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. 2007 May 1;5(3):276–283. doi: 10.1111/j.1582-4934.2001.tb00161.x

Renal cortical remodelling by NO‐synthesis blockers in rats is prevented by angiotensin‐converting enzyme inhibitor and calcium channel blocker

C A Mandarim‐de‐Lacerda 1,✉, Leila M M Pereira 1
PMCID: PMC6741306  PMID: 12067486

Abstract

The cortical remodelling was studied when chronically nitric oxide synthesis (NOs) blockade (L‐NAME‐induced) hypertensive rats are simultaneously treated, or not, with angiotensin‐converting enzyme inhibitor or calcium channel blocker. Four groups of eight rats each were studied as follows: Control (C), L‐NAME (L), L‐NAME+Enalapril (L+E) and L‐NAME+Verapamil (L+V). The systolic blood pressure (SBP) was weekly recorded. The cortex of the left kidneys was analysed according to the vertical section design. The volume‐weighted mean glomerular volume (VWGV) was made through the “point‐sampled intercepts” method. Enalapril and verapamil were efficient in reducing the SBP in rats submitted to NOs blockade. Glomeruli had considerable alterations in L group rats (glomerular hypertrophy or sclerosis) and tubular atrophy. The VWGV was 100% greater in L group rats than in the C group rats, while it was 30% smaller in L+E and L+V groups than in L group. The tubular volume was 30–50% greater, while the tubular lenght was 20–30% smaller in L group than in the other groups. The renal cortical region showed glomerular sclerosis/hypertrophy and tubular remodelling in rats with NOs blockade that was efficiently prevented with the simultaneous treatment with enalapril or verapamil.

Keywords: hypertension, kidney, nitric oxide, renin‐angiotensin system, calcium channel blocker, ACE inhibitor, glomerulus, morphometry, stereology

References

  • 1. Moncada S., Palmer R.M.J., Higgs E.A., Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev., 43: 109–142, 1991. [PubMed] [Google Scholar]
  • 2. Just A., Nitric oxide and renal autoregulation, Kidney Blood Press. Res., 20: 201–204, 1997. [DOI] [PubMed] [Google Scholar]
  • 3. Baylis C., Mitruka B., Deng A., Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage, J. Clin. Invest., 90: 278–281, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Fujihara C.K., Michellazzo S.M., DeNucci G., Zatz R., Sodium excess aggravates hypertension and renal parenchymal injury in rats with chronic NO inhibition, Am. J. Physiol., 266 (Renal Fluid Electrolyte Physiol 35): F697–F705, 1994. [DOI] [PubMed] [Google Scholar]
  • 5. Majid D.S.A., Navar L.G., Nitric oxide in the mediation of pressure natriuresis, Clin. Exp. Pharmacol. Physiol., 24: 595–599, 1997. [DOI] [PubMed] [Google Scholar]
  • 6. Stoos B.A., Garvin J.L., Actions of nitric oxide on renal epithelial transport, Clin. Exp. Pharmacol. Physiol., 24: 591–594, 1997. [DOI] [PubMed] [Google Scholar]
  • 7. Liang M., Knox F.G., Production and functional roles of nitric oxide in the proximal tubule, Am. J. Physiol., 278 (Regulatory Integrative Comp Physiol): R1117–R1124, 2000. [DOI] [PubMed] [Google Scholar]
  • 8. Qiu C., Muchant D., Neierwaltes W.H., Racusen L., Baylis C., Evolution of chronic nitric oxide inhibition hypertension, Hypertension, 31: 21–26, 1998. [DOI] [PubMed] [Google Scholar]
  • 9. Ikenaga H., Ishii N., Didion S.P., Zhang K., Cornish K.G., Patel K.P., Mayhan W.G., Carmines P.K., Suppressed impact of nitric oxide on renal arteriolar function in rats with chronic heart failure, Am. J. Physiol., 276 (Renal Physiol. 45): F79–F87, 1999. [DOI] [PubMed] [Google Scholar]
  • 10. Yoshida Y., Fogo A., Ichikawa I., Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis, Kidney Int., 35: 654–660, 1989. [DOI] [PubMed] [Google Scholar]
  • 11. Schnackenberg C., Patel A.R., Kirchner K.A., Granger J.P., Nitric oxide, the kidney and hypertension, Clin. Exp. Pharmacol. Physiol., 24: 600–606, 1997. [DOI] [PubMed] [Google Scholar]
  • 12. Scherle W., Simple method for volumetry of organs in quantitative stereology, Mikroskopie, 26: 57–60, 1970. [PubMed] [Google Scholar]
  • 13. Weibel E.W., Stereological methods. Practical methods for biological morphometry, Academic Press, London , 1979. [Google Scholar]
  • 14. Gundersen H.J.G., Bendtsen T.F., Korbo L., Marcussen N., Møller A., Nielsen K., Nyengaard J.R., Pakkenberg B., Sørensen F.B., Vesterby A., West M.J., Some new, simple and efficient stereological methods and their use in pathological research and diagnosis, A.P.M.I.S., 96: 379–394, 1988. [DOI] [PubMed] [Google Scholar]
  • 15. Nyengaard J.R., Stereological methods and their application in kidney research, J. Am. Soc. Nephrol., 10: 1100–1123, 1999. [DOI] [PubMed] [Google Scholar]
  • 16. Gundersen H.J.G., Jensen E.B., Stereological estimation of the volume weighted mean volume of arbitrary particles observed on random sections, J. Microsc., 138: 127–142, 1985. [DOI] [PubMed] [Google Scholar]
  • 17. Sørensen F.B., Stereological estimation of the mean and variance of nuclear volume from vertical sections, J. Microsc., 162: 203–229, 1991. [DOI] [PubMed] [Google Scholar]
  • 18. Zar J.H., Biostatistical analysis, Prentice‐Hall, Upper Saddle River , 1999. [Google Scholar]
  • 19. Raij L., Nitric oxide in hypertension: relationship with renal injury and left ventricular hypertrophy, Hypertension, 31 [part 2]: 189–193, 1998. [DOI] [PubMed] [Google Scholar]
  • 20. Pereira L.M.M., Mandarim‐de‐Lacerda C.A., Glomerular profile numerical density per area and mean glomerular volume in rats submitted to nitric oxide synthase blockade, Histol. Histopathol., 16: 15–20, 2001. [DOI] [PubMed] [Google Scholar]
  • 21. Bauer J.H., Modern antihypertensive treatment and the progression of renal disease, J. Hypertens., 16(Suppl. 5):S17–S24, 1998. [PubMed] [Google Scholar]
  • 22. Yoshida Y., Kawamura T., Ikoma M., Fogo A., Ichikawa I., Effects of antihypertensive drugs on glomerular morphology, Kidney Int., 36: 626–635, 1989. [DOI] [PubMed] [Google Scholar]
  • 23. Tolins J.P., Raij L., Comparison of converting enzyme inhibitor and calcium channel blocker in hypertensive glomerular injury, Hypertension, 16: 452–461, 1990. [DOI] [PubMed] [Google Scholar]
  • 24. Nielsen B., Grønbæk H., Osterby R., Flyvbjerg A., Effect of the carcium channel blocker nitrendipine in normotensive and spontaneously hypertensive, diabetic rats on kidney morphology and urinary albumin excretion, J. Hypertens., 17: 973–981, 1999. [DOI] [PubMed] [Google Scholar]
  • 25. Pelayo J.C., Harris D.C.H., Shanley P.F., Miller G.J., Schrier R.W., Glomerular hemodynamic adaptations in remanant nephrons: effects of verapamil, Am. J. Physiol., 254 (Renal Fluid Electrolyte Physiol 23): F425–F431, 1998. [DOI] [PubMed] [Google Scholar]
  • 26. Mandarim‐de‐Lacerda C.A., Pereira L.M.M., Numerical density of cardiomyocytes in chronic nitric oxide synthesis inhibition, Pathobiol., 68: 36–42, 2000. [DOI] [PubMed] [Google Scholar]
  • 27. Gomes‐Pessanha M., Mandarim‐de‐Lacerda C.A., Influence of the chronic nitric oxide synthesis inhibition on cardiomyocytes number, Virchows Arch., 437: 667–674, 2000. [DOI] [PubMed] [Google Scholar]
  • 28. Savill J.S., Mooney A.F., Hughes H., Apoptosis in acute renal imflammation In: Neilson E.G., Couser W.G., eds., Immunologic renal disease, Lippincot‐Raven, Philadelphia , 1998, pp. 209–219. [Google Scholar]
  • 29. Shimizu A., Kitamura H., Masuda Y., Ishizaki M., Sugisaki Y., Yanamaka N., Apoptosis in the repair process of experimental proliferative glomerulonephritis, Kidney Int., 47: 114–121, 1995. [DOI] [PubMed] [Google Scholar]
  • 30. Shimizu A., Masuda Y., Kitamura H., Ishizaki M., Sugisaki Y., Yamanaka N., Recovery of damaged glomerular capillary network with endothelial cell apoptosis in experimental proliferative glomerulonephritis, Nephron, 79: 206–214, 1998. [DOI] [PubMed] [Google Scholar]
  • 31. Sugiyama H., Kashihara N., Makino H., Yamasaki Y., Ota A., Apoptosis in glomerular sclerosis, Kidney Int., 49: 103–111, 1996. [DOI] [PubMed] [Google Scholar]
  • 32. Thomas G.L., Yang B., Wagner B.E., Savill J., EI Nahas A.M., Cellular apoptosis and proliferation in experimental renal fibrosis, Nephrol. Dial. Transplant., 13: 2216–2226, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. Davis M.A., Ryan D.H., Apoptosis in the kidney, Toxicol. Pathol., 26: 810–825, 1998. [DOI] [PubMed] [Google Scholar]
  • 34. Saikumar P., Dong Z., Patel K., Hall K., Hopfer U., Weinberg J.M., Venkatachalam M.A., Role of hypoxia‐induced Bax translocation and cytochrome c release in reoxygenation injury, Oncogene, 17: 3401–3415, 1998. [DOI] [PubMed] [Google Scholar]
  • 35. Sandau K., Pfeilschifter J., Brune B., Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis, Kidney Int., 52: 378–386, 1997. [DOI] [PubMed] [Google Scholar]
  • 36. Aiello S., Remuzzi G., Noris M., Nitric oxide/endothelin balance after nephron reduction, Kidney Int., 53 (Suppl. 65):S63–S67, 1998. [PubMed] [Google Scholar]
  • 37. Amore A., Coppo R., Role of apoptosis in pathogenesis and progression of renal diseases, Nephron, 86: 99–104, 2000. [DOI] [PubMed] [Google Scholar]
  • 38. Ribeiro M.O., Antunes E., DeNucci G., Lovisolo S.M., Zatz R., Chronic inhibition of nitric oxide sythesis. A new model of arterial hypertension, Hypertension, 20: 298–303, 1992. [DOI] [PubMed] [Google Scholar]
  • 39. Bunkenburg B., Van Amelsvoort T., Rogg H., Wood J.M., Receptor mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats, Hypertension, 20: 746–754, 1992. [DOI] [PubMed] [Google Scholar]
  • 40. Kunert R.J., Stepien H., Komorowski J., Pawlikowski M., Stimulatory affect of angiotensin II on the proliferation of mouse spleen lymphocytes in vitro is mediated via both types of angiotensin II receptors, Biochem. Biophys. Res. Commun., 198: 1034–1039, 1994. [DOI] [PubMed] [Google Scholar]
  • 41. Tanaka M., Ohnishi J., Ozawa Y., Sugimoto M., Usuki S., Naruse M., Murakami K., Miyazaki H., Characterization of angiotensin II receptor type 2 during differentiation and apoptosis of rat ovarian cultured granulosa cells, Biochem. Biophys. Res. Commun., 207: 593–598, 1995. [DOI] [PubMed] [Google Scholar]
  • 42. Kajstura J., Cigola E., Malhotra A., Li P., Cheng W., Meggs L.G., Anversa P., Angiotensin II induces apoptosis of adult ventricular myocytes in vitro, J. Mol. Cell. Cardiol., 29: 859–870, 1997. [DOI] [PubMed] [Google Scholar]
  • 43. Cao Z., Kelly D.J., Cox A., Casley D., Forbes J.M., Martinello P., Dean R., Gilbert R.E., Cooper M.E., Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis, Kidney Int., 58: 2437–2451, 2000. [DOI] [PubMed] [Google Scholar]
  • 44. Matsubara B.B., Matsubara L.S., Franco M., Padovani J.C., Janicki J.S., The effect of nonantihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension, Int. J. Exp. Path., 80: 97–104, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Mandarim‐de‐Lacerda C.A., Pereira L.M.M., Volume‐weighted mean nuclear volume and numerical density in the cardiomyocyte following enalapril and verapamil treatment, Virchows Arch., 438: 92–95, 2001. [DOI] [PubMed] [Google Scholar]

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