Sesame oil prevents acute kidney injury induced by the synergistic action of aminoglycoside and iodinated contrast in rats.

The aim of the study was to investigate the effect of sesame oil on acute kidney injury induced by the synergistic action of aminoglycoside and iodinated contrast in rats. Acute kidney injury was induced by a 5-day course of daily gentamicin injections (100 mg/kg of body weight, subcutaneously) and then iodinated contrast (4 ml/kg, intravenously) in male specific-pathogen-free Sprague-Dawley rats. Sesame oil (0.5 ml/kg, orally) was given 1 h before iodinated contrast. Renal function and oxidative stress were assessed 6 h after iodinated contrast injection. Renal function was evaluated by measuring serum blood urea nitrogen and creatinine levels. Renal oxidative stress was assessed by determining renal lipid peroxidation, myeloperoxidase, hydroxyl radical, superoxide anion, nitrite/nitrate, and inducible nitric oxide synthase levels. Sesame oil significantly prevented the rise of serum blood urea nitrogen and creatinine levels. Furthermore, there was a parallel inhibition of the rise in levels of expression of renal lipid peroxidation, myeloperoxidase, hydroxyl radicals, superoxide anion, nitrite/nitrate, and inducible nitric oxide synthase in rats with gentamicin-plus-iodinated contrast-induced acute kidney injury. We conclude that sesame oil may attenuate aminoglycoside-plus-iodinated contrast-induced acute kidney injury by inhibiting renal oxidative stress in rats.

Hydration and N-acetylcysteine in acute renal failure caused by iodinated contrast medium: an experiment with rats.

BACKGROUND: The involvement of nephrotoxic agents in acute renal failure (ARF) has increased over the last few decades. Among the drugs associated with nephrotoxic ARF are the radiologic contrast media whose nephrotoxic effects have grown, following the increasing diagnostic use of these agents. METHODS: We evaluated the effect of iodinated contrast (IC) medium, administered in combination, or not, with hyperhydration or N-acetylcysteine (NAC), on creatinine clearance, production of urinary peroxides and renal histology of rats. Adult Wistar rats treated for 5 days were divided into the following groups: control (saline, 3 ml/kg/day, intraperitoneally [i.p.]), IC (sodium iothalamate meglumine, 3 ml/kg/day i.p.), IC + water (12 mL water, orally + IC, 3 ml/kg/day i.p. after 1 hour), IC + NAC (NAC, 150 mg/kg/day, orally + IC, 3 ml/kg/day i.p. after 1 hour) and IC + water + NAC. RESULTS: IC medium reduced renal function, with maintenance of urinary flow. Hyperhydration did not reduce the nephrotoxic effect of the IC agent, which was observed in the group IC + NAC. The combination of hyperhydration and NAC had no superior protective effect compared with NAC alone. An increase in urinary peroxides was observed in the IC group, with NAC or water or the combination of both reducing this parameter. Histopathologic analysis revealed no significant alterations. CONCLUSIONS: In summary, given 5 days previously, NAC was found to be more effective than hyperhydration alone in the prevention of contrast-induced acute renal failure.

Comparative cytotoxicity of low-osmolar nonionic and high-osmolar ionic contrast media to dog gallbladder epithelial cells.

BACKGROUND: Most studies of the adverse effects of x-ray contrast media used in ERCP have focused on post-ERCP pancreatitis. However, the biliary epithelial cells are also exposed to contrast media during ERCP and acute cholangitis is also a serious complication of ERCP. The present study compared the cytotoxicity with gallbladder epithelial cells of ionic and nonionic contrast agents. METHODS: A high-osmolar ionic contrast agent (meglumine ioxithalamate) and a low-osmolar nonionic contrast agent (iopromide) were tested. Monolayer cell cultures of dog gallbladder epithelial cells were used. The cells were exposed to the 2 contrast agents with increasing iodine concentration and osmolality for 2 days. Cell number, S-phase fraction, aneuploidy, and supernatant LDH activities were measured each day. RESULTS: Cell growth was more severely inhibited by ioxithalamate than iopromide (p < 0.05) and strongly dependent on the osmolality of contrast agent. The cytostatic effect estimated by S-phase fraction was more pronounced for ioxithalamate. Chromosomal damage determined by aneuploidy was more frequently detected with ioxithalamate. CONCLUSIONS: High-osmolar ionic contrast media are more cytotoxic than low-osmolar nonionic contrast media to gallbladder epithelial cells. Animal and clinical studies are needed to estimate the clinical implications of these findings.

A role for nitric oxide in X-ray contrast material toxicity.

RATIONALE AND OBJECTIVES: We assessed the role that nitric oxide (NO) plays in contrast media (CM) toxicity, using 100% lethal dose (LD100) studies in hyperimmune Brown Norway (BN) rats. METHODS: Ninety-two BN rats and 41 Sprague-Dawley (SD) rats underwent CM LD100 tail vein injections with methylglucamine iothalamate or sodium iothalamate to the point of cessation of respiration. Methylglucamine hydrochloride also was injected. The injections were accompanied by L-arginine (L-Arg) or D-arginine (D-Arg) analogues or by an H1 blocker. L-Arg analogues inhibit NO formation, and D-Arg analogues do not. RESULTS: An L-Arg analogue, but not a D-Arg analogue, increased the tolerance of BN rats (p < .005) for methylglucamine iothalamate but not for sodium iothalamate. The L-Arg analogue also protected BN rats against methylglucamine chloride injections (p < .002). H1 blockade protected BN rats against methylglucamine iothalamate (p < .0005) and methylglucamine chloride (p < .005) injections. None of these measures altered the CM tolerance of SD rats. In SD rats, injections of either methylglucamine iothalamate or sodium iothalamate along with a D-Arg analogue or normal saline were better tolerated than similar injections in BN rats (p < .01 and .002 for methylglucamine iothalamate and sodium iothalamate, respectively). In SD rats but not BN rats, sodium iothalamate was better tolerated than was methylglucamine iothalamate (p < .0005). CONCLUSION: NO appears to play a significant role in BN rats LD100 CM toxicity and has been implicated by others in the blood pressure fall characterizing some forms of antigen-induced anaphylaxis [1, 2]. The results of the current study and the literature suggest that methylglucamine-modulated release of histamine from mast cells may underlie the NO production.

Radiocontrast increases plasma and urinary endothelin.

Recent studies indicate that endothelin (ET), a potent endogenous systemic and renal vasoconstrictor peptide, may mediate decreases in GFR in models of acute renal dysfunction. Moreover, in an animal model of radiocontrast-induced nephropathy (RCIN), it was recently demonstrated that early renal hemodynamic responses to radiocontrast are attenuated by intra-arterial atrial natriuretic factor (ANF), which prevents subsequent RCIN. The studies presented here were therefore designed to determine whether i.v. infusion of radiocontrast produces increases in endogenous plasma and urinary ET and whether these responses are modulated by intra-arterial ANF in an animal model of RCIN. In these studies, dogs with pacing-induced heart failure received i.v. radiocontrast in the presence and absence of an intra-aortic infusion of ANF. Significant increases in both plasma and urinary ET were observed during and after radiocontrast. Although coadministration of ANF did not prevent increases in plasma and urinary ET, ANF preserved renal function acutely in this model of RCIN by increasing GFR above baseline levels.

Comparison of nonionic and ionic contrast agents in the rabbit lung.

The objective of this study was to determine the short- and long-term radiographic, physiologic and histologic changes elicited in the lung of rabbits following the aspiration of commonly used radiographic contrast agents. All agents used, including nonionic agents, caused radiographically evident pulmonary edema which cleared by 24 hours. The contrast materials with higher osmolality, viscosity, and iodine content elicited the greatest physiologic and pathologic changes. No differences were found between an ionic and a nonionic agent with similar viscosities and iodine content, despite a lower osmolality in the nonionic agent. No contrast agent is innocuous when introduced into the lung.

Cutaneous ulceration due to contrast extravasation. Experimental assessment of injury and potential antidotes.

Severe cutaneous ulceration may occur as a result of contrast media extravasation. We established a definitive animal model for assessing the cutaneous toxicity of commonly employed agents and used this model to evaluate possible antidotes to the effects of contrast media extravasation. The contrast agents studied were: meglumine/sodium diatrizoate 76%, meglumine iothalamate 60% and 43%, meglumine/sodium ioxaglate 60%, iohexol 350, and iopamidol 370, in varying volumes and osmolalities. Hypertonic saline (950 and 1900 mOsm/kg) also was injected. Agents were injected intradermally into BALB/c mice. The higher osmolality agents produced dose-dependent skin ulcerations. The lower osmolality agents failed to produce any skin lesions after the same volume doses. Hypertonic saline produced skin toxicity in a dose-dependent fashion similar to hyperosmolar contrast agents. Three antidotes were tested: hyaluronidase, topical heat, and topical cold. Hyaluronidase significantly reduced skin toxicity when injected immediately following contrast injection. Cold also significantly reduced skin toxicity, while heat caused no improvement.

Induction and prevention of radiocontrast-induced nephropathy in dogs with heart failure.

Radiocontrast-induced nephropathy (RCIN) is a clinically important cause of acute renal failure with no effective treatment. Recognizing the high incidence of RCIN in humans with severe congestive heart failure (CHF), this study was designed to test the hypotheses that dogs with experimental CHF are at increased risk for RCIN and that pharmacologic renal levels of atrial natriuretic factor (ANF) can prevent RCIN in this model. In chronic experiments, three groups of five conscious dogs received intravenous radiocontrast (7 ml/kg). One group consisted of normal controls, while the two other groups had experimental CHF induced by eight days of ventricular pacing at 250 beats per minute. One of the CHF groups received an infusion of ANF (30 ng/kg/min) into the suprarenal aorta for one hour before, during and after the infusion of radiocontrast to achieve pharmacologic renal plasma levels. Renal function remained stable in the normal controls in contrast to the consistent decreases in daily creatinine clearance during the five days following radiocontrast in experimental CHF. In addition, ANF prevented radiocontrast-induced reductions in creatinine clearance in dogs with experimental CHF. Additional studies performed in two groups of anesthetized dogs with experimental CHF demonstrated that, in this model of RCIN, the reduction in renal function appears biphasic, and the action of ANF may be to increase glomerular filtration rate prior to radiocontrast, thus allowing a maintenance of renal function during and after radiocontrast.

Effects of contrast agents on the fallopian tube in a rabbit model.

The authors evaluated the effect of different iodinated contrast agents on the fallopian tube and adnexal tissue in 15 rabbits. Ethiodized oil, an oil-soluble agent, was used in five rabbits. The following water-soluble agents were used: iothalamate meglumine 30% (n = 3), iothalamate meglumine 60% (n = 3), and ioxilan (n = 4). The agents were injected through catheters placed in the fallopian tubes. Fallopian tubes and peritoneal cavities were histologically evaluated. The contralateral tube served as a control. Ioxilan and iothalamate meglumine 30% produced no pathologic response in the tube or peritoneal cavity. Iothalamate meglumine 60% was associated with mild inflammatory infiltrate, mucosal edema, giant cell reaction, and periovarian adhesions that were bilateral but more pronounced on the injected side. Use of ethiodized oil resulted in papillary fibrous adhesions on the ovarian surface, and fat granulomas were seen in the periovarian tissues. The safety of oil-based contrast agents for use in hysterosalpingography is therefore questioned. No significant differences were found among the water-soluble contrast agents.

Peritoneal reaction resulting from iodinated contrast material: comparative study.

A consensus does not exist as to the optimal contrast agent for hysterosalpingography. This study was undertaken to evaluate the early and delayed inflammatory responses of the peritoneal surfaces to various types of iodinated contrast media. Guinea pigs received intraperitoneal injections of lactated Ringer solution, iothalamate meglumine, diatrizoate sodium, ioxilan, or ethiodized oil. The inflammatory response of the peritoneal surfaces was assessed at 1,7, and 30 days. Five animals were studied at each time point for each agent. No animals that received Ringer lactate or iothalamate meglumine had inflammation at any time. Ioxilan produced inflammation in two of five animals at 7 days and no inflammation at 1 or 30 days. Ethiodized oil produced no inflammation at 1 day; however, three animals had inflammation at 7 days, and all five had inflammation at 30 days. The 30-day group showed striking inflammatory response with granulomatous features. The authors recommend the continued use of meglumine-based water-soluble ionic contrast material for hysterosalpingography.

Role of red blood cell deformation in toxicity of contrast media in cerebral angiography.

The authors investigated the effect on the brain of red blood cells that had been modified by contrast media. Rat blood was mixed with an equivolume of contrast media, and up to 200 microL of the mixture was infused to the internal carotid artery of the rat. Evans blue was administered intravenously to assess the integrity of the blood-brain barrier (BBB). Immediately after the death of the animal, or 2.5 hours after the infusion, the brain was removed for evaluation of the degree of BBB destruction and edema. Extensive destruction of the BBB, cerebral edema, and death of the animals were induced by infusion of blood mixed with an ionic contrast medium, such as diatrizoate and iothalamate, which deformed red blood cells. Microscopic observation showed atrophy and necrosis of nerve cells and decomposition of nerve fibers in the affected area of the brain. Cerebral damage was not observed in rats injected with blood mixed with a nonionic contrast medium such as iopamidol, iopromide, or metrizamide, which had less effect on red blood cells. Cerebral damage also was observed in the rats injected with blood mixed with a hyperosmotic solution of mannitol, as well as washed red blood cells mixed with an ionic contrast medium. This study's results indicate that hyperosmotic ionic contrast media affect red blood cells and cause disturbance in cerebral circulation.

A rat EEG model for evaluating contrast media neurotoxicity.

The electroencephalographic (EEG) effects of intracisternally administered x-ray contrast media were evaluated in rats as a means of assessing neurotoxicity. Rats were ventilated with a mixture of nitrous oxide and oxygen (70/30) sufficient to maintain light anesthesia/analgesia and neuromuscular blockade was induced to prevent movement artifacts. A femoral artery was catheterized for monitoring arterial blood pressure (BP), heart rate, blood gases, and pH. Four 22-gauge stainless steel needle electrodes were inserted underneath the scalp for recording EEG. Approximately 1 hour after the start of EEG recording, test agents were injected via the cisterna magna and rats were placed in a 20 degrees head-down position. EEG and BP were monitored continuously for up to 160 minutes postinjection. Blood gases and pH were monitored periodically. The effects of meglumine iothalamate (IOT), metrizamide (MET), iogulamide (IOG), and ioversol (IOV) were compared at dose levels from 30 to 240 mgI/kg. Normal saline was injected as a control substance and caused no changes in EEG, blood gases, pH, and BP for up to 160 minutes postinjection. IOT (30 mg I/kg) produced profound EEG effects consistent with epileptogenic activity, followed by slowing and subsequent death in 3 of 4 animals. Metrizamide had minimal EEG effects at 30 mg I/kg but at 60 mg I/kg, and 120 mg I/kg produced moderate to severe EEG changes including epileptiform patterns and death in 33% of animals. IOV caused mild EEG abnormalities in 4 of 12 animals at 120 mg I/kg, mild EEG abnormalities in 6 of 11 animals, and moderate EEG abnormalities in 1 of 11 animals at 240 mg I/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of meglumine iothalamate on renal hemodynamics and function in the diabetic rat.

Diabetic rats were given an intravenous (external jugular vein) injection of 3 mg/kg of 60% meglumine iothalamate to test for this contrast agent's functional effects on the kidney. Rats were made diabetic by the intravenous injection of 60 mg/kg streptozotocin six months prior to the experiment and received no treatment during the interim. Glomerular filtration rate, renal blood flow, blood pressure, and sodium reabsorption were measured immediately before and at timed intervals after the administration of the contrast agent. In the diabetic rats, meglumine iothalamate caused a small and brief increase in renal blood flow followed by a sustained decrease; in the control animals an initial rapid rise was followed by a sustained elevation. Glomerular filtration rate also decreased slightly after contrast agent injection and remained depressed below baseline in the diabetic rats, whereas in the control animals it rose slightly above baseline and returned to control values by the end of the experiment. Sodium reabsorption was initially much higher than that of the controls, and it remained much higher throughout the experiment but decreased slightly just after injection of the contrast agent. Volume expansion of the diabetic animals decreased fractional sodium reabsorption to levels similar to those of the control rats but did not normalize the response of renal blood flow, glomerular filtration rate, or sodium reabsorption. Dehydration of control animals increased initial sodium reabsorption to levels similar to those of the diabetic animals but did not normalize the response to the contrast agent of the glomerular filtration rate, renal blood flow, or sodium reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotoxicity of contrast media and clinical adverse effects: a review.

The clinical effects of contrast agents not only result from high osmolality, but also from their own specific pharmacology, which mediates chemotoxic effects. In this review, the chemotoxic effects of the new nonionic agent, iohexol, are compared with those of standard ionic and other low osmolality contrast agents, ionic and nonionic. Iohexol has the lowest chemotoxicity of any agent yet synthesized. Its low systemic toxicity is the combined result of low chemotoxicity and low osmolality. Mechanisms of severe adverse reactions are reviewed, including the views of Lasser and Lalli, and the view that emphasizes the importance of cardiotoxic and hemodynamic effects. It is concluded that whichever view is taken of the mechanisms of severe adverse reactions, the new nonionic agents are likely to be safer than the ionic agents now in use.