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. 1989 Mar;83(3):960–969. doi: 10.1172/JCI113982

Functional effects on glomerular hemodynamics of short-term chronic cyclosporine in male rats.

S C Thomson 1, B J Tucker 1, F Gabbai 1, R C Blantz 1
PMCID: PMC303772  PMID: 2921329

Abstract

We evaluated the effects of chronic cyclosporine (CsA) administration on the determinants of nephron filtration rate (SNGFR) using micropuncture techniques (mp) in male Munich-Wistar rats. Animals received CsA (30 mg/kg SQ) in olive oil daily for 8 d before mp. Controls (PFC) were pair fed. SNGFR, glomerular capillary hydrostatic pressure gradient (delta P), nephron plasma flow (SNPF), plasma protein oncotic pressure (pi A), and glomerular ultrafiltration coefficient (LpA) were quantitated in each experiment. CsA was associated with a lower SNGFR due to decreases in SNPF and a major reduction in delta P but no decrease in LpA. Plasma volume expansion (PVE) caused SNGFR, delta P, and SNPF to increase in both CsA and PFC without eliminating the differences between CsA and PFC. CsA/PVE rats responded normally to angiotensin II (AII) infusion indicating that the low delta P associated with CsA is not due to unresponsiveness to AII. Prior renal denervation caused SNGFR and SNPF to increase in CsA-treated animals but failed to alter the reduction in glomerular capillary pressure after CsA or to eliminate the glomerular hemodynamic differences between treated animals and pair-fed controls. This constellation of glomerular hemodynamic abnormalities suggests that the renal effect of short-term chronic CsA administration is mediated primarily by a reduction in the afferent effective filtration pressure resulting from an imbalance between pre- and postglomerular vascular resistances.

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Selected References

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  1. Bantle J. P., Nath K. A., Sutherland D. E., Najarian J. S., Ferris T. F. Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med. 1985 Mar;145(3):505–508. [PubMed] [Google Scholar]
  2. Barros E. J., Boim M. A., Ajzen H., Ramos O. L., Schor N. Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity. Kidney Int. 1987 Jul;32(1):19–25. doi: 10.1038/ki.1987.166. [DOI] [PubMed] [Google Scholar]
  3. Bennett W. M., Pulliam J. P. Cyclosporine nephrotoxicity. Ann Intern Med. 1983 Dec;99(6):851–854. doi: 10.7326/0003-4819-99-6-851. [DOI] [PubMed] [Google Scholar]
  4. Blantz R. C., Konnen K. S., Tucker B. J. Angiotensin II effects upon the glomerular microcirculation and ultrafiltration coefficient of the rat. J Clin Invest. 1976 Feb;57(2):419–434. doi: 10.1172/JCI108293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blantz R. C., Pelayo J. C. In vivo actions of angiotensin II on glomerular function. Fed Proc. 1983 Nov;42(14):3071–3074. [PubMed] [Google Scholar]
  6. Caterson R. J., Duggin G. G., Critchley L., Baxter C., Horvath J. S., Hall B. M., Tiller D. J. Renal tubular transport of cyclosporine A (CSA) and associated changes in renal function. Clin Nephrol. 1986;25 (Suppl 1):S30–S33. [PubMed] [Google Scholar]
  7. Chapman J. R., Griffiths D., Harding N. G., Morris P. J. Reversibility of cyclosporin nephrotoxicity after three months' treatment. Lancet. 1985 Jan 19;1(8421):128–130. doi: 10.1016/s0140-6736(85)91902-6. [DOI] [PubMed] [Google Scholar]
  8. Duggin G. G., Baxter C., Hall B. M., Horvath J. S., Tiller D. J. Influence of cyclosporine A (CSA) on intrarenal control of GFR. Clin Nephrol. 1986;25 (Suppl 1):S43–S45. [PubMed] [Google Scholar]
  9. Durrett L. R., Ziegler M. G. A sensitive radioenzymatic assay for catechol drugs. J Neurosci Res. 1980;5(6):587–598. doi: 10.1002/jnr.490050613. [DOI] [PubMed] [Google Scholar]
  10. English J., Evan A., Houghton D. C., Bennett W. M. Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function. Transplantation. 1987 Jul;44(1):135–141. doi: 10.1097/00007890-198707000-00027. [DOI] [PubMed] [Google Scholar]
  11. Gabbai F. B., Gushwa L. C., Wilson C. B., Blantz R. C. An evaluation of the development of experimental membranous nephropathy. Kidney Int. 1987 Jun;31(6):1267–1278. doi: 10.1038/ki.1987.140. [DOI] [PubMed] [Google Scholar]
  12. Hermansson K., Larson M., Källskog O., Wolgast M. Influence of renal nerve activity on arteriolar resistance, ultrafiltration dynamics and fluid reabsorption. Pflugers Arch. 1981 Jan;389(2):85–90. doi: 10.1007/BF00582096. [DOI] [PubMed] [Google Scholar]
  13. Humes H. D., Jackson N. M., O'Connor R. P., Hunt D. A., White M. D. Pathogenetic mechanisms of nephrotoxicity: insights into cyclosporine nephrotoxicity. Transplant Proc. 1985 Aug;17(4 Suppl 1):51–62. [PubMed] [Google Scholar]
  14. Kahan B. D. Cyclosporine: the agent and its actions. Transplant Proc. 1985 Aug;17(4 Suppl 1):5–18. [PubMed] [Google Scholar]
  15. Kaskel F. J., Devarajan P., Arbeit L. A., Partin J. S., Moore L. C. Cyclosporine nephrotoxicity: sodium excretion, autoregulation, and angiotensin II. Am J Physiol. 1987 Apr;252(4 Pt 2):F733–F742. doi: 10.1152/ajprenal.1987.252.4.F733. [DOI] [PubMed] [Google Scholar]
  16. Kon V., Ichikawa I. Effector loci for renal nerve control of cortical microcirculation. Am J Physiol. 1983 Nov;245(5 Pt 1):F545–F553. doi: 10.1152/ajprenal.1983.245.5.F545. [DOI] [PubMed] [Google Scholar]
  17. Kopp U., Aurell M., Sjölander M., Ablad B. The role of prostaglandins in the alpha- and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation. Pflugers Arch. 1981 Jul;391(1):1–8. doi: 10.1007/BF00580685. [DOI] [PubMed] [Google Scholar]
  18. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  19. Mihatsch M. J., Ryffel B., Hermle M., Brunner F. P., Thiel G. Morphology of cyclosporine nephrotoxicity in the rat. Clin Nephrol. 1986;25 (Suppl 1):S2–S8. [PubMed] [Google Scholar]
  20. Moran M., Tomlanovich S., Myers B. D. Cyclosporine-induced chronic nephropathy in human recipients of cardiac allografts. Transplant Proc. 1985 Aug;17(4 Suppl 1):185–190. [PubMed] [Google Scholar]
  21. Moss N. G., Powell S. L., Falk R. J. Intravenous cyclosporine activates afferent and efferent renal nerves and causes sodium retention in innervated kidneys in rats. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8222–8226. doi: 10.1073/pnas.82.23.8222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Murray B. M., Paller M. S. Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol. 1986;25 (Suppl 1):S37–S39. [PubMed] [Google Scholar]
  23. Murray B. M., Paller M. S., Ferris T. F. Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int. 1985 Nov;28(5):767–774. doi: 10.1038/ki.1985.196. [DOI] [PubMed] [Google Scholar]
  24. Myers B. D., Ross J., Newton L., Luetscher J., Perlroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med. 1984 Sep 13;311(11):699–705. doi: 10.1056/NEJM198409133111103. [DOI] [PubMed] [Google Scholar]
  25. Paller M. S., Murray B. M. Renal dysfunction in animal models of cyclosporine toxicity. Transplant Proc. 1985 Aug;17(4 Suppl 1):155–159. [PubMed] [Google Scholar]
  26. Paller M. S., Murray B. M. Renal dysfunction in animal models of cyclosporine toxicity. Transplant Proc. 1985 Aug;17(4 Suppl 1):155–159. [PubMed] [Google Scholar]
  27. Pelayo J. C., Ziegler M. G., Blantz R. C. Angiotensin II in adrenergic-induced alterations in glomerular hemodynamics. Am J Physiol. 1984 Nov;247(5 Pt 2):F799–F807. doi: 10.1152/ajprenal.1984.247.5.F799. [DOI] [PubMed] [Google Scholar]
  28. Perico N., Benigni A., Bosco E., Rossini M., Orisio S., Ghilardi F., Piccinelli A., Remuzzi G. Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins? Clin Nephrol. 1986;25 (Suppl 1):S83–S88. [PubMed] [Google Scholar]
  29. Perico N., Zoja C., Benigni A., Ghilardi F., Gualandris L., Remuzzi G. Effect of short-term cyclosporine administration in rats on renin-angiotensin and thromboxane A2: possible relevance to the reduction in glomerular filtration rate. J Pharmacol Exp Ther. 1986 Oct;239(1):229–235. [PubMed] [Google Scholar]
  30. Schurek H. J., Neumann K. H., Jesinghaus W. P., Aeikens B., Wonigeit K. Influence of cyclosporine A on adaptive hypertrophy after unilateral nephrectomy in the rat. Clin Nephrol. 1986;25 (Suppl 1):S144–S147. [PubMed] [Google Scholar]
  31. Stahl R. A., Kudelka S. Chronic cyclosporine A treatment reduces prostaglandin E2 formation in isolated glomeruli and papilla of rat kidneys. Clin Nephrol. 1986;25 (Suppl 1):S78–S82. [PubMed] [Google Scholar]
  32. Sullivan B. A., Hak L. J., Finn W. F. Cyclosporine nephrotoxicity: studies in laboratory animals. Transplant Proc. 1985 Aug;17(4 Suppl 1):145–154. [PubMed] [Google Scholar]
  33. Tilney N. L., Milford E. L., Carpenter C. B., Lazarus J. M., Strom T. B., Kirkman R. L. Long-term results of cyclosporine treatment in renal transplantation. Transplant Proc. 1986 Apr;18(2 Suppl 1):179–185. [PubMed] [Google Scholar]
  34. Tucker B. J., Mundy C. A., Blantz R. C. Adrenergic and angiotensin II influences on renal vascular tone in chronic sodium depletion. Am J Physiol. 1987 May;252(5 Pt 2):F811–F817. doi: 10.1152/ajprenal.1987.252.5.F811. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Wassef R., Cohen Z., Langer B. Pharmacokinetic profiles of cyclosporine in rats. Influence of route of administration and dosage. Transplantation. 1985 Nov;40(5):489–493. doi: 10.1097/00007890-198511000-00004. [DOI] [PubMed] [Google Scholar]

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