A deterioration of renal function is one preoccupying complication of iodinated radiocontrast agents in clinical practice. These compounds have direct toxic effects on renal cells, which are only in ...part related to their physicochemical properties. The hyperosmolal monomeric ionic radiocontrast agents, like diatrizoate, have the highest toxicity, whereas renal cells are less affected by (nonionic) compounds with reduced osmolality. The toxic effects include cellular energy failure, a disruption of calcium homeostasis, a disturbance of tubular cell polarity and programmed cell death (apoptosis). The molecular mechanisms of the direct cytotoxicity are still unclear, although oxidative stress has been implicated. Radiocontrast cytotoxicity has been demonstrated in glomerular mesangial cells and in renal epithelial cells in vitro. In vivo, the direct cellular toxicity of radiocontrast agents is compounded with alterations in blood flow and/or viscosity, ultimately resulting in renal medullary hypoxia, which is a hallmark feature of the complex clinical syndrome of radiocontrast nephropathy.
Hizoh I, Haller C. Radiocontrast-induced renal tubular cell apoptosis. Hypertonic versus oxidative stress. Invest Radiol 2002;37:428–434.
RATIONALE AND OBJECTIVES. Radiocontrast-induced nephropathy ...(RCIN) is a major complication of intravascular radiocontrast administration. Renal tubular cell apoptosis is a feature of RCIN, which is related to hypertonicity of contrast agents. Because a hyperosmolal extracellular environment induces oxidative stress via reactive oxygen species, we tested the hypothesis that antioxidants decrease hypertonicity-induced apoptosis of renal epithelial cells. We analyzed the effects of the antioxidants N-acetylcysteine (NAC) and taurine on hypertonicity-induced apoptosis of renal epithelial cells in vitro.
METHODS. Madin Darby Canine Kidney (MDCK) cells were incubated with the highly hyperosmolal, ionic radiocontrast agent diatrizoate (20% vol/vol, 6 hours) or with equally hyperosmolal (640 mOsm/kg) NaCl solutions. DNA fragmentation, which is a hallmark feature of apoptosis, was assessed quantitatively using flow cytometry after propidium iodide staining and qualitatively using agarose gel electrophoresis.
RESULTS. Both diatrizoate and NaCl induced DNA fragmentation in MDCK cells. Taurine (10 mmol/L) reduced DNA degradation in both diatrizoate- 79.5 ± 2.3% versus 72.2 ± 3.0%;P = 0.0088 and NaCl- 49.5 ± 4.0% versus 39.4 ± 1.0%;P = 0.0271 treated cells. In contrast, NAC (10 mmol/L) failed to reduce the DNA breakdown in this model of hypertonicity-induced renal tubular cell apoptosis.
CONCLUSIONS. The radiocontrast/hypertonicity-induced DNA fragmentation of MDCK cells is attenuated by taurine but not by NAC. Because both agents are antioxidants, the antioxidant property is not sufficient for the observed cytoprotective effect. Hence, the antiapoptotic effect of taurine has to be attributed to other, yet to be defined mechanisms. Our results suggest that pharmacological doses of taurine may be particularly protective against RCIN.
Nitric Oxide–Sensitive Soluble Guanylyl Cyclase Activity Is Preserved in Internal Mammary Artery of Type 2 Diabetic Patients
Klaus Witte 1 ,
Jochen Hachenberger 1 ,
Maria F. Castell 2 ,
Christian F. ...Vahl 2 and
Christlieb Haller 3
1 Faculty of Clinical Medicine Mannheim, Institute of Pharmacology and Toxicology, University of Heidelberg, Mannheim, Germany
2 Department of Thoracic Surgery, University of Heidelberg, Heidelberg, Germany
3 Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany
Address correspondence and reprint requests to Dr. Christlieb Haller, Medizinische Klinik I, Hegau-Klinikum Singen, Virchowstr.
10, 78221 Singen, Germany. E-mail: christlieb.haller{at}hegau-klinikum.de
Abstract
Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity
of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal
mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of
sGC to NO, which is dependent on Fe 2+ -containing heme, was measured in vitro using stimulation with diethylamine NONOate (DEA/NO). In addition, the novel cyclic
guanosine monophosphate–elevating compound HMR-1766 was used to test the stimulation of the oxidized heme-Fe 3+ –containing form of sGC. Basal activity of sGC and its sensitivity to stimulation by DEA/NO and HMR-1766 were not different
between control and type 2 diabetic patients: maximum stimulation by DEA/NO amounted to 475 ± 67 and 418 ± 59 pmol · mg −1 · min −1 in control and type 2 diabetic patients, respectively. The maximum effects of HMR-1766 were 95 ± 18 (control subjects) and
83 ± 11 pmol · mg −1 · min −1 (type 2 diabetic patients). Hypertension, hyperlipidemia, drug treatment with statins, ACE inhibitors, or nitrates had no
effect on sGC activity. In conclusion, the present findings do not support the hypothesis that desensitization of sGC contributes
to the pathogenesis of diabetic vascular dysfunction in humans.
cGMP, cyclic guanosine monophosphate
DEA/NO, diethylamine NONOate
sGC, soluble guanylyl cyclase
Footnotes
K.W. has received research support from Aventis.
Accepted June 24, 2004.
Received May 13, 2004.
DIABETES
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