Assays for plasma complement activation by x-ray contrast media

Hemolytic complement activity and a C3a radioimmunoassay (RIA) were investigated for their ability to characterize contrast media (CM) with respect to complement activation. The CM tested were commercial formulations of diatrizoate, iodamide, iothalamate, ioxaglate, iohexol, and iopamidol. When plasma was exposed to CM, the hemolytic complement activity decreased and the C3a concentration increased. The C3a assay had a larger dynamic range and therefore more ability to discriminate among the CM. Using C3a data from pooled plasma or from individual donors' plasma, nonionic iopamidol (as Isovue 300) had lower complement-activating potential (P less than .005 and P greater than .05, respectively) than all of the ionic media based on diatrizoate, iothalamate, iodamide, and ioxaglate. The ranges of mean C3a values generated by saline, nonionic CM, and ionic CM were 48 to 60, 65 to 173, and 807 to 3272 ng C3a/50 microL, respectively. Complement activation was found to correlate with osmolality (r = 0.945, all media) and with molarity (r = 0.994, diatrizoates).     

The effect of low-osmolar ionic and nonionic contrast media on human blood viscosity, erythrocyte morphology, and aggregation behavior

The effects of three low-osmolar radiographic contrast media (CM)--two nonionic (iohexol, iopamidol) and one ionic (ioxaglate)--on red blood cell (RBC) morphology and aggregation behavior, as well as on blood and plasma viscosity, have been studied. Blood taken from normal, healthy individuals and from patients with uremia was investigated. The authors controlled for the effects of dilution, ionic and nonionic hyperosomolality, and specific chemotoxicity. With ioxaglate, the normal biconcave RBC morphology was fairly well maintained. Iohexol produced a mixture of more-or-less normal cells and echinocytes, while iopamidol yielded only echinocytes. Irregular RBC aggregates have been frequently associated with the presence of echinocyte morphology. In the case of ioxaglate, the capacity of normal blood for rouleaux formation was preserved. This appeared to be compatible with an only moderate decrease in low shear viscosity values. In comparison to the normal control group, RBCs from patients with uremia were clearly more sensitive for hyperosmolar stress. It can be concluded that, in contrast to the nonionic CM, the ionic dimeric compound ioxaglate seems to protect human RBCs against hyperosmolar stress by a mechanism unknown at the present.     

Effects of ionic and nonionic contrast media on the blood coagulation system, the fibrinolytic system and platelets

Effects of ionic and nonionic contrast media (CM) on blood coagulation, fibrinolytic system and platelet function were comparatively studied in vitro. By the gross observation of blood coagulation using mixture 2:8 of each contrast media and blood, its total coagulation time was clearly short with iopamidol and iohexol, and no complete coagulation was observed with ioxaglate and diatrizoate for 180 minutes. Anticoagulant effects of all CM were confirmed by the assays of APTT, PT, thrombin time, antithrombin III, FPA, TAT and anti-Xa activity. But, the ionic high osmolar CM (diatrizoate) and low osmolar CM (ioxaglate) showed a greater anticoagulant effect than nonionic CM. Anticoagulant effect of CM on coagulation system may be mainly caused by antithrombin effect. No effects of CM on the fibrinolytic system were observed by assays of the D-dimer, plasminogen and antiplasmin. And all the contrast media produced inhibitory effects of platelet aggregation induced by ADP. Ionic CM tended to have a little stronger inhibitory effect than non-ionic CM. In conclusion, it was suggested that a greater anticoagulant effect of ioxaglate ensures potential safety for thromboembolic complication during angiographic procedure.     

Antiplatelet action of intravascular contrast media. Implications in diagnostic procedures

The antiplatelet action of intravascular contrast media (CM) Renografin-76 (diatrizoate meglumine and diatrizoate sodium) was studied in vitro and in 21 patients undergoing radiodiagnostic procedures. In vitro studies suggested that in Renografin-76, meglumine was the chief constituent responsible for its antiplatelet action. In post-CM plasma from patients, clotting times were prolonged and platelet aggregation greatly impaired, albeit normal aggregation restored within 3 hours. Although changes in global clotting times and platelet aggregation were mostly transient, it is possible that CM usage in patients with thrombocytopenia, sickle cell phenomenon, and on anticoagulant-antiplatelet drugs may present a serious risk to their hemostatic integrity.     

Effect of various contrast media on coagulation, fibrinolysis, and platelet function. An in vitro and in vivo study

An in vitro and in vivo study of the effect of ionic and nonionic contrast media (CM) on coagulation and platelet function is reported. The methods employed were tests for extrinsic and intrinsic coagulation together with a fibrinolytic parameter and aggregation using ADP and collagen as inducers. The in vivo study utilized patients undergoing routine cerebral angiography. The in vitro results showed a modest influence of the nonionic CM in contrast to the ionic. The marked inhibitory effect of the latter was mainly caused by inherent toxicity, osmolality/ionic strength being of minor importance. The in vivo results showed a negligible influence of CM on systemic hemostatic parameters, but catheter-derived samples indicated desirability of premedication with ASA or heparin. The nonionic CM caused less discomfort than the ionic CM.     

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.     

Effects of uro-angiographic contrast media on blood coagulation--a scanning electron microscopic study on time dependent changes of blood clot and a clinical study]

Anticoagulant activity of ionic and nonionic contrast media (CM) was investigated in vitro and in vivo. Based on the time course of FPA and TAT generations and gross examinations of the blood clots on the catheters placed in CM-blood mixtures [an 2 to 8 ratio (20% v/v)]. It was demonstrated that blood coagulation was activated during the period of 20 to 30 minutes when nonionic CM (iopamidol, iohexol) was employed, but no activation of blood coagulation was noted with ionic CM (diatrizoate, ioxaglate). Scanning electron microscopic examinations of the clots on the catheters revealed that fine fibrin meshwork fibers, in which many red blood cells were trapped in bound, were observed with nonionic CM. In contrast, no fibrin mesh was formed with ionic CM after 30 minutes. In vivo, antithrombin III and fibrinogen significantly decreased in the patients who underwent infusion of nonionic CM. Our studies confirmed that nonionic CM show weaker anticoagulant activity than do ionic CM. And these findings account for previous reported thromboembolic complications with the use of nonionic CM. Extreme caution should be therefore exercised when nonionic CM are employed during prolonged angiographic and interventional procedures.     

Contrast media-induced chromosomal damage in human lymphocyte cultures

Ionic (diatrizoate, ioxaglate) and nonionic (iohexol, iosimide, iopromide, and iotrolan) contrast media (CM) were evaluated for their cytogenetic effects in lymphocytes. Heparinized blood was mixed with culture medium RPMI-1640 supplemented with phytohemagglutinin, fetal calf serum, and antibiotics. Plastic tubes containing blood samples were incubated at 37 degrees C in 5% CO2 humidified air for 48 hours. To these cultures, increasing amounts of CM were added and cells incubated for an additional 24 hours. After this exposure, red blood cells were lysed with hypotonic KC1, lymphocyte smears fixed on glass slides and stained with May-Grünwald Giemsa. Chromosomal damage was analyzed by a micronucleus test. All CM tested induced micronuclei in lymphocytes quite significantly (P less than .001) when compared with the frequency of micronuclei in controls. These observations on the genotoxic potential of nonionic CM suggest that factors other than ionic composition and osmolality are involved in clastogenesis; further studies are needed to establish the molecular mechanisms in CM induced chromosomal damage.     

Granulocyte chemotaxis. Influence of radiographic contrast media on the chemoattractive properties of serum

One of the important functions of granulocytes is the ability to respond to a chemoattractive signal by migration. The influence of radiographic contrast media (CM) on the chemoattractive properties of serum was investigated by under agarose technique for chemotaxis. No chemotactic response was seen when serum was incubated with different concentrations of CM after heat inactivation. The CM did not generate the heat stable complement split product C5a-desarg which would have resulted in a chemotactic response. Without heat inactivation all complement available in the serum was activated by the agarose in the chemotaxis assay. Low concentrations of iohexol and iodixanol brought about an increased chemotactic response relative to a reference with saline instead of CM. This may be due to activation of heat labile chemoattractants from other sources than the complement cascade. At high concentrations of all five investigated CM, a decreased number of granulocytes migrated over a shorter distance when compared with the reference, and this may be due to interactions between the CM and chemoattractants or their precursors.     

Knee arthrography: effects of various contrast media and epinephrine on synovial fluid

Changes in synovial fluid leukocytes, total protein, and total complement were studied in 58 patients after they underwent single contrast material-enhanced knee arthrography with ionic (sodium iothalamate, sodium meglumine diatrizoate, meglumine iothalamate) and nonionic (iopamidol, iohexol) contrast media. In 30 of 58 cases, 0.3 mg epinephrine was also injected. In patients examined without epinephrine, a significant increase in the number of leukocytes was observed when sodium iothalamate and sodium meglumine diatrizoate were used. When administered with epinephrine all ionic compounds produced significant leukocytosis; articular reactions were most evident in patients examined with sodium salts. No inflammatory changes in the synovial fluid were observed when nonionic compounds were used. These data suggest that sodium-containing compounds produce a greater reaction in the joint compared with other contrast media, nonionic compounds are better tolerated by the joint, and epinephrine increases the articular reaction to ionic contrast media.     

Acute cardiac tolerance of current contrast media and the new taxane protaxel using iopromide as carrier during porcine coronary angiography and stenting.

RATIONALE AND OBJECTIVES: The systemic tolerance thresholds of modern low-osmolar x-ray contrast media (CM) are similarly high, but their effects on the cardiovascular system and on the coagulation differ. The aim of this study was to comparatively evaluate the cardiovascular tolerability of iopromide, ioxaglate, and iosmin, and of a novel taxane protaxel, dissolved in iopromide, as a carrier, by coronary angiography and stenting. METHODS: Sixteen pigs were randomized into four groups: iosmin (350 mg iodine/mL, n = 4, nonionic dimer), iopromide (370 mg iodine/mL, n = 4, nonionic monomer), ioxaglate (320 mg iodine/mL, n = 4, ionic dimer), and 70-micromol protaxel dissolved in iopromide 370 mg iodine/mL, intended to prevent restenosis. Coronary angiography was performed via the left carotid artery followed by implantation of stents into the left anterior descending and the circumflex arteries. About 80 mL per animal was used in each group. RESULTS: There were no thrombotic complications and no significant adverse events of electrocardiography, blood pressure, or contractility during or after CM injections. There were no differences among the CM tested except that ioxaglate was the only agent showing a significant reduction in dp/dt after 50 seconds compared to iosmin. The values of preinjection parameters were most rapidly regained after iosmin, compared with other CM tested. CONCLUSIONS: The novel iso-osmolar nonionic CM iosmin is well tolerated in porcine coronary angiography and subsequent stenting. The cardiac tolerance of iopromide has not been adversely affected by addition of the cytostatic protaxel.     

Anticoagulant effects of contrast materials: in vitro study of iohexol, ioxaglate, and diatrizoate

It has been reported that clot formation may occur when blood is mixed directly with nonionic contrast medium in a syringe during angiography. To investigate this possibility, we performed three in vitro experiments to determine the anticoagulant properties of a low-osmolar, nonionic contrast medium (iohexol); a low-osmolar, ionic medium (ioxaglate); and a high-osmolar, ionic medium (diatrizoate). In the first experiment, human arterial blood was incubated at room temperature in an angiographic syringe with each of the three media for 60 min, after which the mixture was filtered for clots. In the second experiment, the clotting times of venous blood in heparinized saline or serial dilutions of the three agents were determined. In the third experiment, the partial thromboplastin time of platelet-poor plasma in heparinized saline or serial dilutions of the three agents was measured. No clots were observed in any of the arterial blood samples. Iohexol prolonged the normal 15-min clotting time of venous blood to 160 min, compared with a clotting time of at least 330 min for ioxaglate and diatrizoate. Iohexol prolonged the normal 36-sec partial thromboplastin time of platelet-poor plasma to 40 sec, compared with 50 sec for diatrizoate and 54 sec for ioxaglate. Our data show that iohexol, like ioxaglate and diatrizoate, inhibits clot formation when mixed with blood in a syringe. It prolongs the clotting time to approximately the same degree as 600 U/l of heparinized saline, but to a lesser degree than the other two media. All three media have a minimal effect on the partial thromboplastin time. Our results do not show any risk of clot formation in the usual clinical setting in which there is inadvertent mixing of blood with iohexol, ioxaglate, or diatrizoate in an angiographic syringe.     

Granulocyte adherence is inhibited by radiographic contrast media in vitro.

Different amounts of diatrizoate, ioxaglate, iohexol, iodixanol, NaCl 1,000 mOsm/kg, mannitol 1,098 mOsm/kg, and meglumine (meglumine concentrations corresponding to the content in the diatrizoate solutions) were added to either whole blood or a suspension of granulocytes in autologous plasma, and the adherence to nylon fibers was determined. At high concentrations all the investigated contrast media (CM) inhibited granulocyte adherence. The degree of inhibition was significantly greater when the ionic CM diatrizoate and ioxaglate were used, as compared with the nonionic media. Meglumine solutions at high concentrations also inhibited adherence but significantly less than diatrizoate solutions containing the same amount of meglumine. Diatrizoate showed the greatest inhibitory effect on granulocyte adherence, and significant inhibition could be detected even with a 1.25% solution.     

Muscular and CNS effects of carotid artery administration of contrast media in rabbits

Facial muscle twitching during intracarotid injections of nonionic contrast media has been observed in rabbits. To investigate the cause of this reaction, cortical EEG and facial EMG recordings were made from rabbits receiving selective internal and external carotid artery injections of control solutions (normal saline, mannitol), an ionic contrast medium (meglumine iothalamate), and three nonionic contrast media (iohexol, iopromide, and iotrolan). Internal carotid artery injections with all contrast media, both ionic and nonionic, produced ipsilateral EEG changes in 24 of 28 animals; however, ipsilateral EMG changes and visible twitching were observed only in animals injected with nonionic contrast media. Internal carotid artery injections with control ionic and nonionic solutions (physiological saline and mannitol, respectively) produced no EEG changes in any animals. Mannitol produced only ipsilateral EMG changes and visible twitching in most animals. The severity of the reaction to mannitol was generally less than that to the nonionic contrast media, and this difference was statistically significant when comparing mannitol with iohexol and iotrolan but not with iopromide. External carotid artery injections with nonionic solutions (contrast media and mannitol) produced significantly more severe ipsilateral EMG changes and visible twitching than were recorded with the internal carotid artery injections. Ionic solutions (contrast media and saline) had no effect. EEG changes were not observed after external carotid artery injection of any solution, with the exception of two of the seven animals injected with iotrolan. Angiography demonstrated retrograde filling of the external carotid arterial system from internal carotid artery injection via functioning orbital anastamoses. In contrast, internal carotid arterial vessels were not seen angiographically after external carotid artery injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of iodinated contrast media on blood clotting

Recently, blood clot formation in catheters used for the injection of nonionic contrast media (CM) during angiography has been reported as being due to activation of hemostasis in the catheter. However, CM exhibit inhibitory properties regarding coagulation and platelet functions. The effect on blood clotting of iohexol, iopamidol, ioxaglate, diatrizoate, and ioxitalamate at a ratio of 10% v/v with nonanticoagulated human whole blood was evaluated using the kinetics of fibrinopeptide A (FpA) generation. Blood aliquots were taken every 2 minutes until blood clot occurred. Two groups of contrast media were identified: (1) iohexol and iopamidol, which increased the clotting time, and (2) ioxaglate, diatrizoate, and ioxitalamate, for which all clotting times were over 30 minutes and no FpA generation occurred.     

Modification of platelet aggregation and thromboxane synthesis by intravascular contrast media

Radiographic contrast media (RCM) decreased significantly platelet aggregation in human platelet-rich plasma (PRP) after addition of arachidonic acid (AA) or adenosine diphosphate (ADP). Unlike hypertonic saline, diatrizoate, ioxaglate, and iopamidol (40 and 160 mM) inhibited AA-induced aggregation. One hundred sixty mM ioxaglate inhibited slightly the concomitant formation of immunoreactive thromboxane B2 (TXB2). The ionic RCM ioxaglate (40 and 160 mM) and diatrizoate (160 mM), but not the nonionic iopamidol, decreased the ADP-induced aggregation more than hypertonic saline. When PRP was incubated with different RCM without any aggregating agents or with ADP, the formation of TXB2 was negligible. Results of this study show that inhibition of AA- and ADP-induced platelet aggregation by RCM is partly due to hypertonicity and partly related to the chemical structure of the RCM molecule. The inhibition of AA-induced aggregation is not caused by the lack of formation of aggregatory TXA2.     

Quality of urography and renal clearance of ionic and nonionic contrast media.

The authors evaluated whether urographic quality correlated with patient hydration and the level of their renal function, depending on whether they received ionic or nonionic contrast media. One hundred patients with normal serum creatinine levels were randomly assigned to receive intravenous urography with either an ionic high-osmolar or a nonionic low-osmolar contrast medium. Patient hydration was evaluated by measuring urine osmolality in a sample voided just before the examination. The plasma concentration of iodine was determined in a single blood sample drawn approximately 3 hours later. From these determinations the plasma clearance of contrast medium was calculated. The urograms were assessed blindly with regard to nephrographic and pyelographic opacification, as well as overall diagnostic quality. The clearance varied between 42 and 115 mL x minutes-1 x 1.73 m-2. No systematic correlation of practical significance was found between the clearances and the urogram quality. A high urinary osmolality before the examination tended to improve quality with both media. It is not possible to assess glomerular filtration rate from nephrographic and pyelographic opacification, or from overall quality of routine urograms in patients with normal serum creatinine levels.     

Activation of the complement system and cytokine production by radiographic contrast media in vascular endothelial cells in vitro

The direct effect of four different radiographic contrast media (RCM) on the release of C3a and C5a and the production of IL-1 alpha and TNF-alpha from vascular endothelial cells was examined in vitro. The test RCM were as follows: diatrizoate (ionic monomer), iopamidol (nonionic monomer), ioxaglate (ionic dimer), and iotrolan (nonionic dimer). These were added to serum-free medium and adjusted to a final concentration of 1% (2.8 mg Iodine/ml). Human microvascular endothelial cells were stimulated by serum-free medium containing the test RCM for eight hours. After incubation, the media were aspirated and assayed for the concentrations of C3a, C5a, IL-1 alpha and TNF-alpha. Finally, the cells were harvested by trypsin, and their viability was determined by the dye-exclusion method. Diatrizoate and iotrolan had higher C3a release than the control (p < 0.05). No increase in C5a, IL-1 alpha or TNF-alpha levels was observed with any of the tested RCM, and there was no significant difference in cell viability with any of the tested RCM. The results of this study suggest that diatrizoate and iotrolan activated the complement system through the alternative pathway by directly stimulating vascular endothelial cells. These observations suggest that a direct effect of RCM on vascular endothelium might play a role in the pathogenesis of local drug eruptions due to RCM.     

In vivo comparative antithrombotic effects of ioxaglate and iohexol and interaction with the platelet antiaggregant clopidogrel

RATIONALE AND OBJECTIVES: Experiments were designed to (1) compare the effects of iodinated contrast media (CM) on a rat model of arterial thrombosis, (2) evaluate which element of the ioxaglate solution supports its antithrombotic activity, and (3) investigate the interaction of ionic and non-ionic CM with the antiplatelet agent clopidogrel. MATERIALS AND METHODS: Carotid thrombosis was induced in rats by extravascular application of a filter paper soaked in FeCl3 (35% vol/wt), proximal to an ultrasonic flow probe. (1) The antithrombotic potential of low-osmolar ionic (ioxaglate Na/meglumine) or nonionic contrast media (iohexol and iodixanol) (all 1600 mg iodine/kg, IV) was assessed by measuring the time to occlusion (TTO) of the carotid artery and the thrombus weight (TW). (2) Isotonic saline and iso-osmolar (280 mOsm/kg) and hyperosmolar (560 mOsm/kg) solutions of meglumine hydrochloride, meglumine ioxaglate (560 mOsm/kg), sodium ioxaglate (600 mOsm/kg) and sodium and meglumine ioxaglate (commercial solution) were tested under similar conditions. (3) Interaction with clopidogrel was tested by injecting lower dose of CM (960 mg iodine/kg) 2 hours after clopidogrel (2 mg/kg per os). RESULTS: (1) Ioxaglate prolonged TTO when compared with saline (30.0 +/- 1.1 minute vs. 19.6 +/- 2.4 minutes, P< 0.001), whereas iohexol had no effect (21.3 +/- 1.3 minutes). Ioxaglate's effect was associated with a reduction in TW with ioxaglate versus saline (2.6 +/- 0.4 mg and 4.7 +/- 0.7 mg, respectively, P< 0.05) whereas TW remained unchanged in the iohexol group (4.2 +/- 0.4 mg). The nonionic dimer iodixanol induced a direct vasoconstrictor effect on the carotid artery and was consequently excluded from the study. (2) Neither iso-osmolar nor hyperosmolar solutions of meglumine had any effect on TTO whereas both sodium and meglumine salts of ioxaglic acid prolonged TTO, suggesting that the antithrombotic effect of ioxaglate is mediated by the ioxaglic acid moiety alone as neither meglumine, osmolality or sodium played a significant role. (3) A synergistic effect on TTO was found when ioxaglate was associated with clopidogrel whereas no such effect was observed with iohexol. CONCLUSIONS: These data show a greater in vivo antithrombotic potential for the ionic contrast medium ioxaglate than for the non-ionic contrast medium iohexol and, for the first time, a synergistic effect between a contrast medium and a platelet antiaggregant drug in vivo.     

Cytostatic effects of radiographic contrast media in synchronized cell cultures

The cytostatic effects of conventional high osmolal ionic contrast media (meglumine-calcium metrizoate and Na-metrizoate) and new low osmolal nonionic contrast media (iohexol and iopamidol) in synchronized cell cultures were tested. The cell-cycle prolongation was most pronounced when the contrast media were added in the G1 phase, but there was also a marked effect when the contrast media were added in the S phase or late in the G2 phase. The cytostatic effect even persisted into the first cell cycle following the termination of the exposure. All four contrast media exerted effects stronger than that of equiosmolal saline. Iohexol and iopamidol produced a more severe effect than meglumine-calcium metrizoate and Nametrizoate at equal osmolality. Thus, the cytostatic effect of contrast media cannot be explained only by hypertonicity; the contrast media must have an additional specific cytostatic effect. When the cytostatic effect was related to iodine concentration, the new low osmolal nonionic contrast media influenced the cell cycle less than the conventional high osmolal ionic contrast media.