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Journal of Renin-Angiotensin-Aldosterone System
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Renin-angiotensin blockade improves renal cGMP production via non-AT2-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat

Nina Uhlenius

Minerva Foundation Institute for Medical Research, nina.uhlenius@ hel.f

Olli Vuolteenaho

Department of Physiology, University of Oulu

Ilkka Tikkanen

Minerva Foundation Institute for Medical Research, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

Background

To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS) blockade.

Methods

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT 1-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP), urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.

Results

Captopril and L-158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT1 -receptor binding in the kidney was inhibited to about 40% of the control value after administration of L-158,809. The AT2-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.

Conclusion

Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT1-receptor antagonism on cGMP production was not mediated by AT2-receptor-dependent mechanisms, since renal AT2-receptor binding density was suppressed following treatment with L-158,809. AT1-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.

Key Words: angiotensin II • nitric oxide • cyclic GMP • hypertension • kidney

References

  • Ribeiro MO, Antunes E., de Nucci G., Lovisolo SA, Zatz R. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.Hypertension 1992;20:298-303.[Abstract/Free Full Text]
  • 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;90:278-81.[Web of Science][Medline] [Order article via Infotrieve]
  • Remuzzi A., Puntorieri S., Baltaglia C., Bertani T., Remuzzi G. Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 1990;85:541-9.[Web of Science][Medline] [Order article via Infotrieve]
  • Lafayette RA, Mayer G., Park SK, Meyer TW Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass.JClin Invest 1992:90;766-71.[Web of Science][Medline] [Order article via Infotrieve]
  • Gilbert RE, Wu LL, Kelly DJ, Cox A., Wilkinson-Berka JL, Johnston CI, Cooper ME Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy. Implications for the pathogenesis of tubulointerstitial fibrosis. Am J Pathol 1999;155:429-40.[Abstract/Free Full Text]
  • Palmer RMJ, Moncada S. A novel citulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun 1989;158:348-52.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kone BC Localization and regulation of nitric oxide synthase isoforms in the kidney. Semin Nephrol 1999;19:230-41. 8. Gabbai FB, Blanz RC Role of nitric oxide in renal hemodynamics. Semin Nephrol 1999;19:242-50.[Web of Science][Medline] [Order article via Infotrieve]
  • Schnackenberg CG, Wilkins FC, Granger JP Role of nitric oxide in modulating the vasoconstrictor actions of angiotensin II in preglomerular and postglomerular vessels in dogs. Hypertension 1995;26[part 2]:1024-9.[Abstract/Free Full Text]
  • Lapinsky R., Perico N., Remuzzi A., Sangalli F., Benigni A., Remuzzi G. Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney. J Am Soc Nephrol 1996;7:653-60.[Abstract]
  • Remuzzi G., Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998;339:1448-56.[Free Full Text]
  • Rajagopalan S., Kurz S., Münzel T., Tarpey M., Freeman BA, Griendling KK, Harrison DG Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. J Clin Invest 1996;97:1916-23.[Web of Science][Medline] [Order article via Infotrieve]
  • Kagami S., Border WA, Miller DE, Noble NA Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells. J Clin Invest 1994;93:2431-7.[Web of Science][Medline] [Order article via Infotrieve]
  • Rajagopalan S., Laursen JB, Borthayre A. et al. Role of endothelin-1 in angiotensin II-mediated hypertension. Hypertension 1997; 30:29-34.[Abstract/Free Full Text]
  • Timmermans Pbmwm, Chiu AT, Herblin WF, Wong PC Angiotensin II receptor subtypes. Am J Hypertens 1992; 5:406-10.[Web of Science][Medline] [Order article via Infotrieve]
  • Timmermans Pbmwm, Wong PC, Chiu AT et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205-51.[Web of Science][Medline] [Order article via Infotrieve]
  • Miyata N., Park F., Li XF, Cowley AW Jr. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am J Physiol 1999;277:F437-F446.[Web of Science][Medline] [Order article via Infotrieve]
  • Sadoshima J-I., Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: Critical role of the AT1-receptor subtype. Circ Res 1993;73:413-23.[Abstract/Free Full Text]
  • Allen AM, Zhuo J., Mendelsohn FA Localization and function of angiotensin AT1 receptors. Am J Hypertens 2000;13:31S-8S.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Carey RM, Wang Z-Q., Siragy HM Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.Hypertension 2000;35[part 2]:155-63.[Abstract/Free Full Text]
  • Sigary HM, Carey RM The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest 1997;100:264-9.[Web of Science][Medline] [Order article via Infotrieve]
  • Nakajima M., Hutchinson HG, Fujinaga M. et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA 1995;92:10663-7.[Abstract/Free Full Text]
  • Praga M., Hernández C., Montoyo C.,Andérs A., Ruilope LM, Rodicio JL Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992;20:240-8.[Web of Science][Medline] [Order article via Infotrieve]
  • Maki DD, Ma JZ, Louis TA, Kasiske BL Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 1995;155:1073-80.[Abstract/Free Full Text]
  • MacLaughlin M., Monserrat AJ, Muller A., Matoso M., Amorena C. Role of kinins in the renoprotective effect of angiotensin-converting enzyme inhibitors in experimental chronic renal failure. Kidney Blood Press Res 1998;21:329-34.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Farhy RD, Carretero OA, Ho K-L., Scicli AG Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res 1993; 72:1202-10.[Abstract/Free Full Text]
  • Chen TB, Lotti VJ, Chang RSL. Characterization of the binding of [3H]L-158,809:A new potent and selective nonpeptide angiotensin II receptor (AT1) antagonist radioligand. Mol Pharmacol 1992;42:1077-82.[Abstract]
  • Buñag RD Validation in awake rats of a tail-cuff method for measuring systolic pressure. J Appl Physiol 1973;34:279-82. 29. Fyhrquist F., Soveri P., Puutula L., Stenman U-H. Radioimmunoassay of plasma renin activity Clin Chem 1976;22:250-6.[Abstract/Free Full Text]
  • Tikkanen I., Fyhrquist F., Puutula-Räsänen L. Enzyme inhibitors for renin assay in rat plasma. Clin Sci 1980;59:381-3.[Web of Science][Medline] [Order article via Infotrieve]
  • Laine M., Id L., Vuolteenaho O., Ruskoaho H., Weckström M. Role of calcium in stretch-induced release and mRNA synthesis of natriuretic peptides in isolated rat atrium. Pflugers Arch 1996;432:953-60.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Zhuo J., Ohishi M., Mendelsohn FAO. Roles of AT1- and AT2receptors in the hypertensive Ren-2 gene transgenic rat kidney. Hypertension 1999;33[part II]:347-53.[Abstract/Free Full Text]
  • Mendelsohn FAO, Dunbar M.,Allen A., Chou ST, Millan MA, Aguilera G., Catt KJAngiotensin II receptors in the kidney. Fed Proc 1986;45:1420-5.[Web of Science][Medline] [Order article via Infotrieve]
  • Mendelsohn FAO, Millan M., Quirion R., Aguilera G., Chou S.-T, Catt KJ Localization of angiotensin II receptors in rat and monkey kidney by in vitro autoradiography. Kidney Int 1987;31:S40-S44.[Web of Science]
  • Fyhrquist F., Tikkanen I., Grönhagen-Riska C., Hortling L., Hichens M. Inhibitor binding assay for angiotensin-converting enzyme. Clin Chem 1984;30:696-700.[Abstract/Free Full Text]
  • Kohzuki M., Johnston CI, Chai SY, Jackson B., Perich R., Paxton D., Mendelsohn FAO. Measurement of angiotensin converting enzyme induction and inhibition using quantitative in vitro autoradiography: tissue selective induction after chronic lisinopril treatment. J Hypertens 1991;9:579-87.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Turkstra E., Braam B., Koomans HA Losartan attenuates modest but not strong renal vasoconstriction induced by nitric oxide inhibition. J Cardiovasc Pharmacol 1998;32:593-600.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Uhlenius N., Tikkanen T., Miettinen A. et al. Renoprotective effects of captopril in hypertension induced by nitric oxide synthase inhibition in experimental nephritis. Nephron 1999;81:221-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Uhlenius N., Miettinen A., Vuolteenaho O., Tikkanen I. Renoprotective mechanisms of angiotensin II antagonism in experimental chronic renal failure. Kidney Blood Press Res 2002 (in press).
  • Ignarro LJ Nitric oxide: a novel signal transduction mechanism for transcellular communication. Hypertension 1990; 16:477-83.[Abstract/Free Full Text]
  • Li JY, Berthelon MC, Langlois D., Saez JM Transcriptional and translational regulation of angiotensin II type 2 receptor by angiotensin II and growth factors. Endocrinology 1999; 140:4988-94.[Abstract/Free Full Text]
  • Gansevoort RT, de Zeeuw D., de Jong PE Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int 1994;45:861-7.[Web of Science][Medline] [Order article via Infotrieve]
  • Timmermans Pbmwm, Benfield P., Chiu AT, Herblin WF, Wong PC, Smith RD Angiotensin II receptors and functional correlates.AmJHypertens 1992;5:221S-35S.[Medline] [Order article via Infotrieve]
  • Gohlke P., Linz W., Schölkens BA,Wiemer G., Unger T. Cardiac and vascular effects of the long-term losartan treatment in stroke-prone spontaneously hypertensive rats. Hypertension 1996;28:397-402.[Abstract/Free Full Text]
  • Gohlke P., Pees C., Unger T. AT2-receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism.Hypertension 1998;31[part 2]:349-55.[Abstract/Free Full Text]
  • Wong KR, Xie M.-H, Shi L.-B, Liu F.-Y, Huang C.-L, Gardner DG, Cogan MG Urinary cGMP as biological marker of the renal activity of atrial natriuretic factor. Am J Physiol 1988; 255:F1220-F1224.[Web of Science][Medline] [Order article via Infotrieve]
  • Uhlenius N.,Tikkanen I.,Tikkanen T.,Miettinen A.,TörnrothT, Fyhrquist F. Chronic inhibition of nitric oxide synthase in Heymann nephritis.Nephron 1996;74:144-9.[Web of Science][Medline] [Order article via Infotrieve]
  • Zafari AM, Ushio-Fukai M., Akers M. et al. Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 1998;32:488-95.[Abstract/Free Full Text]
  • Verhagen AMG, Braam B., Boer P., Gröne H.-J, Koomans HA, Joles JA Losartan-sensitive renal damage caused chronic NOS inhibition does not involve increased renal angiotensin II concentrations. Kidney Int 1999;56:222-31.[Web of Science][Medline] [Order article via Infotrieve]
  • Navarro-Cid J., Maeso R., Rodrigo E., Muñoz-García R., Ruilope LM, Lahtera V., Cachofeiro V. Renal and vascular consequences of the chronic nitric oxide synthase inhibition: Effects of antihypertensive drugs. J Am Hypertens 1996;9:1077-83.[CrossRef]
  • Katoh M., Egashira K., Usui M. et al. Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats. Circ Res 1998;83:743-51.[Abstract/Free Full Text]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 4, 233-239 (2001)
DOI: 10.3317/jraas.2001.037
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