[Physico-chemical and toxicological profile of gadolinium chelates as contrast agents for magnetic resonance imaging]. / Physico-chimie et profil toxicologique d'agents de contraste pour l'imagerie par résonance magnétique, les chélates de gadolinium.

Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases.

[In vivo imaging for biodistribution and metabolism evaluations of new chemical entities]. / Applications de l'imagerie pour l'étude de la biodistribution et du métabolisme de nouvelles molécules.

Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities.

Contrast medium extravasation injury: guidelines for prevention and management.

Extravasation of contrast material is a well-recognized complication of contrast-enhanced imaging studies. The management of this complication is contentious; therefore, the Contrast Media Safety Committee of The European Society of Urogenital Radiology decided to review the literature and issue guidelines. A comprehensive literature search was carried out. The resulting report was discussed at the 8th European Symposium on Urogenital Radiology in Genoa, Italy. Automated power injection may result in extravasation of large volumes and may or can lead to severe tissue damage. Infants, young children and unconscious and debilitated patients are particularly at risk of extravasation during contrast media injection. Fortunately, most extravasations result in minimal swelling or erythema, with no long-term sequelae; however, severe skin necrosis and ulceration may occur. Large volumes of high osmolar contrast media are known to induce significant tissue damage. Compartment syndrome may be seen associated with extravasation of large volumes. Conservative management is often adequate, but in serious cases the advice of a plastic surgeon is recommended. Based on the review simple guidelines for prophylaxis and management of contrast medium extravasation injuries are proposed.

Physicochemical and biological evaluation of P792, a rapid-clearance blood-pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: To summarize the physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P792, a new monogadolinated MRI blood-pool agent. METHODS: The molecular modeling of P792 was described. The r1 relaxivity properties of P792 were measured in water and 4% human serum albumin at different magnetic fields (20, 40, 60 MHz). The stability of the gadolinium complex was assessed. The pharmacokinetic and biodistribution profiles were studied in rabbits. Renal tolerance in dehydrated rats undergoing selective intrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B4 release were also tested. RESULTS: The mean diameter of P792 is 50.5 A and the r1 relaxivity of this monogadolinium contrast agent is 29 L x mmol(-1) x s(-1) at 60 MHz. The stability of the gadolinium complex in transmetallation is excellent. The pharmacokinetic and biodistribution profiles are consistent with that of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomerular filtration, and its diffusion across normal endothelium is limited. Renal and hemodynamic safety is comparable to that of the nonspecific agent gadolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotriene B4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS: The relaxivity of P792 at clinical field is very high for a monogadolinium complex without protein binding. The pharmacokinetic and biodistribution profiles are consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Experimental and clinical studies are underway to confirm the potential of P792 in MRI.

P792: a rapid clearance blood pool agent for magnetic resonance imaging: preliminary results.

An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r(1) relaxivity in the clinical field for MRI: 29 mM(-1)xs(-1) at 60 MHz, (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.

Comparative effects of ionic and nonionic iodinated low-osmolar contrast media on platelet function with the PFA-100 (platelet function analyzer).

RATIONALE AND OBJECTIVES: This study was designed to (1) compare the effects of ionic (ioxaglate) and nonionic (iodixanol and iohexol) iodinated low-osmolar contrast media (CM) on platelet function in human whole blood by using the new PFA-100trade mark, a "platelet function analyzer"; (2) determine the animal species closest to human with regard to platelet reactivity to CM; and (3) evaluate which element of the ioxaglate solution supports this activity. METHODS: For all studies, platelet adhesion and aggregation were measured using the PFA-100trade mark system with adenosine diphosphate-primed collagen membrane cartridges. Results are shown as the membrane closure time (MCT; the longer the MCT, the greater the antiaggregatory effect) and given as medians. Citrated whole-blood samples from six healthy volunteers were mixed for 1 minute with a 10% (vol/vol) solution of ioxaglate, iodixanol, or iohexol or their respective ionic and nonionic controls (isotonic saline and mannitol). The test solution/control solution ratio for the MCT was calculated for the blood of humans, guinea pigs, rabbits, dogs, and rats. Isotonic saline and iso-osmolar (280 mOsm/kg) and hyperosmolar (560 mOsm/kg) solutions of meglumine hydrochloride, meglumine ioxaglate (560 mOsm/kg), and sodium ioxaglate (600 mOsm/kg) were tested under similar conditions. RESULTS: All three CM caused significant prolongation of MCT when compared with their respective controls (ioxaglate: 300 seconds, ie, "no closure" on the PFA-100trade mark system; iodixanol: 179 seconds; iohexol: 171 seconds; saline: 115 seconds; mannitol: 118 seconds). The antiplatelet effect of ioxaglate was higher than that of iodixanol and iohexol (P < 0.05). The animal species tested did not differ significantly from the human species with regard to an effect of their blood on MCT. Both ioxaglic acid salts caused a higher prolongation of MCT when compared with saline (sodium salt: 259 seconds; meglumine salt: 212 seconds; P < 0.05 vs. saline) but not versus the ioxaglate commercial solution. Conversely, both iso- and hyperosmolar solutions of meglumine hydrochloride (108 and 128 seconds, respectively) did not lengthen MCT versus saline, but their MCTs were shorter than that of the commercial solution of ioxaglate (P < 0.05). CONCLUSIONS: The ionic CM ioxaglate displayed a greater antiaggregatory effect on human platelets than did both iso-osmolar (iodixanol) and hyperosmolar (iohexol) nonionic CM. This effect seems to be linked to the ioxaglic moiety, because neither osmolality nor sodium or meglumine appeared to play a significant role.

Preclinical profile of the monodisperse iodinated macromolecular blood pool agent P743.

RATIONALE AND OBJECTIVES: To summarize the chemical synthesis, physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P743, a new macromolecular iodinated contrast medium. METHODS: The synthesis and molecular modeling of the iodinated macromolecule P743 are described. The pharmacokinetic profile was established in rabbits and rats. Acute toxicity in mice, renal tolerance in normal rabbits, and renal tolerance in uninephrectomized, dehydrated rats undergoing selective intrarenal injection was evaluated. In vitro permeability effects on isolated mastocytes and on the coagulation pathways were carried out. Computed tomography vascular imaging was performed after intravenous injection of P743 (300 mg I/kg) in rabbits and compared with the nonspecific nonionic agent iobitridol. RESULTS: P743 is a monodisperse, macromolecular iodinated contrast medium. In both rabbits and rats, P743 showed a pharmacokinetic profile consistent with that of a rapid-clearance blood-pool agent. Its diffusion through the endothelium was found to be low in vitro, thus confirming early confinement of this macromolecule, unlike nonspecific contrast media. In both species, P743 was excreted by glomerular filtration. Acute toxicity disclosed no mortality at the highest volume that could be injected into mice, leading to a median lethal dose greater than 8.9 g I/kg. Renal tolerance was found to be good in both euvolemic rabbits and uninephrectomized, dehydrated rats. No histamine or leukotriene B4 release was found on RBL-2H3 isolated mastocytes. P743 did not interfere with the coagulation pathways. Imaging experiments confirmed that P743 remains in the vascular compartment for a longer time than does iobitridol, thus allowing vascular enhancement that is twice as high as that of iobitridol in the recirculation phase. CONCLUSIONS: The pharmacokinetic and imaging profiles of P743, a new, monodisperse, macromolecular blood-pool iodinated contrast medium, were consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Further experimental imaging studies are required to define the clinical interest in such molecules.

Reversibility of experimental acute renal failure in rats: assessment with USPIO-enhanced MR imaging.

The purpose of this study was to evaluate the potential reversibility of kidney lesions in an experimental model of acute renal failure using ultra-small particles of iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging. This study was conducted in 21 uninephrectomized rats using a model of iodinated contrast media-induced renal failure. Thirteen rats received selective intraarterial renal administration of diatrizoate (370 mg/ml) and were compared with two control groups, including six animals injected with saline and two noninjected animals. MR imaging was performed 28 hours, 8 days, and 22 days after the procedure. Each MR session included axial and coronal T1- and coronal T2-weighted images before and after intravenous administration of 60 micromol Fe/kg of USPIO. The rats were sacrificed immediately after the last MR session for pathologic evaluation. MR images were qualitatively and quantitatively interpreted with respect to pathologic data, and differences were statistically studied. At day 22, histology showed 4 severely diseased kidneys with focal areas of necrosis, 5 mildly diseased kidneys with tubular vacuolization, and 12 normal kidneys. On quantitative data, a high correlation between the percentage of negative enhancement and histologic data was observed (P < 0.05). Qualitative interpretation showed a sensitivity and specificity of USPIO-enhanced T2-weighted MR images of 88% and 91%, respectively. Follow-up enhancement curves showed a constant increase of intrarenal USPIO negative enhancement in normal kidneys between day 1 and day 22, whereas all severely involved kidneys displayed higher USPIO negative enhancement at day 1 without significant changes over time until day 22. USPIO may be useful for in vivo follow-up of the reversibility of experimentally induced iodinated contrast media renal impairment in animals.

Renal safety pharmacology: value of sensitized experimental models.

The kidneys are an important target for toxic effects of drug candidates. It is mandatory to select accurate, clinically relevant parameters in order to be in a position to detect putative nephrotoxic effects during the safety pharmacology programme. The glomerular filtration rate appears to be of major interest since it is associated with the definition of acute renal failure. Measurement of the renal blood flow, proteinuria, enzymuria, fractional excretion of sodium, etc. are also highly useful to detect any possible renal impact of a new compound. Although the rat is, by far, the most widely used animal species, there are no specific (clinically relevant) reasons to choose it. Various parameters may vary according to the species, sex, strain, age, etc. Since in most cases acute renal failure occurs following administration of drugs in patients with pre-existing risk factors, it is suggested that sensitized animal models be validated and used (salt depletion, dehydration, co-administration of pharmacologic agents, etc.).

Effects of non-ionic monomeric and dimeric iodinated contrast media on renal and systemic haemodynamics in rats.

Non-ionic dimeric contrast media (CM) are a new class of CM which are iso-osmolar with plasma. The aim of this study was to investigate their effects on systemic and renal haemodynamics. The non-ionic dimeric CM iodixanol and the non-ionic monomeric agent iobitridol (both at a dose of 1,600 mgI/kg) were compared in terms of their effects on systemic blood pressure (BP) and renal blood flow (RBF) in two strains of rats (Wistar and Sprague Dawley). Iodixanol significantly lowered BP in Wistar rats (-33 +/- 9% of baseline, 10 min post-injection, P < 0.001 vs. saline and iobitridol). Iobitridol had virtually no effect on BP. Iobitridol and iodixanol significantly decreased RBF. This effect was more marked following injection of the dimer rather than the monomer (iodixanol: -32 +/- 13% iobitridol: -20 +/- 4 of baseline at 16 min, P < 0.05). For both agents, RBF was still decreased 50 min following injection (iodixanol: -30 +/- 11%, and iobitridol: -20 +/- 5% of baseline). Iodixanol also decreased RBF in Sprague Dawley rats, while BP remained unchanged. This suggests that changes in BP/RBF autoregulation do not account for the renal haemodynamic effects of this agent. When measured 2 h following injection, the iodixanol-induced renal hypoperfusion was still detectable (-29% vs. saline-treated rats), although not significant (P = 0.06). This effect was no longer observed 4 h following injection. Increasing the saline infusion rate (18 mL/h vs. 2 mL/h) during the experiment did not significantly decrease the effects of iodixanol on BP and RBF in Wistar rats. In spite of its iso-osmolality, iodixanol, a non-ionic dimeric CM, depressed RBF and BP significantly more than iobitridol, a monomeric non-ionic agent, in Wistar rats. This effect was long-lasting and was not alleviated by increasing the hydration rate.

Influence of the viscosity of iodixanol on medullary and cortical blood flow in the rat kidney: a potential cause of Nephrotoxicity.

The aim of the present study was to investigate the effects of four iodinated contrast media on cortical, inner medullary and outer medullary blood flow in the rat kidney by using laser-Doppler flowmetry. The high-osmolar contrast medium diatrizoate did not significantly modify medullary perfusion but moderately decreased the cortical blood flow when injected at a dose of 1600 mg iodine kg(-1). Similar effects were obtained with the low-osmolar contrast media ioxaglate and iobitridol. In contrast, the new iso-osmolar contrast medium iodixanol induced a dose-dependent reduction of perfusion in all regions tested. This effect was accompanied by concomitant hypotension. The reduction of inner medullary and cortical blood flow induced by iodixanol was partially alleviated by heating the solution prior to injection and subsequently reducing its viscosity. In the outer medulla, however, this procedure did not improve blood flow. These results suggest that lowering the viscosity may palliate the harmful effects of iodixanol on the inner medulla and cortex, but may not protect the outer medulla from hypoxic injury.

Thrombotic risk associated with the use of iodinated contrast media in interventional cardiology: pathophysiology and clinical aspects.

A review of the current knowledge of the anti-thrombotic properties of iodinated contrast media (CM) has been conducted. CM are classified according to their chemical structure, either ionic or non-ionic (monomeric or dimeric). Numerous in vitro and in vivo data show that, although all CM have anti-coagulant properties, ionic molecules are more potent than non-ionic and, furthermore, do not activate resting platelets, unlike non-ionic agents. These properties may lead to a decrease in thrombus formation during interventional procedures. Several clinical trials have shown that CM may play a role in the occurrence of acute thrombotic complications but also in delayed ischaemic events during interventional procedures. A recent meta-analysis showed that, compared to non-ionic monomers, ionic low-osmolar CM reduce the rate of coronary artery abrupt closure, but no significant difference was found with respect to ischaemic complications. Ionic CM lead to a lower deposit of thrombotic materials on catheters and guide-wires. To date, clinical data comparing ionic CM and non-ionic dimers are scarce, significantly heterogeneous and, unlike experimental data, they do not show differences between both classes of CM. Further studies are required to better understand the precise mechanisms of such interactions and to analyse the effect of CM when new antiplatelet agents or new procedures (stenting) are used, to comply with new clinical strategies.

Interference of magnetic resonance imaging contrast agents with the serum calcium measurement technique using colorimetric reagents.

A possible interaction between either linear (Gd-DTPA-BMA and Gd-DTPA) or macrocyclic (Gd-DOTA) gadolinium complexes used as magnetic resonance imaging (MRI) contrast agents and colorimetric technique reagents for the measurement of serum calcium was evaluated on human serum pools, and its mechanism was investigated by means of UV spectrometry and electro-spray ionization mass spectrometry (ESI-MS). The highest concentration tested was 2.5 mM (corresponding to a putative strictly intravascular distribution of the compound) and the lowest dose was 0.2 mM (i.e. about two elimination half lives). Serum calcium was dosed in duplicate by conventional colorimetric techniques involving o-cresol-phthalein complexone (OCP) or methylthymol blue (MTB) as reagents. No interference was detected when mixing Gd DOTA with serum, whatever the concentration. Gd DTPA (2.5 mM) did not interfere with the colorimetric technique either. Conversely, the Gd DTPA-BMA solution induced a concentration-related variation in apparent calcium levels. In the UV experiments, solutions of 2.5 mM MRI contrast media were mixed with OCP or MTB and UV absorption spectra were recorded between 400 and 800 nm. For Gd-DOTA/OCP and Gd-DOTA/MTB, no significant variations in the absorbance were detected. However, in the presence of Gd DTPA BMA, the absorbance of OCP and MTB showed substantial and immediate variations over time. The ESI-MS studies showed a complete displacement of Gd3+ ion in the case of Gd-DTPA BMA. In the presence of OCP, we observed the disappearance of Gd-DTPA BMA and the formation of the free ligand DTPA BMA and a new complex Gd OCP with an original stoichiometry of 2/2. Such a phenomenon did not occur in the case of Gd DOTA and Gd DTPA. The decomplexation of Gd-DTPA BMA in the presence of OCP can probably be explained by the weaker thermodynamic stability of Gd-DTPA BMA compared to that of Gd-DOTA and Gd DTPA.

Role of sodium in contrast medium-induced polymorphic ventricular tachycardia: results in a rabbit model of lengthened QT interval.

RATIONALE AND OBJECTIVES: The authors (a) compared the proarrhythmic effects of ioxaglate (152 mmol/L sodium) and iohexol (no sodium) in a rabbit model and (b) assessed the effect of adding 150 mmol/L sodium to isotonic iohexol. MATERIALS AND METHODS: Either ioxaglate (320 mg of iodine per milliliter) or iohexol (350 mg of iodine per milliliter) was selectively injected into the right coronary artery (1.5 mL over 30 seconds) of 10 rabbits, some of which also received the alpha 1-adrenergic receptor agonist methoxamine. To validate the model, the class III antiarrhythmic agent clofilium was injected intravenously during methoxamine infusion. Frontal electrocardiography was performed continuously to detect polymorphic ventricular tachycardia (PVT). In a second study, the authors assessed the frequency of arrhythmias after injection of isotonic iohexol solution (145 mg of iodine per milliliter), either alone or with 150 mmol/L sodium. RESULTS: Methoxamine significantly lengthened the QT, QTc, and RR intervals (P < .05). The use of clofilium alone induced no PVT, whereas five of eight methoxamine-infused rabbits developed PVT after clofilium injection (P = .03). Both contrast media prolonged the repolarization period. Iohexol alone induced a higher frequency of PVT than did ioxaglate alone (P = .0006). Methoxamine infusion did not potentiate the frequency of PVT in the ioxaglate-injected rabbits. The addition of sodium to isotonic iohexol prevented the occurrence of PVT (P = .0006). CONCLUSION: Although ioxaglate prolonged the repolarization period, it did not cause a higher frequency of arrhythmia when injected in association with methoxamine. Iohexol, which contains no sodium, induced a high frequency of arrhythmia. The addition of a physiologic concentration of sodium to isotonic iohexol can prevent ventricular arrhythmias.

Structure-activity relationship of macrocyclic and linear gadolinium chelates: investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme.

Transmetallation between commercially available solutions of gadolinium (Gd) chelates and the zinc (Zn)-dependent angiotensin-converting enzyme (ACE) was investigated. In vitro, the strongest inhibitions were observed for the linear Gd complexes, Gd diethylenetriamine pentaacetic acid (DTPA) bis-methylamide (BMA) (IC50 = .016 +/- .006 mmol/l) and Gd-DTPA (IC50 = .350 +/- .034 mmol/l). The two macrocycles Gd tetraazacyclododecane tetraacetic acid (DOTA) and Gd-HP-DO3A were similar and 400 times less active than Gd-DTPA-BMA. These effects were mainly due to the presence of free ligand for DTPA and calcium (Ca) chelate in the case of DTPA-BMA because the addition of Zn2+ in the same quantities suppresses their inhibitory effects. In vivo, these two solutions of linear Gd chelates significantly inhibited ACE activity (Gd-DTPA: (67 +/- 9% versus baseline; and Gd-DTPA-BMA: 73 +/- 2% versus baseline at the clinical dose of .1 mmol/kg), whereas no significant effect was observed for the two macrocyclic chelates Gd-DOTA and Gd-HP-DO3A. Formulating the Gd chelate solution with either an excess of free ligand or Ca chelate (to decrease Gd3+ release) in the case of linear Gd chelate may have deleterious biologic consequences.

Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation.

Several studies were undertaken to compare four magnetic resonance imaging (MRI) contrast media (CM) as regards acute haemodynamic effects in rats and to investigate the mechanisms involved. (1) Normotensive rats received a rapid bolus intravenous injection of 0.5 mmol kg-1 of each CM. The effects of Gd-DOTA, Gd-HP-DO3A, Gd-DTPA and Gd-DTPA-BMA on blood pressure (BP) were compared. (2) The haemodynamic effects of Gd-DTPA (0.5 mmol kg-1) were compared to those of isovolumic and isoosmolar Zn-DTPA and glucose solutions. (3) The haemodynamic profiles of Gd-DTPA and Gd-DTPA-BMA were recorded with and without addition of ionized calcium. (4) The mechanism of Gd-HP-DO3A-induced transient rise in BP was investigated by evaluating the effects of phentolamine or diltiazem pretreatment. For (1) the greatest drop in BP occurred following Gd-DTPA (a linear chelate) injection (-18 +/- 2% vs baseline, P < 0.01). Gd-DTPA-BMA, another lineate chelate, also induced a slight but significant reduction in BP (-8 +/- 2% at 45 s, P < 0.05). Gd-DOTA, a macrocyclic CM, had virtually no haemodynamic effects. For (2) the Gd-DTPA-induced drop in BP was greater than that of the osmolality-matched glucose control and lower than that of osmolality-matched Zn-DTPA. For (3) a transmetallation phenomenon versus free ionized calcium is possible in the case of both linear CM (Gd-DTPA and Gd-DTPA-BMA) since Ca2+ significantly reduced the CM-induced decrease in BP. For (4) a transient rise in BP was observed following Gd-HP-DO3A, another macrocyclic chelate, associated with a concomitant increase in stroke volume. This effect was antagonized neither by phentolamine nor by diltiazem. The decrease in BP following injection of Gd-DTPA or Gd-DTPA-BMA may not only be osmolality-related since (a) Gd-DOTA solution, whose osmolality is greater than that of Gd-DTPA-BMA, had a lesser effect, and (b) this hypotensive effect was corrected by a addition of ionized calcium. The transient Gd-HP-DO3A-induced rise in BP is probably the consequence of a positive inotropic effect.

Comparative cytotoxicity of low- and high-osmolar contrast media to human fibroblasts and rat mesangial cells in culture.

RATIONALE AND OBJECTIVES: The authors investigate the relative sensitivity of rat mesangial cells to iodinated contrast media (CM) and control solutions versus less differentiated cells (ie, human fibroblasts) and compare the effects of low-osmolar ionic (ioxaglate) and nonionic (iopamidol) and high-osmolar ionic (diatrizoate) CM on rat mesangial cells. METHODS: The cytotoxic effects of ioxaglate and control solutions of sodium chloride and mannitol were assessed by neutral red uptake in isolated rat mesangial cells and human fibroblasts. In a second series of studies, the cytotoxic effects of ioxaglate, iopamidol, and diatrizoate (0 to 100 mg I/mL) on rat mesangial cells were compared. RESULTS: Rat mesangial cells were more sensitive to the cytotoxic effects of ioxaglate than the less differentiated human fibroblasts between 70 and 100 mg I/mL. A similar discrepancy was observed in the case of control solutions, sodium chloride, and mannitol. Ioxaglate and iopamidol induced a similar level of cytotoxicity in rat mesangial cells whereas the high-osmolar agent diatrizoate was significantly more cytotoxic. However, the calculated inhibitory concentrations of 50% of all three CM were associated with similar osmolalities, suggesting a major role for this parameter in the case of such media. CONCLUSIONS: Rat mesangial cells are more sensitive to the cytotoxic effects of CM and hyperosmolar solutions than the less differentiated human fibroblasts. High-osmolar CM are more cytotoxic than ionic and nonionic low-osmolar CM to rat mesangial cells. Ionicity seems to play no deleterious role at similar iodine concentrations because ioxaglate and iopamidol had equivalent cytotoxic effects on mesangial cells.

Role of endothelium-derived nitric oxide-endothelin balance in contrast medium-induced acute renal vasoconstriction in dogs.

RATIONALE AND OBJECTIVES: The authors evaluated the involvement of nitric oxide and endothelin in radiographic contrast medium-induced changes in renal hemodynamics. METHODS: Eleven anesthetized healthy dogs were each studied during three periods. Thirty minutes before the first, second, and third periods, the dogs received 1 mL per kilogram of body weight of isotonic saline, L-N-nitro-L-arginine-methyl-ester (L-Name, 10 mg/kg intravenously), and L-arginine (500 mg/ kg intravenously), respectively. Renal blood flow (RBF) and mean arterial blood pressure were continuously monitored. The glomerular filtration rate (GFR) was evaluated by means of polyfructosan clearance. RESULTS: Contrast medium induced a significant (P < .05) decrease in RBF and GFR and a significant (P < .05) increase in urinary endothelin excretion. L-Name enhanced the effect of contrast media on RBF and GFR. L-arginine attenuated the effect of L-Name on the contrast medium-induced reduction of GFR. CONCLUSION: These findings support the hypothesis that acute contrast medium-induced intrarenal vasoconstriction may involve an imbalance of endothelial vasoactive agents, nitric oxide, and endothelin, and they confirm the involvement of hemodynamic changes in contrast medium-induced nephropathy.