Angiotensin II Subtype AT1 Receptor Blockade Prevents Hypertension and Renal Insufficiency Induced by Chronic NO-synthase Inhibition in Rats

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2003 Mar 20

PMID 12644905

Citations 1

Authors

M Hropot

K H Langer

Gabriele Wiemer

H Grotsch

W Linz

Affiliations

Soon will be listed here.

Abstract

Aim of the present study was to investigate the influence of the angiotensin II (ANG II) subtype 1 (AT(1)) receptor blockers fonsartan and losartan on blood pressure, cardiac -dynamics and -metabolism as well as functional and morphological changes in the kidney of rats after long-term inhibition of the nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester (L-NAME). Oral chronic treatment with L-NAME in a dose of 25 mg/kg/d over 6 weeks caused a significant increase in systolic blood pressure (198+/-13 mmHg) when compared to untreated rats (144+/-4 mmHg). Animals receiving simultaneously L-NAME and fonsartan (10 mg/kg/d) or losartan (30 mg/kg/d) were protected against blood pressure increase. L-NAME treatment caused a significant decrease in glomerular filtration rate (GFR) from 4.52+/-0.81 to 1.34+/-0.26 ml/kg(-1)/min(-1) and renal plasma flow (RPF) from 10.52+/-1.29 ml/kg(-1)/min(-1) to 5.66+/-1.06 ml/kg(-1)/min(-1). Co-treatment with fonsartan and losartan prevented L-NAME-induced reduction in GFR and RPF. There was no difference in urine, sodium and potassium excretion in groups under investigation. Plasma renin activity (PRA) was further stimulated by fonsartan and losartan treatment. L-NAME produced a significant elevation in urinary protein excretion which was antagonised by both AT(1) blockers. Isolated hearts from animals treated with L-NAME showed a significant prolongation in the duration of ventricular fibrillation and a significant decrease in coronary flow as compared to control hearts. Treatment with fonsartan and losartan significantly decreased the duration of ventricular fibrillation as compared to L-NAME group. In addition, both AT(1) blockers given alone significantly reduced the duration of ventricular fibrillation as compared to hearts from untreated controls. During ischemia the cytosolic enzymes lactate dehydrogenase and creatine kinase as well as lactate in the coronary effluent were significantly increased in the L-NAME group. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased. Fonsartan and losartan treatment totally abolished these effects. Histological examination of kidneys revealed that simultaneous administration of fonsartan and losartan with L-NAME abolished L-NAME-induced arteriolar hyalinosis, segmental sclerosis of glomerular capillaries and focal tubular atrophies. In conclusion, long-term blockade of ANG II subtype AT(1) receptors by fonsartan and losartan prevented L-NAME-induced hypertension, renal insufficiency, as well as cardio-dynamic, cardio-metabolic, and morphological deteriorations.

Citing Articles

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References

Lindholm L, Ibsen H, Dahlof B, Devereux R, Beevers G, de Faire U . Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359(9311):1004-10. DOI: 10.1016/S0140-6736(02)08090-X. View

Baylis C, Mitruka B, Deng A . Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992; 90(1):278-81. PMC: 443093. DOI: 10.1172/JCI115849. View

Deprez P, Guillaume J, Becker R, CORBIER A, Didierlaurent S, Fortin M . Sulfonylureas and sulfonylcarbamates as new non-tetrazole angiotensin II receptor antagonists. Discovery of a highly potent orally active (imidazolylbiphenylyl)sulfonylurea (HR 720). J Med Chem. 1995; 38(13):2357-77. DOI: 10.1021/jm00013a013. View

Gohlke P, Linz W, Scholkens B, Wiemer G, Unger T . Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats. Hypertension. 1996; 28(3):397-402. DOI: 10.1161/01.hyp.28.3.397. View

Linz W, Scholkens B, Han Y . Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts. J Cardiovasc Pharmacol. 1986; 8 Suppl 10:S91-9. DOI: 10.1097/00005344-198600101-00017. View

Linz W, Heitsch H, Scholkens B, Wiemer G . Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats. Hypertension. 2000; 35(4):908-13. DOI: 10.1161/01.hyp.35.4.908. View

Brunner H, Nussberger J, Waeber B . Angiotensin II blockade compared with other pharmacological methods of inhibiting the renin-angiotensin system. J Hypertens Suppl. 1993; 11(3):S53-8. View

Linz W, Wiemer G, Gohlke P, Unger T, Scholkens B . Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995; 47(1):25-49. View

Walser M, Davidson D, ORLOFF J . The renal clearance of alkali-stable inulin. J Clin Invest. 1955; 34(10):1520-3. PMC: 438729. DOI: 10.1172/JCI103204. View

10.

Salazar F, Pinilla J, Lopez F, Romero J, Quesada T . Renal effects of prolonged synthesis inhibition of endothelium-derived nitric oxide. Hypertension. 1992; 20(1):113-7. DOI: 10.1161/01.hyp.20.1.113. View

11.

Zatz R, Nucci G . Effects of acute nitric oxide inhibition on rat glomerular microcirculation. Am J Physiol. 1991; 261(2 Pt 2):F360-3. DOI: 10.1152/ajprenal.1991.261.2.F360. View

12.

Ribeiro M, Antunes E, Nucci G, Lovisolo S, Zatz R . Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension. 1992; 20(3):298-303. DOI: 10.1161/01.hyp.20.3.298. View

13.

Schelling P, Fischer H, Ganten D . Angiotensin and cell growth: a link to cardiovascular hypertrophy?. J Hypertens. 1991; 9(1):3-15. View

14.

Yang Y, Macdonald G, Duggan K . A study of angiotensin II receptors after chronic inhibition of nitric oxide synthase in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol. 1996; 23(5):441-3. DOI: 10.1111/j.1440-1681.1996.tb02757.x. View

15.

Burnier M . Angiotensin II type 1 receptor blockers. Circulation. 2001; 103(6):904-12. DOI: 10.1161/01.cir.103.6.904. View

16.

Morton J, Beattie E, Speirs A, Gulliver F . Persistent hypertension following inhibition of nitric oxide formation in the young Wistar rat: role of renin and vascular hypertrophy. J Hypertens. 1993; 11(10):1083-8. DOI: 10.1097/00004872-199310000-00012. View

17.

Kung C, Moreau P, Takase H, Luscher T . L-NAME hypertension alters endothelial and smooth muscle function in rat aorta. Prevention by trandolapril and verapamil. Hypertension. 1995; 26(5):744-51. DOI: 10.1161/01.hyp.26.5.744. View

18.

Bartels H, Bohmer M, Heierli C . [Serum creatinine determination without protein precipitation]. Clin Chim Acta. 1972; 37:193-7. DOI: 10.1016/0009-8981(72)90432-9. View

19.

Pollock D, Polakowski J, Divish B, Opgenorth T . Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition. Hypertension. 1993; 21(5):660-6. DOI: 10.1161/01.hyp.21.5.660. View

20.

Bravo R, Somoza B, Ruiz-Gayo M, Gonzalez C, Ruilope L, Fernandez-Alfonso M . Differential effect of chronic antihypertensive treatment on vascular smooth muscle cell phenotype in spontaneously hypertensive rats. Hypertension. 2001; 37(5):E4-E10. DOI: 10.1161/01.hyp.37.5.e4. View