Role of autocrine stimulation for the effects of cyclic AMP on protein and lipid phosphorylation in platelets activated by particles.

We have compared responses in platelets stimulated with the particulate materials, Intralipid (liposome-suspension) and a potential contrast medium IEEC (1'-(ethyloxycarbonyloxy)-ethyl-5-acetyl-amino-3-(N-methyl-acetyla mino)-2,4,6-triiodo-benzenecarboxylate coated with human serum albumin), with and without forskolin and inhibitors of autocrine stimulation (IAS: an ADP-removing system of creatine phosphate/creatine phosphokinase; RGDS to prevent fibrinogen/fibronectin binding to GPIIb/IIIa; SQ 29.548 as a TXA2 receptor antagonist; cyproheptadine as a serotonin receptor antagonist; BN 52021 as a platelet-activating factor receptor antagonist). The pattern of tyrosine-phosphorylated proteins, phosphorylation of initial lipids and phosphorylation of pleckstrin (P47) were used as markers for early signal transducing responses, while secretion of ADP+ATP and beta-N-acetyl-glycosaminidase were used as final responses. Intralipid showed no platelet activation except for some weak tyrosine protein phosphorylation that was inhibited by elevated cAMP. IEEC induced strong platelet activation that was partly inhibited by increased levels of cAMP and IAS. The inhibition of elevated cAMP seemed to be due to removal of the G protein-mediated activation from secreted autocrine stimulators either by IAS or forskolin. The remaining activity is a pure effect from IEEC which is not affected by elevated cAMP.

Effects of iodinated x-ray contrast media on renal epithelial cells in culture.

RATIONALE AND OBJECTIVES: To study cellular mechanisms that cause contrast media nephropathy, an in vitro system for proximal and distal tubular cells has been established to evaluate the influence of x-ray contrast media on tubular function. METHODS: Confluent cell cultures of the two renal cell lines, proximal tubule (LLC-PK1) and distal tubule (MDCK), were exposed for 20 hours to 0 to 100 mg iodine/mL of the ionic monomer metrizoate, the ionic dimer ioxaglate, and the non-ionic monomer iohexol. Toxicity was assessed by electron microscopy, cell viability, and biochemical assays of brush-border and lysosomal marker enzymes. RESULTS: The results demonstrated a concentration-dependent toxic effect from the contrast media on cellular appearance consisting of an increased vacuolization and on the activity of brush-border and lysosomal marker enzymes in cells and in culture media. CONCLUSION: The results, in which the nonionic x-ray contrast media iohexol appeared to be less toxic than the ionic x-ray contrast media investigated, demonstrated that defined renal cells in culture are valuable tools in studies regarding renal toxicity of x-ray contrast media.

The effect of various contrast media on the activation of plasminogen by streptokinase or recombinant tissue plasminogen activator in vitro.

RATIONALE AND OBJECTIVES: Radiologic contrast media (CM) may influence processes of coagulation and fibrinolysis. In the current study, the effects of various CM on the formation of plasmin were examined in an in vitro buffer system. METHODS: The effects of three clinically relevant concentrations of seven different iodine-containing CM and gadolinium-DTPA on streptokinase (SK) or recombinant tissue plasminogen activator (rt-PA)-induced plasmin formation was monitored using a plasmin-sensitive chromogenic substrate. RESULTS: Contrast media generally had an inhibitory effect at the plasminogen activation step; this effect was particularly noticeable with the ionic CM. CONCLUSIONS: Contrast media influence plasminogen activation by SK and rt-PA in vitro. Ionic CM have a more pronounced inhibitory effect than the nonionic media. The ionic Gd-DTPA shows a less inhibitory effect than the ionic iodine-containing CM. However, they must be regarded separately because of the different chemical composition of the magnetic resonance imaging and x-ray CM.

Effects on the ATP content of cultured cells after radiographic contrast media exposure. Evidence for accumulation of contrast media in cultured cells.

The ATP content of cultured cells after exposure to meglumine-calcium metrizoate, sodium metrizoate, iohexol, iopamidol and saline was studied. Initially, the ATP content diminished rapidly for a short period and thereafter slowly during the incubation. After incubation with contrast media or saline, the ATP content slowly increased to normal when the cells were reincubated with fresh nutrient medium. Different contrast media and saline with the same final osmolality produced a similar effect on the ATP content of the cultured cells. Cellular association of meglumine-sodium diatrizoate, sodium metrizoate, sodium-iothalamate, iohexol and iopamidol was also examined. The established cell line NHIK 3025 as well as primary cultures of human umbilical endothelium were found to accumulate contrast media in a time- and concentration-dependent manner. When the incubation was carried out at 4 degrees C, the cellular accumulation of contrast medium was less than 35 per cent of that seen at 37 degrees C. It therefore seems that energy-dependent processes are involved to some degree.

Effects of iopentol, iohexol and metrizoate on the contractility of the isolated rabbit heart.

Fifteen isolated rabbit hearts were perfused with Krebs' solution according to the Langendorff technique. Before, during, and after perfusion of the heart with iopentol, iohexol and metrizoate at doses 1 ml, 2 ml and 4 ml (350 mg I/ml), ECG and left ventricular contractile force were registered. The contractile force was measured with a strain gauge sutured to the wall of the left ventricle. At each dose 12 perfusions were made. At each dose iohexol and iopentol produced a smaller decrease in contractile force than metrizoate (p less than 0.001). There was no difference in effect on contractile force between iohexol and iopentol.

Effects of iodixanol, iopentol, iohexol and metrizoate on femoral blood flow after injection into the femoral artery of the dog.

The femoral blood flow was measured before, during and three min after random injection of iodixanol, iopentol, iohexol and metrizoate into the femoral arteries of 12 beagle dogs. The doses were 0.15 and 0.30 ml/kg body weight. Concentrations were 320 mg I/ml. The maximal increases in blood flow were (median values are presented and the lower dose is given first): iodixanol 9% and 32%, iopentol 28% and 66%, iohexol 43% and 77%, and metrizoate 161% and 215%. At both doses iodixanol produced significantly smaller flow increase than any other medium. At both doses iopentol and iohexol produced significantly smaller flow increase than metrizoate (p less than 0.005). There was no significant difference between iopentol and iohexol (p greater than 0.1).

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.

Effects of iohexol and metrizoate on myocardial blood flow and metabolism.

In 10 patients coronary sinus blood flow (CSBF) was measured during and after injection of iohexol and meglumine-Na-Ca metrizoate in the left coronary artery. Oxygen saturation, lactate concentration and hematocrit were determined in the aorta and coronary sinus before and after a second injection of the two contrast media. The increase in CSBF was significantly more marked and sustained after injection of metrizoate than after iohexol and myocardial arterio-venous oxygen difference was significantly lower. Myocardial oxygen consumption and lactate metabolism were not adversely affected by any of the contrast media. The fall in hematocrit in coronary sinus blood was significantly greater after metrizoate.

Experimental myocardial ischemia II: radiographic contrast media toxicity.

The comparative effects of meglumine sodium diatrizoate (MSD), sodium meglumine calcium metrizoate (SMCM), and metrizamide (M) were studied in an isolated canine heart preparation. The parameters observed were coronary blood flow (CBF), myocardial contractile force (MCF), positive and negative dF/dt, and perfusion pressure during normal and ischemic perfusion conditions. MSD had an initial negative inotropic effect but baseline MCF returned in 1 min during normal perfusion and 2 min under ischemic conditions. SMCM and M had only a positive inotropic effect under normal perfusion. However, during ischemia, the positive effect of SMCM was followed by a decrease in contractile force. M showed only a positive effect on force during ischemia. Our results indicate that calcium additive may increase the risk of coronary arteriography in patients with severe coronary artery disease.

Cytogenetic in vivo and in vitro effects of low dose radiation and contrast agents.

Chromosome analysis was performed on five persons before and after urographic examination. Despite a small increase in chromosome aberration frequency after the examination, no statistically significant increase was demonstrated. Whole body lymphocytes were analyzed for chromosome aberrations after exposure to low dose radiation, contrast agents and radiation together with a contrast medium. A significant increase in aberration frequencies at the 2.5% level was observed in irradiated blood samples containing the iodized contrast agent metrizoate.

Effects of intracoronary administration of contrast materials on left ventricular function in the presence of severe coronary artery stenosis.

The effects of intracoronary administration of contrast materials on regional and global left ventricular (LV) function were assessed in anesthetized dogs with segmental myocardial ischemia produced by critical stenosis of the circumflex coronary artery. Effects caused by sodium meglumine diatrizoate (R76), sodium meglumine calcium metrizoate (ISO), and metrizamide were evaluated. In the nonischemic state R76 produced an early (0-10 seconds) decrease in LV contractility followed by a late (10-20 seconds) positive inotropic effect. In the presence of regional ischemia there was prolongation of the negative inotropic effect. ISO produced only positive inotropic effects without significant differences between responses in the nonischemic and ischemic states. Metrizamide produced almost no alterations in LV function.

Effect of catheter flush fluids on blood coagulation and aggregation of platelets.

The effect upon blood coagulation and aggregation of platelets of a polysaccharide catheter flush fluid (flush fluid E) was investigated and compared with isotonic saline and Isopaque Cerebral. The result indicates that flush fluid E does not activate the coagulation system.

Electrophysiological and mechanical effects of contrast media on isolated rat atria.

Cardiac complications caused by contrast media may occur during angiocardiography. The present study on spontaneously beating and electrically stimulated isolated rat atrial preparations investigated the direct effects on the myocardium of four different contrast media. A low-osmolar non-ionic compound, metrizamide, was compared with three ionic contrast media having different cation compositions: meglumine-Na-Ca metrizoate, meglumine-Na diatrizoate and meglumine iothalamate. The ionic contrast media at an organ bath concentration of 30 mg I.cm-3 produced a striking shortening of the effective refractory period. In addition, they reduced the spontaneous rate of contractions, prolonged sinus node recovery time and decreased excitability. Meglumine-Na diatrizoate and meglumine iothalamate induced great reductions in contractile force and "force-rate" product. Metrizamide influenced both the electrical and mechanical activities of the isolated rat atrial preparations to a smaller extent than the three ionic contrast media. The present study demonstrated direct arrhythmogenic and cardiodepressive effects of commonly used ionic contrast media. The low-osmolar non-ionic medium, metrizamide, appears to have lower cardiotoxicity than the ionic contrast media.

Effect of angiographic contrast media on the liver. I. Serum concentration of enzymes after coeliacography with balloon catheter in the pig.

In pigs serum concentrations of ASAT, ALAT, gamma GT, AP and amylase were determined during one week after coeliacography balloon catheter for temporary arterial occlusion. One group of pigs was injected with iohexol (non-ionic contrast medium) and another group with metrizoate (ionic contrast medium) and another group with metrizoate (ionic contrast medium). In a control group metrizoate was injected into the lumbar artery. Small and transient increases in serum concentrations of hepatic enzymes and amylase were recorded 180 min to one day after the injection in all 3 groups. No significant differences in enzyme reactions between the groups were observed.

Effects of contrast media on aortic endothelium. Experiments in the rat with non-ionic monomeric and monoacidic dimeric contrast media.

Injury to the aortic endothelium in rats was evaluated under a light microscope by a silver staining method after application of ionic monomeric (diatrizoate and metrizoate), non-ionic monomeric (C29 with different pH and buffers, 593, iohexol and metrizamide) and monoacidic dimeric (ioxaglate) contrast media, and iso- and hypertonic solutions of sodium chloride. In iodine equivalent concentrations the ionic monomers were significantly more toxic than the other contrast media. No significant was found between the non-ionic monomers, monoacidic dimer and sodium chloride solutions equiosmolal to the ionic monomers. Isotonic saline was the least harmful solution.

Coronary angiography with iohexol and other contrast media in the dog. II. Left ventricular contractility and work.

At left coronary angiography in the dog the non-ionic media iohexol, 711 and metrizamide caused a similar reduction of the left ventricular pressure, stroke volume and work as Na/Ca/meglumine metrizoate but less than diatrizoate. After the initial reduction all media produced equal increase in the data, exceeding their preinjection levels. The calcium ameliorating the reduced cardiac function produced by metrizoate did not seem to impose an extra load on the left ventricle during the second phase.