nlm-ta): Nephron Physiol

Journal ID (doi): 10.1159/issn.1660-2137

Title: Nephron Physiology

Publisher: S. Karger AG

ISSN (Electronic): 1660-2137

Publication date Subscription-year: 2004

Publication date (Print): March 2004

Publication date (Electronic): 29 March 2004

Volume: 96

Issue: 3

Pages: p91-p98

Affiliations

Departments of ^aPharmacological Sciences, ^bInternal Medicine, and ^cImmunopharmacological Research Group, University of Tampere; Departments of ^dAnaesthesia and Intensive Care, and ^eClinical Physiology, Tampere University Hospital, Tampere; ^fDepartment of Medicine, Helsinki University Central Hospital, and ^gMinerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland

Article

Publisher ID: 76754 Other ID: Nephron Physiol 2004;96:p91–p98

DOI: 10.1159/000076754

PubMed ID: 15056982

SO-VID: 9e794f77-0c9f-4acc-a51a-4ceac8b57a5d

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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.

History

Date received : 07 May 2003

Date accepted : 14 November 2003

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Figures: 2, Tables: 3, References: 34, Pages: 1

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Effect of Angiotensin II Type 1 Receptor Blockade on Conduit Artery Tone in Subtotally Nephrectomized Rats

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Karger: Nephrology

Most cited references 7

Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.

Angiotensin II inhibits rat arterial KATP channels by inhibiting steady-state protein kinase A activity and activating protein kinase Ce.

AT1 receptor blockade improves vasorelaxation in experimental renal failure.

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