Restricted accessOtherFirst published online 2001-12
Renin-angiotensin blockade improves renal cGMP production via non-AT2-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat
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.
Ribeiro MO, Antunes E., de Nucci G., Lovisolo SA, Zatz R.Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension .Hypertension1992;20:298-303.
2.
Baylis C., Mitruka B., Deng A.Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest1992;90:278-81.
3.
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 Invest1990;85:541-9.
4.
Lafayette RA , Mayer G., Park SK, Meyer TWAngiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass .JClin Invest1992:90;766-71.
5.
Gilbert RE, Wu LL, Kelly DJ, Cox A., Wilkinson-Berka JL, Johnston CI, Cooper MEPathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy. Implications for the pathogenesis of tubulointerstitial fibrosis. Am J Pathol1999;155:429-40.
6.
Palmer RMJ , Moncada S.A novel citulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells . Biochem Biophys Res Commun1989;158:348-52.
7.
Kone BCLocalization and regulation of nitric oxide synthase isoforms in the kidney . Semin Nephrol1999;19:230-41. 8. Gabbai FB, Blanz RCRole of nitric oxide in renal hemodynamics. Semin Nephrol1999;19:242-50.
8.
Schnackenberg CG, Wilkins FC, Granger JPRole of nitric oxide in modulating the vasoconstrictor actions of angiotensin II in preglomerular and postglomerular vessels in dogs . Hypertension1995;26[part 2]:1024-9.
9.
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 Nephrol1996;7:653-60.
10.
Remuzzi G., Bertani T.Pathophysiology of progressive nephropathies. N Engl J Med1998;339:1448-56.
11.
Rajagopalan S., Kurz S., Münzel T., Tarpey M., Freeman BA, Griendling KK, Harrison DGAngiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. J Clin Invest1996;97:1916-23.
12.
Kagami S., Border WA, Miller DE, Noble NAAngiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells . J Clin Invest1994;93:2431-7.
13.
Rajagopalan S., Laursen JB, Borthayre A. et al. Role of endothelin-1 in angiotensin II-mediated hypertension. Hypertension1997 ; 30:29-34.
14.
Timmermans Pbmwm, Chiu AT, Herblin WF, Wong PCAngiotensin II receptor subtypes . Am J Hypertens1992; 5:406-10.
15.
Timmermans Pbmwm, Wong PC, Chiu AT et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev1993 ;45:205-51.
16.
Miyata N., Park F., Li XF, Cowley AW Jr.Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney . Am J Physiol1999;277:F437-F446.
17.
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 Res1993;73:413-23.
18.
Allen AM, Zhuo J., Mendelsohn FALocalization and function of angiotensin AT1 receptors. Am J Hypertens2000;13:31S-8S.
19.
Carey RM, Wang Z-Q., Siragy HMRole of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.Hypertension2000 ;35[part 2]:155-63.
20.
Sigary HM, Carey RMThe subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest1997 ;100:264-9.
21.
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 USA1995;92:10663-7.
22.
Praga M., Hernández C., Montoyo C.,Andérs A., Ruilope LM, Rodicio JLLong-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis1992;20:240-8.
23.
Maki DD, Ma JZ, Louis TA, Kasiske BLLong-term effects of antihypertensive agents on proteinuria and renal function . Arch Intern Med1995;155:1073-80.
24.
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 Res1998;21:329-34.
25.
Farhy RD, Carretero OA, Ho K-L., Scicli AGRole of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res1993; 72:1202-10.
26.
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 Pharmacol1992;42:1077-82.
27.
Buñag RDValidation in awake rats of a tail-cuff method for measuring systolic pressure . J Appl Physiol1973;34:279-82. 29. Fyhrquist F., Soveri P., Puutula L., Stenman U-H.Radioimmunoassay of plasma renin activityClin Chem1976;22:250-6.
28.
Tikkanen I. , Fyhrquist F., Puutula-Räsänen L.Enzyme inhibitors for renin assay in rat plasma. Clin Sci1980;59:381-3.
29.
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 Arch1996;432:953-60.
30.
Zhuo J., Ohishi M., Mendelsohn FAO . Roles of AT1- and AT2receptors in the hypertensive Ren-2 gene transgenic rat kidney. Hypertension1999;33[part II]:347-53.
31.
Mendelsohn FAO , Dunbar M.,Allen A.,Chou ST, Millan MA, Aguilera G., Catt KJAngiotensin II receptors in the kidney. Fed Proc1986;45:1420-5.
32.
Mendelsohn FAO , Millan M., Quirion R., Aguilera G., Chou S.-T, Catt KJLocalization of angiotensin II receptors in rat and monkey kidney by in vitro autoradiography . Kidney Int1987;31:S40-S44.
33.
Fyhrquist F. , Tikkanen I., Grönhagen-Riska C., Hortling L., Hichens M.Inhibitor binding assay for angiotensin-converting enzyme. Clin Chem1984;30:696-700.
34.
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 Hypertens1991;9:579-87.
35.
Turkstra E. , Braam B., Koomans HALosartan attenuates modest but not strong renal vasoconstriction induced by nitric oxide inhibition . J Cardiovasc Pharmacol1998;32:593-600.
36.
Uhlenius N. , Tikkanen T., Miettinen A. et al. Renoprotective effects of captopril in hypertension induced by nitric oxide synthase inhibition in experimental nephritis. Nephron1999;81:221-9.
37.
Uhlenius N. , Miettinen A., Vuolteenaho O., Tikkanen I.Renoprotective mechanisms of angiotensin II antagonism in experimental chronic renal failure . Kidney Blood Press Res2002 (in press).
38.
Ignarro LJNitric oxide: a novel signal transduction mechanism for transcellular communication . Hypertension1990; 16:477-83.
39.
Li JY, Berthelon MC, Langlois D., Saez JMTranscriptional and translational regulation of angiotensin II type 2 receptor by angiotensin II and growth factors. Endocrinology1999; 140:4988-94.
40.
Gansevoort RT, de Zeeuw D., de Jong PEIs the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system?Kidney Int1994;45:861-7.
41.
Timmermans Pbmwm, Benfield P., Chiu AT, Herblin WF, Wong PC, Smith RDAngiotensin II receptors and functional correlates .AmJHypertens1992;5:221S-35S.
42.
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. Hypertension1996;28:397-402.
43.
Gohlke P., Pees C., Unger T.AT2-receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism.Hypertension1998 ;31[part 2]:349-55.
44.
Wong KR, Xie M.-H, Shi L.-B, Liu F.-Y, Huang C.-L, Gardner DG, Cogan MGUrinary cGMP as biological marker of the renal activity of atrial natriuretic factor. Am J Physiol1988; 255:F1220-F1224.
45.
Uhlenius N. ,Tikkanen I.,Tikkanen T.,Miettinen A.,TörnrothT,Fyhrquist F.Chronic inhibition of nitric oxide synthase in Heymann nephritis.Nephron1996;74:144-9.
46.
Zafari AM, Ushio-Fukai M., Akers M. et al. Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension1998;32:488-95.
47.
Verhagen AMG , Braam B., Boer P., Gröne H.-J, Koomans HA, Joles JALosartan-sensitive renal damage caused chronic NOS inhibition does not involve increased renal angiotensin II concentrations . Kidney Int1999;56:222-31.
48.
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 Hypertens1996;9:1077-83.
49.
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 Res1998;83:743-51.
