Search

Background Context: Ioxitalamate (Telebrix 300) is an ionic iodinated contrast medium commonly used for discography or percutaneous endoscopic lumbar discectomy (PELD), though it has side effects such as anaphylactic shock and renal toxicity. Indigocarmine is an organic compound dye with a distinctive blue color that is commonly used during PELD to stain the acidic, degenerated nucleus pulposus (NP). Although ioxitalamate and indigocarmine are widely used in spinal surgery, there have been no reports on their effects on NP cells. We studied the toxicities of both ioxitalamate and indigocarmine to NP cells., Purpose: To determine the toxicities of both ioxitalamate and indigocarmine to NP cells in vitro., Study Design: In vitro, controlled study of the toxicities of both ioxitalamate and indigocarmine to human NP cells., Methods: Nucleus pulposus cells were obtained via discectomy from lumbar disc patients and isolated. Nucleus pulposus cells were cultured in three-dimensional (3D) alginate beads with 0.001, 0.1, 10, and 100 mg/mL ioxitalamate, 0.00001, 0.001, 0.1, and 10 mg/mL indigocarmine, or a mixture of both for 1, 2, or 3 days. The living cells were analyzed with trypan blue staining. Fluorescence Activated Cell Sorting analysis using Annexin V and propidium iodide and 3D alginate bead immunostaining was performed to identify live, apoptotic, and necrotic cells., Results: Ioxitalamate, indigocarmine, and their combination induced statistically significant NP cell injury that was both time- and dose dependent (p<.05). Also, at the same concentration, ioxitalamate was more cytotoxic than was indigocarmine or the combination (p<.05). All three treatments also showed dose-dependent cytotoxicity according to flow cytometry and immunostaining., Conclusions: Ioxitalamate and indigocarmine are toxic to human NP cells in vitro in a time- and dose-dependent manner. We assume that ioxitalamate and indigocarmine may have similar effects in patients undergoing discography and PELD. Thus, we suggest that ioxitalamate and indigocarmine should be used carefully at low concentrations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Iodinated X-ray contrast media (ICM) were investigated as a source of iodine in the formation of iodo-trihalomethane (iodo-THM) and iodo-acid disinfection byproducts (DBPs), both of which are highly genotoxic and/or cytotoxic in mammalian cells. ICM are widely used at medical centers to enable imaging of soft tissues (e.g., organs, veins, blood vessels) and are designed to be inert substances, with 95% eliminated in urine and feces unmetabolized within 24 h. ICM are not well removed in wastewater treatment plants, such that they have been found at elevated concentrations in rivers and streams (up to 100 μg/L). Naturally occurring iodide in source waters is believed to be a primary source of iodine in the formation of iodo-DBPs, but a previous 23-city iodo-DBP occurrence study also revealed appreciable levels of iodo-DBPs in some drinking waters that had very low or no detectable iodide in their source waters. When 10 of the original 23 cities' source waters were resampled, four ICM were found--iopamidol, iopromide, iohexol, and diatrizoate--with iopamidol most frequently detected, in 6 of the 10 plants sampled, with concentrations up to 2700 ng/L. Subsequent controlled laboratory reactions of iopamidol with aqueous chlorine and monochloramine in the absence of natural organic matter (NOM) produced only trace levels of iodo-DBPs; however, when reacted in real source waters (containing NOM), chlorine and monochloramine produced significant levels of iodo-THMs and iodo-acids, up to 212 nM for dichloroiodomethane and 3.0 nM for iodoacetic acid, respectively, for chlorination. The pH behavior was different for chlorine and monochloramine, such that iodo-DBP concentrations maximized at higher pH (8.5) for chlorine, but at lower pH (6.5) for monochloramine. Extracts from chloraminated source waters with and without iopamidol, as well as from chlorinated source waters with iopamidol, were the most cytotoxic samples in mammalian cells. Source waters with iopamidol but no disinfectant added were the least cytotoxic. While extracts from chlorinated and chloraminated source waters were genotoxic, the addition of iopamidol enhanced their genotoxicity. Therefore, while ICM are not toxic in themselves, their presence in source waters may be a source of concern because of the formation of highly toxic iodo-DBPs in chlorinated and chloraminated drinking water.

To investigate the unrecognized role of renal efferent nerve activity (RENA) in iodinated contrast media (CM)-induced acute kidney injury, we explored the effects of CM on RENA, renal hemodynamics, plasma renin activity (PRA), reactive oxygen species (ROS) production, and renal injury in rats. Four types of CM including ioxitalamate (high osmolar and ionic), ioxaglate (low osmolar and ionic), iohexol (low osmolar and nonionic), and iodixanol (iso-osmolar and nonionic) were given iv (1600 mg I/kg body weight) to urethane-anesthetized female Wistar rats. We measured RENA by electrophysiologic recording techniques, renal blood flow with Doppler ultrasound, PRA by radioimmunoassay, and ROS by an in vivo chemiluminescence method. We graded the severity of CM-induced vacuoles in cortical tubular cells stained by hematoxylin and eosin and apoptosis production in outer medulla by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Besides, the effects of pretreatment with iv beta-adrenoceptor antagonist propranolol (10 mg/kg body weight), antioxidant N-acetylcysteine (100 mg/kg body weight), and renal denervation on CM-induced pathophysiologic parameters were determined. Ioxitalamate significantly increased RENA and renal vascular resistance, PRA, renal ROS production within 1 h, and formation of vacuoles and TUNEL apoptosis in renal tubular cells 2 h later; other CM had less effect on these parameters. On the other hand, propranolol, N-acetylcysteine, or renal denervation partially attenuated the ioxitalamate-aggravated responses on RENA, PRA, ROS production, and vacuole and TUNEL apoptosis formation in renal tubular cells. In conclusion, we suggest that ioxitalamate may induce acute tubular injury via aggravation of RENA, adrenergic signaling, PRA, and ROS production.

Objectives: The loss of renal function continues to be a frequent complication of the iodinated contrast agents used to perform diagnostic angiography and endovascular procedures. This study examined the hypothesis that contrast-induced renal injury is partly due to a decrease in cortical and medullary microvascular blood flow after the downregulation of endogenous renal cortical and medullary nitric oxide (NO) synthesis., Methods: Anesthetized male Sprague-Dawley rats (300 g) had microdialysis probes or laser Doppler fibers inserted into the renal cortex to a depth of 2 mm and into the renal medulla to a depth of 4 mm. Laser Doppler blood flow was continuously monitored, and the microdialysis probes were connected to a syringe pump and perfused in vivo at 3 muL/min with lactated Ringer's solution. Dialysate fluid was collected at time zero (basal) and 60 minutes after infusion of either saline or Conray 400 (6 mL/kg). Both groups were treated with saline carrier, N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 30 mg/kg), L-arginine (400 mg/kg), or superoxide dismutase (10,000 U/kg), an oxygen-derived free radical scavenger. Dialysate was analyzed for total NO and eicosanoid synthesis. The renal cortex and medulla were analyzed for inducible NO synthase (iNOS), cyclooxygenase-2 (COX2), prostacyclin synthase, and prostaglandin E(2) (PGE(2)) synthase content by Western blot analysis., Results: Conray caused a marked decrease in cortical and medullary blood flow with a concomitant decrease in endogenous cortical NO, PGE(2), and medullary NO synthesis. The addition of L-NAME to the Conray further decreased cortical and medullary blood flow and NO synthesis, which were restored toward control by L-arginine. Neither L-NAME nor L-arginine (added to the Conray) altered cortical or medullary eicosanoids release. Medullary PGE(2) synthesis decreased when superoxide dismutase was added to the Conray treatment, suggesting that oxygen-derived free radicals had a protective role in maintaining endogenous medullary PGE(2) synthesis after Conray treatment. Conray did not significantly alter iNOS, COX-2, prostacyclin synthase, or PGE(2) synthase content., Conclusions: These findings suggest that the downregulation of renal cortical and medullary NO synthesis contributes to the contrast-induced loss of renal cortical and medullary microvascular blood flow. Preservation of normal levels of renal cortical and medullary NO synthesis may help prevent or lessen contrast-induced renal vasoconstriction and lessen contrast-induced renal injury found after diagnostic and therapeutic endovascular procedures.

Purpose: In order to alleviate the adverse effects of contrast media (CMs) on the vascular system, the role of Ca2+ in the viability of vascular smooth muscle cells (VSMCs) was investigated., Material and Methods: VSMCs were obtained from swine thoracic aorta. The number of VSMCs was counted under a microscope using the trypan blue dye-exclusion method 24 h after culture in RPMI containing physiological saline (SAL) as control, iothalamate (IOT), or iohexol (IOH) at 10% by volume with CaCl2 added at 0 to 2.0 mmol/l. Free Ca2+ in the above media was measured using an ion-selective electrode., Results: Free Ca2+ was 0.4 to 1.5 mmol/l with ionic IOT and 0.4 to 1.8 mmol/l with non-ionic IOH as well as with control. The ratio of viable cells grown in the presence of CMs to those grown in the control was optimal at approximately 0.60 near 1 mmol/l Ca2+ and decreased markedly to 0.00 at 1.5 mmol/l Ca2+ in the presence of IOT and to 0.39 at 1.8 mmol/l Ca2+ in the presence of IOH, while the ratios decreased gradually to 0.28 in the presence of IOT and 0.53 in the presence of IOH at 0.4 mmol/l Ca2+., Conclusion: Ionic IOT is more cytotoxic to VSMCs than non-ionic IOH. However, the cytotoxicity was minimal and similar between both CMs at 1 mmol/l Ca2+ in accordance with the sodium-calcium balance.

Unlabelled: The endothelium plays a central role in the regulation of blood flow and coagulation. The impact of radiocontrast agents on endothelial cells is therefore potentially clinically important, particularly in percutaneous interventions for acute coronary thrombosis. The effects of radiocontrast agents on endothelial cell viability and determinants of thrombogenicity were studied in human umbilical vein endothelial cells (HUVECs) in vitro. Intercellular tight junctions were assessed using immunofluorescence microscopy and measurement of the transmonolayer electrical resistance (TMR). The concentrations of endothelin-1 (E), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin (T) were measured in the cell culture media. The ionic, high osmolal radiocontrast agent diatrizoate induced concentration-dependent cell death and an opening of tight junctions with the attendant abolition of the TMR. The concentration of E decreased, vWF increased in the cell culture media, the concentration of PAI-1 and T was not significantly changed by diatrizoate. Radiocontrast agents with reduced osmolality (ioxaglate: ionic; iopamidol: non-ionic) induced an increase in PAI-1 and vWF, but E and T were not significantly changed., Conclusions: Radiocontrast agents have differential effects on endothelial cells in vitro including the secretion of modulators of thrombogenesis. The effects are most pronounced in the markedly hyperosmolal compound diatrizoate suggesting a contributory role of hypertonicity. Ioxaglate and iopamidol both increased the prothrombotic factors vWF and PAI-1 to the same degree indicating a similar risk of thrombogenicity between low-osmolal ionic and non-ionic radiocontrast agents in this in vitro model.

Purpose: To quantitatively evaluate endothelial injury in vivo and to assess the time course of cellular repair after endothelial cell exposure to ionic and non-ionic contrast media., Material and Methods: Local changes at the cellular level following intraaortic injection of 1 ml of the ionic contrast agent ioxithalamate or 1 ml of the non-ionic contrast agent iomeprol, each with an iodine content of 300 mg/ml, were investigated using rat endothelium as an in vivo model. A sorbitol solution iso-osmolar to iomeprol served as control. Quantitative analysis of endothelial changes by autoradiography of 3H-thymidine-labeled endothelial cells was assessed after 3, 5 and 10 days, determining the 3H-thymidine index and the DNA synthesis rate., Results: Ioxithalamate showed a clear harmful effect on the endothelium, with an elevated 3H-thymidine index of 7.68% on day 3 and 6.89% on day 5, versus 2.97% on day 3 and 2.55% on day 5 for iomeprol and 2.29% on day 3 and 1.91% on day 5 for the control., Conclusion: Ionic contrast agents lead to reversible transient focal endothelial cell injury. No such side effect was detectable for non-ionic contrast agents.

The pathogenesis of radiocontrast nephropathy is poorly understood. In an animal model, inhibition of the synthesis of nitric oxide and prostaglandins appears to predispose rats to severe renal injury following the administration of radiocontrast. Here we have investigated whether administration of radiocontrast, as well as changes in renal medullary oxygenation following pharmacologic inhibition of nitric oxide and prostaglandin synthesis, might be evaluated by blood oxygenation level-dependent (BOLD) MRI. Nineteen anesthetized (Inactin 100 mg/kg) rats were studied. BOLD MRI measurements were performed following administration of L-NAME (N-nitro-L-arginine methyl ester, 10 mg/kg), Indomethacin (10 mg/kg), and a radiocontrast agent (sodium iothalamate 60%, 6 mL/kg). Marked sequential changes in medullary R(*)(2), presumably reflecting decline in medullary pO(2), were noted after each of the pharmacological interventions employed. These results, obtained by noninvasive MRI, are consistent with prior direct recordings of pO(2) and doppler flow in the rat renal medulla after administration of L-NAME, Indomethacin and iothalamate. Medullary oxygenation in rats was reduced by inhibition of the synthesis of prostaglandins and nitric oxide, as well as by intravenous injection of radiocontrast agents. BOLD MRI can noninvasively evaluate changes in medullary oxygenation in rats that appear to predispose acute renal failure. J. Magn. Reson. Imaging 2001;13:744-747., (Copyright 2001 Wiley-Liss, Inc.)

The response of insulin-like growth factor (IGF) I in acute renal failure was evaluated in a model of radiocontrast nephropathy associated with selective necrosis of medullary thick ascending limbs. In brief, rats were administered radiocontrast medium or vehicle injections for controls after combined inhibition of prostanoids and nitric oxide. Twenty-four hours after the insult, tissue mRNAs for IGF-I, the IGF-I receptor, and IGF-binding proteins (IGFBP) 1 and 3 were assayed in cortex, medulla, and liver by solution hybridization-RNase protection assay, and IGFBPs were measured in serum and tissue by Western ligand blotting. Cortical IGF-1 increased, whereas medullary IGF-I mRNA decreased. Renal IGFBPs decreased, whereas IGFBP-1 mRNA increased. The IGF system in the liver was unchanged. We conclude that general changes in renal IGFBPs in this experimental model of acute renal failure might increase the level of cortical IGF-I in a way that could modulate medullary recovery.

Purpose: To study the effects of iothalamate sodium and two dosages of iopromide in acute cerebral ischemia on infarction volume, neurologic performance, and mortality in a rat model of middle cerebral artery occlusion., Materials and Methods: Sixty-four rats underwent endovascular occlusion of the middle cerebral artery. Four hours later, 16 animals received iothalamate sodium (588 mg iodine per kilogram); 16, iopromide as a single bolus (518 mg iodine per kilogram); and 16, iopromide as a double bolus (1,036 mg iodine per kilogram). Sixteen animals received equivolumetric saline (control group). Neurologic score and body weight were recorded every 8 hours. Twenty-four hours after occlusion, all animals were killed; brains were stained to assess the infarction size., Results: Single and double doses of iopromide did not affect infarction volume or neurologic performance. Iothalamate caused an increase in infarction volume and worsening of the neurologic score (p < .05). Mortality rate was 25% in the iothalamate group, 12% in the control group, and 6% in the iopromide groups., Conclusion: Bolus injection of the nonionic iopromide does not statistically significantly affect infarction volume or cerebral ischemia symptoms. Nonionic rather than ionic contrast agents should be preferred during acute cerebral ischemia.

Radiocontrast agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the diagnosis and treatment of renal colic. We studied their impact during unilateral acute urinary outflow obstruction upon renal microcirculation and parenchymal integrity. Laser-Doppler and ultrasonic regional flow measurements demonstrated selective decline of outer medullary blood flow by 23 +/- 2% during an acute increase of intra-pelvic pressure to 50 to 55 cm H2O (N = 28, X +/- SEM, P < 0.01). In rats preconditioned with indomethacin, this manipulation reduced medullary blood flow by 50 +/- 4% (N = 16, P < 0.01 vs. obstruction alone), with cortical and total renal blood flow declining by 18 +/- 4% and 16 +/- 2%, respectively (P < 0.01). Unilateral obstruction alone for 24 hours in intact rats resulted in injury (hemorrhage and necrosis) to the papilla and fornix (formed laterally by inner stripe and medially by the inner medulla). These changes were detected as early as 30 minutes after ureteral ligature by staining for fragmented nuclear DNA (TUNEL). Mild damage of thick ascending limbs (mTALs) was associated with substantial medial fornix injury. Indomethacin markedly increased mTAL injury in obstructed kidneys, but attenuated inner medullary damage, both in the medial border of the urinary space and at the papilla. This latter protective effect, probably mediated by the decrease in intrapelvic pressure, was blunted by concomitant intravenous fluid load. Contrast media (iothalamate) and L-NAME (N omega nitro-L-arginine methyl ester) both augmented inner stripe and inner medullary damage in hydronephrotic kidneys. In rats concomitantly subjected to radiocontrast, indomethacin and L-NAME (an acute renal failure protocol, J Clin Invest 94:1069, 1994), unilateral obstruction augmented inner stripe hypoxic damage (65 +/- 6% vs. 24 +/- 11% of mTALs in contralateral kidneys, N = 7, P < 0.01). Injury was maximal at the fornix (93 +/- 6% vs. 39 +/- 14% of mTALs in the mid-inner stripe, P < 0.01) and extended to the outer stripe and medullary rays. Thus, in the rat acute ureteral obstruction alters medullary blood flow and within 24 hours produces medullary damage in both forniceal and inner medullary locations, that is exacerbated by concomitant measures which limit medullary oxygenation. Contrast studies, forced hydration and NSAIDs for renal colic are potentially harmful and their use should be re-evaluated.

Exogenous insulin-like growth factor 1 (IGF-1) has been reported to improve experimental ischemic acute renal failure. We investigated a possible beneficial role of IGF-1 in a model of radiocontrast nephropathy induced by indomethacin, nitro-L-arginine ester and iothalamate. Multiple injections of recombinant human IGF-1 (or its vehicle) at 150 microg/100 g body weight/day were given for 24 h starting 1 h after radiocontrast, or initiated 1 day after the insults and continued for 48 h. IGF-1 prevented neither the fall in creatinine clearance nor medullary thick ascending limb necrosis observed at 24 h. Similarly IGF-1, given for 2 days after renal failure had been established, did not accelerate functional recovery at 72 h, did not ameliorate catabolism and did not alter the morphological evolution of intrarenal damage. In conclusion, IGF-1 had no beneficial effects in this model of radiocontrast nephropathy.

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.

In a double blind clinical study, 50 patients with healthy kidneys were tested for the discharge of renal marker proteins before and after receiving a high or low osmoloar contrast medium (Meglium-Ioglicinat, Imeprol) using i.v. urography. The renal excretion of the tubular indicator enzymes alanine aminopeptidase, beta-Glutamyltranspeptidase and alkaline phosphatase increased in all patients after administration of the contrast media. The enzymuria was significantly lower with the non-ionic contrast medium with the ionic one, thus demonstrating that the non-ionic contrast medium has a lower nephrotoxic potential than the conventional ionic contrast medium. Three independent investigators evaluated the radiograms with regard to the contrast quality using prearranged criteria in a 5 point system. The diversity of the evaluations clearly favoured the non-ionic contrast medium.

Human radiocontrast nephrotoxicity is predicted by the presence of multiple risk factors, often associated with compromised renal circulation. To produce a simple model of radiocontrast nephropathy, rats were pretreated with indomethacin and N omega-nitro-L-arginine methyl ester (L-NAME, to inhibit nitric oxide synthesis) before the administration of iothalamate. Acute renal failure consistently developed, with a decline in creatinine clearance from 1.05 +/- 0.10 to 0.27 +/- 0.05 ml/min (P < 0.001) associated with selective necrosis of 49 +/- 9% of medullary thick ascending limbs. Hemodynamic studies using laser-Doppler probes revealed that when injected alone, iothalamate increased outer medullary blood flow to 196 +/- 25% of baseline (P < 0.001). Pretreatment by L-NAME or indomethacin both reduced basal medullary blood flow and transformed the medullary vasodilator response to radiocontrast into vasoconstriction, with a prolonged reduction of medullary blood flow to less then half of baseline. Combined administration of indomethacin, L-NAME, and iothalamate lowered medullary blood flow to 12 +/- 4% of baseline. We conclude that prostanoids and nitric oxide have an important protective role in the renal response to radiocontrast material. Reduced synthesis of these vasoactive substances in renal/vascular diseases may predispose patients to radiocontrast nephropathy.

In lightly-anesthetized dogs, ionic or non-ionic RCM (Iotalamato and iohexol, respectively) when injected by intracarotid route (i.c.), elicit a pain response comparable to that caused by bradykinin (BK) or capsaicin (CAP). This response, which is characterized by vocalization, hyperpnea, bradycardia and neck muscle contraction, was dose dependent and related to the osmolarity of the RCM. In the present study we observed that indomethacin did not interfere with CAP and RCM-induced pain at dose (2 mg/kg i.c.) that reduced BK-elicited responses. In contrast, Ruthenium Red (RR), in dose (1 mg/kg i.c.) that reduced CAP and/or RCM-induced effects did not affect BK-induced phenomena. We also verified that L-NAME (50 mg/kg i.c.) reduced the BK-, but not the CAP- and/or RCM-induced pain responses which suggests that an L-arginine-derived NO or related compound is involved in BK activation of perivascular nociceptors. Indeed, we found that i.c. injection of 20 mg of S-nitrosocysteine, a putative EDRF, caused BK-like responses. On the other hand, RCM and CAP appear to activate the same RR sensitive ionic channels of primary afferent endings. Therefore, RR-analogues could constitute a novel approach to minimizing or eventually abolishing the RCM side effects.

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.

We evaluated the acute changes in cortical and outer medullary oxygen tension and the alterations in renal function and morphology within the first 90 minutes after the administration of indomethacin and iothalamate to anesthetized Sprague-Dawley rats. Both agents were found to produce marked and protracted outer medullary hypoxia averaging 12 +/- 4 and 9 +/- 2 mm Hg, respectively (mean +/- SE). Given together to salt depleted uninephrectomized rats they produced an early hypoxic injury localized selectively in the outer medulla. This lesion progressed from 3 +/- 1% of medullary thick ascending limbs (mTALs) at 15 minutes to 22 +/- 7% at 24 hours. Condensed "dark" cells were observed at 15 minutes, probably representing a type of early injury. Residual red cell mass, quantified in the outer medullary vasculature of perfusion-fixed kidneys and presumably reflecting stasis, was substantially increased in iothalamate treated rats. Red cell mass in the interbundle zone correlated with mTAL necrosis. Taken together, these results show an early period of medullary hypoxia, accompanied by a selective injury to mTALs in the central interbundle zone with apparent stasis. These findings contrast sharply with the ischemia-reflow pattern of renal damage and emphasize the important role of medullary hypoxia in the genesis of acute renal failure in this model.

We studied the effect of an ionic high osmolar contrast medium (Ioxitalamate), an ionic low osmolar contrast medium (Ioxaglate) and various nonionic low osmolar contrast media (Iopamidol, Iopromide and Iohexol) on thrombus growth in a rabbit jugular vein thrombosis model. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen onto autologous preformed thrombi in rabbit jugular veins at various time-intervals from 15 min up to 10 h after infusion of the study solution. The ionic low osmolar contrast medium markedly inhibited thrombus growth whereas all nonionic low osmolar contrast media promoted thrombus growth. The ionic high osmolar, contrast medium inhibited thrombus growth, but less than the ionic low osmolar contrast medium. Within the group of nonionic contrast media, the Iopamidol associated promotion of thrombus growth was significantly higher than the Iopromide or Iohexol associated effects. The simultaneous administration of the apparently most potent thrombus growth promoting contrast medium (i.e. Iopamidol) and heparin resulted in complete abolishment of the increase in thrombus growth. These results support the claims of prothrombotic properties of nonionic as compared to ionic contrast media and could explain the clinically encountered thromboembolic complications after the use of nonionic low osmolar contrast media.

The authors compared the renal toxicity of the low osmolality radiocontrast agents, iohexol and ioxaglate, and the ionic agent, iothalamate, at equivalent iodine dose, using experimental models in vitro and in vivo. In isolated perfused rat kidneys, all agents induced comparable biphasic hemodynamic changes, associated with similar declines in glomerular filtration rate (GFR) and tubular necrosis. In two different in vivo models (using multiple insults combined with the administration of radiocontrast), iothalamate appeared to induce more severe morphologic injury. Despite similar nephrotoxic potential in vitro, the newer radiocontrast agents, iohexol and ioxaglate, cause in vivo less renal injury than iothalamate in the experimental models.

We have compared the renal effects of ioxitalamate, ioxaglate, and iopamidol in patients with chronic renal failure. Sixty consecutive patients with an estimated creatinine clearance (ECRCl) less than 60 ml/min were randomly assigned to receive either ioxitalamate, iopamidol, or ioxaglate. All patients received 500 cm3 isotonic saline before the procedure. Serum creatinine and ECRCl were estimated before, 1 and 2 or 3 days after the procedure. There was no statistical difference between the three groups with respect to age, sex, weight, renal function, amount of iodine, and type of procedure. Mean serum creatinine and ECRCl remained unchanged after administration of contrast media. No patient had nephrotoxicity or acute oliguria requiring dialysis as a result of the administration of contrast material. The number of patients with an increase in the serum creatinine level greater than 10% from the basal value did not differ in the treatment groups. The maximal increases in serum creatinine were 52 mumol/l (29%) in the ioxitalamate group, 56 mumol/l (18%) in the ioxaglate group, and 57 mumol/l (23%) in the iopamidol group (p = NS). Using a population carefully randomized and matched for renal insufficiency, we could not show any differences in nephrotoxicity between these three contrast agents. Clinically serious renal impairment was uncommon in our study, regardless of the contrast agent used. However, the interpretation of these favorable findings requires a cautionary note. All patients in this study were well hydrated before and after uro-/angiography, and none had a recent renal injury or a treatment with a nephrotoxic agent that would predispose to injury from contrast material.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Various water soluble contrast media (WSCM) were injected subcutaneously into 970 hind feet of 485 rats. Gross morphologic changes were seen after the injection and analyzed as a function of various physicochemical characteristics of WSCM. The WSCM of larger volume, higher osmolality, higher iodine content, and meglumine salts rather than sodium salts caused more severe tissue damage; younger rats showed more severe tissue damage by WSCM of high osmolality.

Sodium iothalamate was injected intravenously into mice to test the hypothesis that reactions to contrast media are controlled by the central nervous system. Particular emphasis was placed on (a) the effect of the limbic portion of the brain on the hypothalamus and (b) the outflow through the autonomic nervous system. Diazepam and hexamethonium significantly affected the LD50; in addition, in comparison trials with control mice, they markedly decreased the death rate (p < 0.0005). High doses of methylprednisolone sodium succinate, given every 6 hours before the contrast medium, had no effect.

Groups each consisting of ten patients underwent lumbar and cervical myelography with metrizamide and iopamidol, together with a control group of ten patients who underwent lumbar punctures only. These groups were studied with a psychopathometric test procedure in order to demonstrate and quantify mental disturbances. It was shown that in contrast to myelography with iopamidol, mild mental disturbances are common after myelography with metrizamide. The severity of the mental disturbances after myelography with metrizamide was dependent on the quantity of contrast medium which diffused into the intracranial space after myelography, suggesting a dose-related neurotoxic effect of this substance. Such a correlation was not found with iopamidol.

Intravenous injections of ionic contrast media increase extravascular lung water in patients with elevated left atrial pressure, particularly in the presence of myocardial ischemia. The authors compared bolus injections of sodium methylglucamine diatrizoate and iopamidol on extravascular lung water at several levels of left atrial pressure in dogs. Methylglucamine increased lung water by a maximum of approximately 25-30% above baseline levels at low (less than 3 mm Hg), moderate (approximately equal to 15 mm Hg), and elevated left atrial pressures (greater than or equal to 25 mm Hg). At matched pressures, the peak change in lung water in the dogs given iopamidol was +4%, +7%, and +6%, respectively. In dogs with myocardial ischemia, the differences were even more pronounced (+45%, +60%, and +70%, respectively, for ionic media, and +7%, +12%, and +21% for iopamidol). The authors caution against using ionic contrast media in patients with left ventricular dysfunction, particularly associated with ischemia. In such cases, non-ionic media appear safer.

High intravenous doses of diatrizoate are known to induce pulmonary edema in the rat. The newer generation of contrast media--nonionics and monovalent dimers--are considered less toxic than diatrizoate. In this study we evaluated the degree of pulmonary edema induced by a high dose (6 g I/kg) of these new agents and found that Ioxaglate produced higher lung weights than Renografin 60 and Iopamidol. Iohexol and Amipaque did not induce a significant degree of edema. The model used in this study demonstrates distinct differences in pulmonary toxicity among these new agents, when given in doses exceedingly higher than given in clinical practice.

Monolayer cell culture techniques for neuronal and glial cells and fibroblasts were used for the investigation of the direct toxicity of x-ray contrast media. The effect of various concentrations of sodium diatrizoate, methylglucamine salts of diatrizoate, iothalamate, iodamide, metrizamide, iocarmate, ioserate, and ioglycamate were studied. The intravenous biliary contrast medium--ioglycamate--was most toxic to all cell types. All the contrast media studied were somewhat toxic to neurons in the concentration of 50 mmol/l and showed variable glial toxicity. In equiosmolar concentrations the contrast media studied showed toxicity on neurons in the following order: iothalamate, diatrizoate, iodamide, ioserate, iocarmate, ioglycamate. Fresh metrizamide solution in equimolar concentrations showed the least toxic effects on neurons but interfered considerably with the growth and survival of glial cells. Metrizamide solution proved to be highly toxic to neurons when refrigerated for two weeks. Methylgucamine iocarmate produced a peculiar swelling of fibroblasts.

The neurotoxicity of four contrast media--iotrol, iopamidol, metrizamide, and ioglunide--was studied by subarachnoid injection in 14 rabbits implanted with four cerebral electrodes. Thirty-four recordings and quantitative analyses were carried out of spontaneous electrical brain activity, seizure activity, and visual- and somatosensory-evoked potentials. The quantitative study of the electroencephalograms showed differences among the four products. All four of the contrast media induced a general slowing of the electroencephalographic activity and, 30 min after injection, slow waves and a shift of the spectrum energy toward the slow frequencies (0.5-3.5 Hz). The slowing of the recording was the least marked with iotrol and recovery of a normal recording was also quickest with iotrol. The quantitative study of electrical seizures and paroxysms revealed higher seizure activity with ioglunide and iopamidol. The study of the evoked potentials does not permit any distinction among the four contrast agents. Metrizamide induced the fewest seizures, but, considering the slow waves and the seizures, iotrol appears to be the least neurotoxic.

Both ionic and nonionic, monomeric and dimeric contrast media were found to release serotonin from intact human platelets in vitro. The monomeric contrast media were compared at the concentration range of 25 mg I/ml. Iothalamate was the strongest and the statistically equal metrizamide iopamidol, and P-297 were the weakest releasers. Monomeric and dimeric contrast media were compared at concentration ranges of 50 and 100 mg I/ml. They ranked, in descending order of serotonin releasing potency: iodipamide, iothalamate, P-127, iopamidol, and a statistically indistinguishable group of the monoacid dimer P-286, the nonionic dimer ZK 74 435, and metrizamide. The capability of contrast media to release serotonin seems to be a composite result of their specific physical and molecular structural properties.

Iosefamate meglumine has attracted attention as a possible hepatobiliary contrast agent for CT scanning. However, its limited hepatic opacification has prevented clinical acceptance. To find a more efficient agent, the efficacy and toxicity of six derivatives of iosefamate were compared with those of the parent compound in dogs. Twenty dogs received intravenous doses ranging from 150 to 600 mg I/kg of one of these seven water-soluble, ionic, dimeric agents. Three control animals received equivalent amounts of physiologic saline. The CT densities of liver, biliary tract, kidneys, and blood were then measured for up to 3 hr. Toxicity tests of liver and kidney function were performed for up to 3 days. Among the new agents, only MI-294, a previously unreported compound, proved to be a slightly more efficient hepatic opacifier than iosefamate (0.40 vs. 0.34 H per mg I/kg, respectively). MI-294 was also the least toxic. However, transient abnormalities in at least one liver function test were observed with every agent at some dose level. One animal died with hepatic necrosis after receiving iosefamate. No renal impairment was noted in any case. MI-294 has advantages over iosefamate as a CT liver and biliary opacifier in dogs. Potential hepatotoxicity of this class of agents needs to be more fully evaluated.

The effects of five iodinated contrast media and of physiologic saline on bladder capacity were studied. It was found that a significantly greater volume of sodium chloride was tolerated than of Cysto-Conray, Conray 30. Hypaque meglumine 30, Hypaque sodium, and Dimer X. Dimer X was tolerated in the smallest volume. The reason for the difference in volume tolerated is not known. The bladder mucosa showed dehydration changes 6 hr after saline cystogram with no change at 24 hr, 48 hr, 7 days, and 3 months. The contrast media produced dehydration and hydropic and desquamative changes in the bladder mucosa with at least one of these changes persisting up to 3 months. There was no significant difference in the severity of the changes produced by the various contrast media. No evidence of inflammatory changes was seen in the bladder mucosa or wall or in the ureter with any of the agents.

A study comparing the effects of diatrizoate, ioxitalamate, metrizamide, ioxaglate, and a 22% sorbitol on aortic endothelia of the rat was performed. In each case 1 ml of the respective solution was injected in a single dose into the aorta. Endothelial damage was seen after injection of metrizamide, diatrizoate, and ioxitalamate. After injection of ioxaglate or sorbitol, only minor endothelial changes were observed.

The effect of diatrizoate, ioxitalamate, metrizamide, and ioxaglate on the aortic endothelium of the rat was investigated using transmission electron microscopy and DNA synthesis autoradiography. One milliliter of each contrast medium, containing 300 mg iodine per ml, was injected into the aorta. The types of lesions seen on electron microscopy and the rate of DNA synthesis seen on autoradiography established the degree of endothelial damage that had been produced. Of the four contrast agents tested, ioxaglate produced the least amount of cellular change.

Omnipaque (iohexol) 350 mg I/ml has been compared with Telebrix (ioxithalamate) 380 mg I/ml in 48 patients undergoing intravenous urography. The contrast medium dose corresponded to 400 mg I/kg body weight. No cardiovascular reactions (BP and pulse rate) were observed. Subjective reactions occurred somewhat more frequently after Telebrix than after Omnipaque. Sensation of warmth was significantly less with Omnipaque (p less than or equal to 0.05). The overall radiological quality was equally good for the two contrast media.

The histologic effects of Amipaque and various commonly used contrast media on mouse peritoneum were studied by intraperitoneal injections of Amipaque 370 mg I/ml and 170 mg I/ml, Conray 300 mg I/ml, Conray Meglumine 282 mg I/ml, Urografin 60% and 76%, Gastrografin and barium sulfate. Amipaque and the other water-soluble media cause no deleterious effects, whereas barium sulfate evokes granulomatous inflammatory reaction. Amipaque is suitable for gastrointestinal studies when leakage into the peritoneal cavity is expected.

The risk of arachnoiditis from aqueous myelographic contrast media has been assayed reliably only in experimental animals. The effect of contrast media on protein and collagen production by fibroblasts in vitro was studied. Iocarmate, metrizamide, and iopamidol added to the culture medium caused cells to produce more protein and collagen. The degree to which the contrast medium stimulated collagen production correlated with the risk of arachnoiditis from the intrathecal use of the contrast medium. In vitro testing appears to be an effective assay for arachnoiditis.

The authors describe an experimental model for the study of nephrotoxicity induced by contrast media, based on a standardized injection combined with occlusion of the renal artery so as to expose the kidney to a high concentration of contrast medium for ten minutes. Iopamidol, ioxaglate, and both isosmolar and hyperosmolar saline were well tolerated, but diatrizoate caused marked radiological and pathological changes. This model may be helpful in studies of the mechanisms underlying contrast medium nephrotoxicity and evaluating differences in toxicity between contrast agents.

Segmental reflexes in the spinal cords of cats anesthetized with chloralose were used to evaluate the neurophysiologic effects of radiographic contrast agents. The exposed lumbar spinal cord was bathed with concentrations of ionic and nonionic agents including saline, sodium meglumine diatrizoate, meglumine iothalamate, meglumine iocarmate, and metrizamide. The following responses were evaluated: flexor and extensor monosynaptic reflex; polysynaptic flexion reflexes; spontaneous ventral root activity. Hypertonic solutions generally produced a transient decrease in all reflex activity for up to 1 hour. Isotonic solutions produced no significant changes in the monosynaptic responses, but an increase in amplitude of polysynaptic responses, and increased spontaneous activity. The usual facilitory effects of flexion reflex on the flexor monosynaptic reflex were unchanged, but the expected inhibitory effect of flexion reflex on the extensor monosynaptic reflex was changed to excitatory. The relative ability to produced these effects was sodium meglumine diatrizoate greater than meglumine iothalamate greater than meglumine iocarmate greater than metrizamide.

The side effects associated with the use of Iotrol were determined in 100 patients and compared with metrizamide and iopamidol in two double-blind studies. The relevance of the distribution of the contrast medium in the CSF space to the occurrence of headache is discussed. The low persistence of iotrol in the brain parenchyma is demonstrated on CT density profiles, compared with metrizamide and iopamidol. Iotrol seems to be the safest contrast substance for intrathecal use.