Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats

B. Peter Sawaya, H. Weihprecht, W. R. Campbell, J. N. Lorenz, R. C. Webb, J. P. Briggs, J. Schnermann

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70 Scopus citations

Abstract

In anesthetized rats we tested the hypothesis that amphotericin B (AmB) reduces glomerular filtration rate (GFR) by activating the tubuloglomerular feedback (TGF) mechanism. Infusion of 1 mg/kg AmB over 50 min was followed by a reduction in kidney GFR (from 0.47±0.03 to 0.39±0.02 ml/min per 100 g body wt during the second hour after infusion; P < 0.05) and by an increase in urine flow and urinary chloride excretion. Single-nephron GFR (SNGFR) measured in proximal (TGF interrupted) or distal tubules (TGF intact) decreased to a similar degree from 33.4±1.8 and 30.6±1.2 nl/min in the control period to 19.7±1.9 and 21.2±1.6 nl/min during the second hour after AmB infusion (P < 0.05). Distal chloride concentrations and TGF responses to changes in loop of Henle flow rate were not significantly altered by AmB. AmB at 10-5 M reduced the diameter of isolated perfused afferent arterioles from rabbit kidneys. In isometrically contracting rings of rabbit aorta and renal artery in vitro AmB produced endothelium-independent constriction, with half-maximal contraction (EC50) being achieved by 1.8 X 10-6 and 2.6 X 10-6 M in intact vessels and 1.3 X 10-6 and 1.7 X 10-6 M in endothelium-denuded vessels respectively. Tension development did not occur in Ca-free media or in the presence of Ca channel blockers. Pretreatment with ouabain or Bay K 8644 potentiated the effect of AmB. The vasoconstrictive effect of AmB was counteracted by aminophyltine and atrial natriuretic peptide. We conclude that the AmB-induced reduction in GFR is not caused by TGF activation and that AmB has a direct vasoconstrictor effect that is probably initiated by depolarization-induced opening of Ca channels. This effect may be an important component of the nephrotoxic actions of AmB.

Original languageEnglish (US)
Pages (from-to)2097-2107
Number of pages11
JournalJournal of Clinical Investigation
Volume87
Issue number6
DOIs
StatePublished - Jun 1991
Externally publishedYes

Keywords

  • Afferent arteriole
  • Aminophylline
  • Micropuncture
  • Rabbit aorta
  • Tubuloglomerular feedback
  • Verapamil

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Sawaya, B. P., Weihprecht, H., Campbell, W. R., Lorenz, J. N., Webb, R. C., Briggs, J. P., & Schnermann, J. (1991). Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats. Journal of Clinical Investigation, 87(6), 2097-2107. https://doi.org/10.1172/JCI115240