Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Aug;96(2):793–800. doi: 10.1172/JCI118125

Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys.

K A Griffin 1, M M Picken 1, A K Bidani 1
PMCID: PMC185265  PMID: 7635974

Abstract

Hypertensive mechanisms are postulated to play a major role in the progressive glomerulosclerosis (GS) after renal mass reduction. But, in contrast to converting enzyme inhibitors, BP reduction by calcium channel blockers, has not provided consistent protection. Radiotelemetric BP monitoring for 7 wk was used to compare nifedipine (N) and enalapril (E) in the rat approximately 5/6 renal ablation model. After the first week, rats received N, E, or no treatment (C). The overall averaged systolic BP in C (173 +/- 7 mmHg) was reduced by both E and N (P < 0.001), but E was more effective (113 +/- 2 vs. 134 +/- 3 mmHg, P < 0.01). GS was prevented by E (2 +/- 1 vs. 26 +/- 5% in C) but not by N (25 +/- 6%). GS correlated well with the overall averaged BP in individual animals of all groups, but the slope of the relationship was significantly steeper in N compared with C+E rats (P < 0.02), suggesting greater pressure transmission to the glomeruli and GS for any given BP. Since autoregulatory mechanisms provide the primary protection against pressure transmission, renal autoregulation was examined at 3 wk in additional rats. Autoregulation was impaired in C rats, was not additionally altered by E, but was completely abolished by N. These data demonstrate the importance of autoregulatory mechanisms in the pathogenesis of hypertensive injury and suggest that calcium channel blockers which adversely affect pressure transmission may not provide protection despite significant BP reduction.

Full text

PDF
793

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akselrod S., Gordon D., Ubel F. A., Shannon D. C., Berger A. C., Cohen R. J. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981 Jul 10;213(4504):220–222. doi: 10.1126/science.6166045. [DOI] [PubMed] [Google Scholar]
  2. Anderson S. Renal hemodynamic effects of calcium antagonists in rats with reduced renal mass. Hypertension. 1991 Mar;17(3):288–295. doi: 10.1161/01.hyp.17.3.288. [DOI] [PubMed] [Google Scholar]
  3. Anderson S., Rennke H. G., Brenner B. M. Nifedipine versus fosinopril in uninephrectomized diabetic rats. Kidney Int. 1992 Apr;41(4):891–897. doi: 10.1038/ki.1992.136. [DOI] [PubMed] [Google Scholar]
  4. Anderson S., Rennke H. G., Brenner B. M. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest. 1986 Jun;77(6):1993–2000. doi: 10.1172/JCI112528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bakris G. L. Renal effects of calcium antagonists in diabetes mellitus. An overview of studies in animal models and in humans. Am J Hypertens. 1991 Jul;4(7 Pt 2):487S–493S. doi: 10.1093/ajh/4.7.487s. [DOI] [PubMed] [Google Scholar]
  6. Baldwin D. S., Neugarten J. Hypertension and renal diseases. Am J Kidney Dis. 1987 Sep;10(3):186–191. doi: 10.1016/s0272-6386(87)80173-7. [DOI] [PubMed] [Google Scholar]
  7. Bidani A. K., Griffin K. A., Picken M., Lansky D. M. Continuous telemetric blood pressure monitoring and glomerular injury in the rat remnant kidney model. Am J Physiol. 1993 Sep;265(3 Pt 2):F391–F398. doi: 10.1152/ajprenal.1993.265.3.F391. [DOI] [PubMed] [Google Scholar]
  8. Bidani A. K., Griffin K. A., Plott W., Schwartz M. M. Renal ablation acutely transforms 'benign' hypertension to 'malignant' nephrosclerosis in hypertensive rats. Hypertension. 1994 Sep;24(3):309–316. doi: 10.1161/01.hyp.24.3.309. [DOI] [PubMed] [Google Scholar]
  9. Bidani A. K., Mitchell K. D., Schwartz M. M., Navar L. G., Lewis E. J. Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model. Kidney Int. 1990 Jul;38(1):28–38. doi: 10.1038/ki.1990.163. [DOI] [PubMed] [Google Scholar]
  10. Bidani A. K., Schwartz M. M., Lewis E. J. Renal autoregulation and vulnerability to hypertensive injury in remnant kidney. Am J Physiol. 1987 Jun;252(6 Pt 2):F1003–F1010. doi: 10.1152/ajprenal.1987.252.6.F1003. [DOI] [PubMed] [Google Scholar]
  11. Brenner B. M. Nephron adaptation to renal injury or ablation. Am J Physiol. 1985 Sep;249(3 Pt 2):F324–F337. doi: 10.1152/ajprenal.1985.249.3.F324. [DOI] [PubMed] [Google Scholar]
  12. Brunner F. P., Thiel G., Hermle M., Bock H. A., Mihatsch M. J. Long-term enalapril and verapamil in rats with reduced renal mass. Kidney Int. 1989 Dec;36(6):969–977. doi: 10.1038/ki.1989.289. [DOI] [PubMed] [Google Scholar]
  13. Carmines P. K., Navar L. G. Disparate effects of Ca channel blockade on afferent and efferent arteriolar responses to ANG II. Am J Physiol. 1989 Jun;256(6 Pt 2):F1015–F1020. doi: 10.1152/ajprenal.1989.256.6.F1015. [DOI] [PubMed] [Google Scholar]
  14. Cohen A. J., Fray J. C. Calcium ion dependence of myogenic renal plasma flow autoregulation: evidence from the isolated perfused rat kidney. J Physiol. 1982 Sep;330:449–460. doi: 10.1113/jphysiol.1982.sp014351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Daniels B. S., Hostetter T. H. Adverse effects of growth in the glomerular microcirculation. Am J Physiol. 1990 May;258(5 Pt 2):F1409–F1416. doi: 10.1152/ajprenal.1990.258.5.F1409. [DOI] [PubMed] [Google Scholar]
  16. Daniels F. H., Arendshorst W. J., Roberds R. G. Tubuloglomerular feedback and autoregulation in spontaneously hypertensive rats. Am J Physiol. 1990 Jun;258(6 Pt 2):F1479–F1489. doi: 10.1152/ajprenal.1990.258.6.F1479. [DOI] [PubMed] [Google Scholar]
  17. Dworkin L. D., Benstein J. A., Parker M., Tolbert E., Feiner H. D. Calcium antagonists and converting enzyme inhibitors reduce renal injury by different mechanisms. Kidney Int. 1993 Apr;43(4):808–814. doi: 10.1038/ki.1993.114. [DOI] [PubMed] [Google Scholar]
  18. Epstein M. Calcium antagonists and the kidney: future therapeutic perspectives. Am J Kidney Dis. 1993 Jun;21(6 Suppl 3):16–25. doi: 10.1016/0272-6386(93)70120-n. [DOI] [PubMed] [Google Scholar]
  19. Griffin K. A., Bidani A. K., Ouyang J., Ellis V., Churchill M., Churchill P. C. Role of endothelium-derived nitric oxide in hemodynamic adaptations after graded renal mass reduction. Am J Physiol. 1993 Jun;264(6 Pt 2):R1254–R1259. doi: 10.1152/ajpregu.1993.264.6.R1254. [DOI] [PubMed] [Google Scholar]
  20. Griffin K. A., Bidani A. K., Picken M., Ellis V. R., Churchill P. C. Prostaglandins do not mediate impaired autoregulation or increased renin secretion in remnant rat kidneys. Am J Physiol. 1992 Dec;263(6 Pt 2):F1057–F1062. doi: 10.1152/ajprenal.1992.263.6.F1057. [DOI] [PubMed] [Google Scholar]
  21. Griffin K. A., Picken M., Bidani A. K. Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury. J Am Soc Nephrol. 1994 Jun;4(12):2023–2031. doi: 10.1681/ASN.V4122023. [DOI] [PubMed] [Google Scholar]
  22. Griffin K. A., Picken M., Bidani A. K. Radiotelemetric BP monitoring, antihypertensives and glomeruloprotection in remnant kidney model. Kidney Int. 1994 Oct;46(4):1010–1018. doi: 10.1038/ki.1994.361. [DOI] [PubMed] [Google Scholar]
  23. Haller H. Calcium antagonists and cellular mechanisms of glomerulosclerosis and atherosclerosis. Am J Kidney Dis. 1993 Jun;21(6 Suppl 3):26–31. [PubMed] [Google Scholar]
  24. Harris D. C., Hammond W. S., Burke T. J., Schrier R. W. Verapamil protects against progression of experimental chronic renal failure. Kidney Int. 1987 Jan;31(1):41–46. doi: 10.1038/ki.1987.6. [DOI] [PubMed] [Google Scholar]
  25. Holstein-Rathlou N. H., Wagner A. J., Marsh D. J. Tubuloglomerular feedback dynamics and renal blood flow autoregulation in rats. Am J Physiol. 1991 Jan;260(1 Pt 2):F53–F68. doi: 10.1152/ajprenal.1991.260.1.F53. [DOI] [PubMed] [Google Scholar]
  26. Hostetter T. H., Olson J. L., Rennke H. G., Venkatachalam M. A., Brenner B. M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 1981 Jul;241(1):F85–F93. doi: 10.1152/ajprenal.1981.241.1.F85. [DOI] [PubMed] [Google Scholar]
  27. Jackson B., Johnston C. I. The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: effect of treatment with an angiotensin converting enzyme inhibitor or a calcium inhibitor. J Hypertens. 1988 Jun;6(6):495–501. doi: 10.1097/00004872-198806000-00010. [DOI] [PubMed] [Google Scholar]
  28. Kakinuma Y., Kawamura T., Bills T., Yoshioka T., Ichikawa I., Fogo A. Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Kidney Int. 1992 Jul;42(1):46–55. doi: 10.1038/ki.1992.259. [DOI] [PubMed] [Google Scholar]
  29. Klahr S., Schreiner G., Ichikawa I. The progression of renal disease. N Engl J Med. 1988 Jun 23;318(25):1657–1666. doi: 10.1056/NEJM198806233182505. [DOI] [PubMed] [Google Scholar]
  30. Loutzenhiser R., Epstein M. Effects of calcium antagonists on renal hemodynamics. Am J Physiol. 1985 Nov;249(5 Pt 2):F619–F629. doi: 10.1152/ajprenal.1985.249.5.F619. [DOI] [PubMed] [Google Scholar]
  31. Miller P. L., Rennke H. G., Meyer T. W. Glomerular hypertrophy accelerates hypertensive glomerular injury in rats. Am J Physiol. 1991 Sep;261(3 Pt 2):F459–F465. doi: 10.1152/ajprenal.1991.261.3.F459. [DOI] [PubMed] [Google Scholar]
  32. Navar L. G., Champion W. J., Thomas C. E. Effects of calcium channel blockade on renal vascular resistance responses to changes in perfusion pressure and angiotensin-converting enzyme inhibition in dogs. Circ Res. 1986 Jun;58(6):874–881. doi: 10.1161/01.res.58.6.874. [DOI] [PubMed] [Google Scholar]
  33. Olson J. L., Heptinstall R. H. Nonimmunologic mechanisms of glomerular injury. Lab Invest. 1988 Nov;59(5):564–578. [PubMed] [Google Scholar]
  34. Pagani M., Lombardi F., Guzzetti S., Rimoldi O., Furlan R., Pizzinelli P., Sandrone G., Malfatto G., Dell'Orto S., Piccaluga E. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res. 1986 Aug;59(2):178–193. doi: 10.1161/01.res.59.2.178. [DOI] [PubMed] [Google Scholar]
  35. Parati G., Omboni S., Di Rienzo M., Frattola A., Albini F., Mancia G. Twenty-four hour blood pressure variability: clinical implications. Kidney Int Suppl. 1992 Jun;37:S24–S28. [PubMed] [Google Scholar]
  36. Pelayo J. C., Harris D. C., Shanley P. F., Miller G. J., Schrier R. W. Glomerular hemodynamic adaptations in remnant nephrons: effects of verapamil. Am J Physiol. 1988 Mar;254(3 Pt 2):F425–F431. doi: 10.1152/ajprenal.1988.254.3.F425. [DOI] [PubMed] [Google Scholar]
  37. Pelayo J. C., Westcott J. Y. Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant nephron. J Clin Invest. 1991 Jul;88(1):101–105. doi: 10.1172/JCI115264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Purkerson M. L., Hoffsten P. E., Klahr S. Pathogenesis of the glomerulopathy associated with renal infarction in rats. Kidney Int. 1976 May;9(5):407–417. doi: 10.1038/ki.1976.50. [DOI] [PubMed] [Google Scholar]
  39. SEMPLE S. J., DE WARDENER H. E. Effect of increased renal venous pressure on circulatory autoregulation of isolated dog kidneys. Circ Res. 1959 Jul;7(4):643–648. doi: 10.1161/01.res.7.4.643. [DOI] [PubMed] [Google Scholar]
  40. Shimamura T., Morrison A. B. A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol. 1975 Apr;79(1):95–106. [PMC free article] [PubMed] [Google Scholar]
  41. Tolins J. P., Raij L. Angiotensin converting enzyme inhibitors and progression of chronic renal failure. Kidney Int Suppl. 1990 Nov;30:S118–S122. [PubMed] [Google Scholar]
  42. WOLF A. V. Demonstration concerning pressure-tension relations in various organs. Science. 1952 Feb 29;115(2983):243–244. doi: 10.1126/science.115.2983.243. [DOI] [PubMed] [Google Scholar]
  43. Wallenstein S., Zucker C. L., Fleiss J. L. Some statistical methods useful in circulation research. Circ Res. 1980 Jul;47(1):1–9. doi: 10.1161/01.res.47.1.1. [DOI] [PubMed] [Google Scholar]
  44. Yoshida Y., Fogo A., Ichikawa I. Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis. Kidney Int. 1989 Feb;35(2):654–660. doi: 10.1038/ki.1989.35. [DOI] [PubMed] [Google Scholar]
  45. Yoshida Y., Kawamura T., Ikoma M., Fogo A., Ichikawa I. Effects of antihypertensive drugs on glomerular morphology. Kidney Int. 1989 Oct;36(4):626–635. doi: 10.1038/ki.1989.239. [DOI] [PubMed] [Google Scholar]
  46. Yoshioka T., Shiraga H., Yoshida Y., Fogo A., Glick A. D., Deen W. M., Hoyer J. R., Ichikawa I. "Intact nephrons" as the primary origin of proteinuria in chronic renal disease. Study in the rat model of subtotal nephrectomy. J Clin Invest. 1988 Nov;82(5):1614–1623. doi: 10.1172/JCI113773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zatz R., Meyer T. W., Rennke H. G., Brenner B. M. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5963–5967. doi: 10.1073/pnas.82.17.5963. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES