Reduced cerebrospinal fluid production in the rat and rabbit by diatrizoate. Ventriculocisternal perfusion.

The effect of the radiographic contrast agent diatrizoate on cerebrospinal fluid (CSF) production was determined by ventriculocisternal perfusion. The lateral ventricle and cisterna magna of anesthetized rats and rabbits were cannulated stereotactically and perfused continuously with a H-3 inulin-labeled artificial CSF solution. Baseline collections of CSF began after steady state outflow was established; then, diatrizoate was administered intravenously for 1 hour. The baseline rate of CSF production was compared with that measured during and after the diatrizoate infusion. The baseline CSF production rate was 3.7 +/- 0.1 and 18.6 +/- 1.4 microL/minute in the rat and rabbit, respectively. Diatrizoate decreased the CSF production rate to 2.9 +/- 0.1 and 13.9 +/- 0.9 microL/minute. This reduced rate continued for at least 90 minutes after the end of the diatrizoate infusion, averaging 3.0 +/- 0.1 and 12.0 +/- 0.6 microL/minute in the rat and rabbit, respectively. These results confirm that decreased CSF production induced by the intravenous administration of diatrizoate is not species specific and is observed with the ventriculocisternal perfusion method of measuring CSF production rates.

Contrast media-induced blood-brain barrier damage. Potentiation by hypertension.

Large doses of an ionic contrast medium (CM) can disrupt the blood brain barrier (BBB) osmotically. Acute hypertension (HT) also is known to open the BBB. We tested the hypothesis that these two factors potentiate each other in a rat model. Adult male Wistar rats, anesthetized with pentobarbital, underwent tracheostomy. An external carotid artery catheter was placed so that it opened into the patent common carotid artery; arterial blood pressure was recorded continuously. Of three groups of animals, two (HT) groups received metaraminol to elevate and maintain blood pressure in the range of 165 to 190 mm Hg. The third (normotensive) group received an equivalent volume of saline. Five minutes after injection of Evan's blue, either sodium/meglumine diatrizoate or saline was infused into the carotid cannula (2 mL in 30 seconds). Twenty minutes later the cardiovascular system was flushed with saline, and the brain was removed, frozen, and sectioned for gross and histofluorescent microscopic examination of BBB opening. The carotid injection of CM at a concentration of 1000 mosm/kg water did not produce gross evidence of BBB opening in the normotensive group. Similarly, hypertension at levels below 190 mm Hg did not produce gross evidence of opening in the carotid saline group. However, the combination of carotid CM and HT produced significant BBB opening. These results suggest that the risk factor of acute HT potentiates CM-induced BBB opening.

Penetration of vascular contrast media into brain tissue and cerebrospinal fluid. An experimental study in rats.

Recent studies suggest that intravenously administered contrast media (CM) penetrate into cerebrospinal fluid (CSF), and the concentration of CM in CSF increases significantly following acetazolamide or probenecid pretreatment. However, corresponding levels of CM in brain tissue and extracellular fluid (ECF) have not been reported. Adult anesthetized rats were injected intravenously with sodium/meglumine diatrizoate and iohexol. The control group received no pretreatment, and the pretreated group received acetazolamide and probenecid before the CM. The amount of each contrast agent was measured in brain tissue and in CSF by high performance liquid chromatography. Pretreated animals attained significantly higher CSF concentrations of diatrizoate and iohexol than control animals. However, tissue ECF concentrations in pretreated animals were not significantly different than in control animals for either agent. The results are consistent with the idea that a flushing action of CSF helps to remove CM from the brain ECF.

Decreased cerebrospinal fluid production by intravenous sodium diatrizoate.

Intravenous administration of the radiographic contrast agent sodium diatrizoate (50%, 2ml/kg) significantly decreased cerebrospinal fluid (CSF) production in dogs for up to 40 minutes as measured from a lateral ventricular cannula. The magnitude of this decrease exceeded the decrease induced by hypertonic saline. Since hypertonicity could not explain the decrease, an enzymatic mechanism was sought. Choroid plexus carbonic anhydrase (CA) has been implicated in the elaboration of CSF. The assay of CA activity was a colorimetric measure of the hydration of CO2 where reaction time is related to the amount of active CA present. The inhibition of dog red blood cell and choroid plexus CA by sodium diatrizoate was compared with that by the known CA inhibitor acetazolamide. Acetazolamide (48 mM) produced almost complete inhibition whereas the inhibition by sodium diatrizoate (84 mM) was not significantly different from control. These results suggest that neither hypertonicity nor CA inhibition is the cause of the reduced CSF production after intravenous injection of sodium diatrizoate in dogs.

Pharmacologic manipulation of the flushing action of cerebrospinal fluid. Effect on CSF diatrizoate levels.

The continual production and absorption of cerebrospinal fluid (CSF) provides for the dilution and removal of potentially toxic substances from the central nervous system (CNS). This study quantified changes in the CSF concentration of diatrizoate following pretreatment with various drugs that alter CSF production. Adult rats, pretreated with one of ten drugs or normal saline (control) and anesthetized, received sodium diatrizoate (2 mL/kg, IV). Blood and CSF were sampled 2 hours later, and the diatrizoate concentrations were measured. Serum diatrizoate levels in the control group averaged 144.3 micrograms/mL. There were no significant differences in serum levels between control and pretreated groups. The CSF diatrizoate concentration in the control group averaged 10.8 micrograms/mL. Pretreatment with acetazolamide, ritodrine, or probenecid resulted in a significant increase in the CSF concentration, to 24.7 micrograms/mL or 228% of control in the case of acetazolamide. Pretreatment with salicylate, carbachol, or aminophylline resulted in significantly lower CSF diatrizoate levels than control; 3.2 micrograms/mL (30% of control) for carbachol. Digoxin, furosemide, dibutyryl cAMP, or dexamethasone pretreatments had no significant effect on CSF diatrizoate concentrations. Thus, a wide range of drugs may significantly alter the concentration of diatrizoate in the CNS. Drug-induced changes in the rate of CSF production may be responsible for this action.

Intravascular contrast media and the blood-brain barrier. Testing the new nonionic agent ioxilan.

The effects of diatrizoate, iohexol, and ioxilan on the blood-brain barrier (BBB) were investigated in normal and hypertensive rats. Anesthetized Wistar rats received 14C-inulin as an indicator for BBB disruption. Diatrizoate, iohexol, or ioxilan (350 and 175 mgI/mL) or normal saline was then injected into the carotid artery (2 mL in 30 seconds). Twenty minutes later, the cardiovascular system was flushed, the brain removed, and each hemisphere was digested. BBB disruption, expressed as counts/minute/mg protein, was compared for each hemisphere in each group by analysis of variance. BBB damage in the diatrizoate-350 group was significantly greater than that in all other groups. No significant BBB damage resulted from iohexol or ioxilan relative to normal saline.

Opiate involvement in contrast media-induced blood pressure changes.

The intravenous administration of contrast media (CM) often alters blood pressure (BP). Osmolality plays a role, but the magnitude and even direction of change varies under similar (osmotic) conditions, indicating the involvement of other mechanisms. Male Wistar rats, anesthetized with pentobarbital, received sodium/meglumine diatrizoate, iohexol, or normal saline, 4 ml/kg, via a tail vein, while blood pressure was recorded continuously. Additional groups were pretreated with the opiate antagonist, naloxone (1 mg/kg, IV), or with an equal volume of normal saline 5 minutes prior to the diatrizoate injection. Comparisons of BP change were made with the Student's t-test. Diatrizoate caused a significant (P less than .0002) increase in BP relative to the saline control group, iohexol did not. Thus, the increase with diatrizoate was significantly greater than with iohexol (P less than .00006). Neither the saline nor naloxone pretreatment altered BP significantly. Saline pretreatment did not alter the significant increase in BP produced by the diatrizoate. However, the diatrizoate-induced increase in BP was prevented by the naloxone pretreatment and was significantly less than after the saline pretreatment (P less than .0001). Based on these and previous results, the authors hypothesize that release of endogenous opioids may play a role in BP changes caused by intravenous CM and that significant CM-induced changes may be prevented pharmacologically with the selective opiate blocker, naloxone.

Iohexol inhibits adenylate cyclase.

Previous studies demonstrated that the intravenous administration of the ionic radiographic contrast agent, diatrizoate, and the nonionic agent, iohexol, causes a decrease in the rate of cerebrospinal fluid (CSF) production. Evidence suggests that adrenergic-mediated adenylate cyclase (AC) activity controls CSF production. Diatrizoate was found to inhibit AC activity. The authors now report that iohexol inhibits activity of this enzyme. Adenylate cyclase activity was measured in membrane fractions of bovine choroid plexus in the presence of various concentrations of iohexol. A concentration-dependent inhibition of basal and adrenergic-stimulated AC activity by the contrast agent was observed. The concentration of iohexol that produced a 50% inhibition was about 2.3 mM. This is similar to the concentration of diatrizoate that produced equivalent enzyme inhibition. These results support the contention that one mechanism for the action of contrast media in reducing CSF production involves inhibition of AC activity.

Diatrizoate levels in cerebrospinal fluid following intravenous administration. Role of fluid production rate.

The central nervous system (CNS) may be highly susceptible to the toxic effects of conventional contrast media (CM). The current study quantifies levels of diatrizoate in canine cerebrospinal fluid (CSF) following intravenous administration and examines how these levels change as CSF production rate is reduced. Cerebrospinal fluid was collected continuously from the cisterna magna of anesthetized dogs before and after the administration of diatrizoate (1 mL/kg bolus followed by a 12.5 microliters/kg/minute maintenance infusion, IV). The influence of CSF production rate on CSF diatrizoate levels was examined by injecting acetazolamide (30 mg/kg, IV). Diatrizoate levels in CSF were quantified by a high performance liquid chromatography (HPLC) method. Baseline CSF production was 81.5 microliters/minute and dropped to 37.4 microliters/minute following diatrizoate and to 29.5 microliters/minute following acetazolamide. The concentration of diatrizoate in CSF averaged 166 micrograms/mL and increased significantly to 379 micrograms/mL following acetazolamide with no change in serum concentration (1.3 mg/mL). These experimental results suggest that appreciable quantities of intravenously administered diatrizoate may enter the CNS, and that these quantities may increase significantly with reduced CSF production. This may help to explain CSF enhancement and certain CNS toxicity after the intravenous administration of CM.

Tissue fluid shifts during renal arteriography with conventional and low osmolality agents.

The osmotic effects caused by conventional and low osmolality radiopaque agents have been studied in the isolated perfused canine kidney. Changes in vein flow, hematocrit, osmolality, and iodine content were measured at injection doses of 0.25 and 0.5 ml/kg (300 mgI/ml). Increases in osmolality and decreases in hematocrit were significantly greater with the conventional ionic monomer meglumine/sodium diatrizoate than with the low osmolality agents iohexol, iopamidol, and ioxaglate. The standard renal vein flow response for all agents was an increase (loss of renal water) followed by a decrease (gain of renal water). Diatrizoate produced the greatest increase in outflow at 0.25 ml/kg, but the differences between agents were not statistically significant. At the 0.5 ml/kg dose the differences in peak renal vein flow between agents were negligible. Renal vein iodine was highest with the dimer, ioxaglate and lowest with the diatrizoate. The nonionics iohexol and iopamidol produced essentially the same renal vein iodine levels and clearance. The new low osmolality agents have significantly less effect on osmolality and hematocrit and produce higher venous iodine levels than a conventional ionic monomer. The only difference between the low osmolality agents was the higher venous iodine seen with the dimer ioxaglate.

Deleterious synergism of a cardiac glycoside and sodium diatrizoate.

Studies were performed in mice to determine if the cardiac glycoside, Strophanthin-K, and the contrast medium, sodium diatrizoate, interact synergistically to produce death. Intravenous injections of lethal and near lethal doses of the two agents produced a significantly greater mortality than the individual agents alone. Low or near clinical doses of Strophanthin-K, when given with doses of diatrizoate in the lethal range, produced mortalities significantly greater than did the diatrizoate alone. Similarly, low or near clinical doses of diatrizoate given with doses of Strophanthin-K in the lethal range produced mortalities significantly greater than for the Strophanthin-K alone. Isotonic or hypertonic saline, when substituted for diatrizoate or Strophanthin-K did not produce synergistic increases in mortality. Thus neither the injection volume, nor agent hypertonicity or ionic strength, seem to be the primary factors in the synergism to produce death. The diatrizoate anion appears to be an important factor. Until more information is available from other animal models it appears that patients receiving cardiac glycoside should be considered to have a higher than normal risk of serious reactions to contrast media in intravenous urography.

In vitro models for testing the metabolic effects of myelographic contrast media.

Water-soluble nonionic x-ray contrast media have greatly improved the quality and safety of myelography. Toxic side effects are still observed however. The side effects are generally worse with the first nonionic agent, metrizamide, which has a glucoselike side group. Two in vitro models were developed to examine the effects of contrast media on glucose metabolism. Using rat hippocampus slices, the authors observed significant depression of carbon dioxide production by metrizamide and by deoxyglucose, a known metabolic inhibitor. Iohexol and iopamidol did not cause significant depressions. In rat brain synaptosomes the authors did not observe a depression of the uptake of deoxyglucose 14C by any media tested. These studies indicate that metrizamide can create metabolic depression but that it does not compete with glucose for the membrane glucose carrier.

The effects of iodixanol and iopamidol on hemodynamic and cardiac electrophysiologic parameters in vitro and in vivo.

Iodixanol is a new, nonionic, dimeric contrast medium which, in concentrations appropriate for radiographic use, is hypotonic with respect to plasma. The purpose of these in vivo and in vitro studies was to compare the effects of iopamidol, iodixanol formulated to isotonicity with sodium salts (sodium formulation), and iodixanol formulated to isotonicity with sodium, calcium, and magnesium salts (cationic formulation) on hemodynamic and electrophysiologic parameters. In vitro, the spontaneous rate of contraction by guinea pig right atrial and force development by right ventricular papillary muscles were evaluated in the presence of 1% to 100% (v/v) of the three contrast media. Iopamidol significantly (P less than .05) decreased the rate of atrial contraction to a greater extent than either formulation of iodixanol. Iopamidol decreased papillary muscle force development more than the sodium formulation of iodixanol (P less than .05). The cationic formulation of iodixanol had little effect (less than 30% change) on papillary muscle force development at concentrations up to 100%. The contrast media were also injected into the left coronary arteries of open-chest, anesthetized dogs at 0.8 mL/second for 5 to 30 seconds. All contrast media increased (P less than .05) systolic blood pressure (SBP), mean arterial pressure (MAP), and peak left ventricular pressure (LVP). Iopamidol increased LVP and LV end diastolic pressure to a greater extent (P less than .05) than the cationic formulation of iodixanol. We conclude that iopamidol affected cardiovascular parameters more than iodixanol.

Role of angiotensin II in renal hemodynamic functions during the initial stages of acute ureteral obstruction.

This investigation examines the role of Angiotensin II in renal hemodynamic functions during acute unilateral ureteral obstruction (UUO) in a dog model. An electro magnetic flow probe was utilized to assess renal blood flow while the arteriovenous extraction technique of technetium 99m DTPA was utilized for the assessment of changes in filtration fraction and glomerular filtration rate. The effects of Angiotensin II receptor blockade on renal hemodynamic functions during acute UUO was evaluated in six dogs and compared to acute ureteral obstruction without receptor blockade in seven dogs. Angiotensin II blockade with (Sar1, Thr8)-Angiotensin II during UUO led to a striking increase in renal blood flow that was significantly different in comparison to normalized values from UUO alone (+delta 63 +/- 17 vs. +delta 22 +/- 6% at 30 min; p less than 0.05). There were, however, no significant differences in the magnitude of the decrease in filtration fraction and glomerular filtration rate in comparison to UUO alone. This investigation demonstrates that Angiotensin II has an inhibitory effect on the initial increase in renal blood flow with acute UUO. The possibility of successful pharmacologic intervention in the setting of UUO can be examined using animal models similar to the one described here. Pharmacologic treatment in the setting of acute UUO in patients might permit better preservation of renal function.

Iodinated nanoparticles for indirect computed tomography lymphography of the craniocervical and thoracic lymph nodes in normal dogs.

RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an interstitially or intraperitoneally delivered iodinated particulate contrast agent for computed tomography (CT) lymphography of the craniocervical and thoracic lymph nodes. METHODS: We injected 2-4 ml of 15% wt/vol iodinated nanoparticle suspension subcutaneously, submucosally, or intraperitoneally in eight normal dogs. CT and plain radiographic images were obtained prior to contrast administration and 4 hr, 24 hr, and 7 days after injection. Correlation was made to detailed postmortem assessment. RESULTS: CT images showed enhancement of regional nodes draining injection sites. Mean attenuation of opacified nodes was 313 +/- 297 (mean +/- standard deviation), 536 +/- 453, and 492 +/- 372 Hounsfield units at 4 hr, 24 hr, and 7 days postinjection, respectively. Lymph node opacification on CT images correlated well with node location found at postmortem. CONCLUSION: Craniocervical and thoracic lymph nodes can be effectively opacified from interstitial or intraperitoneal delivery of this iodinated nanoparticulate contrast agent.

Indirect computed tomography lymphography of subdiaphragmatic lymph nodes using iodinated nanoparticles in normal dogs.

RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an iodinated particulate contrast agent for indirect computed tomography (CT) lymphography of normal subdiaphragmatic lymph nodes in dogs. METHODS: Four milliliters of a 15% (wt/vol) iodinated nanoparticle suspension was injected into the gastric, colonic, rectal, or cervical submucosa, loose paraprostatic fascia, or metatarsal subcutaneous tissues in 10 healthy beagles. Endoscopic, CT, or ultrasound guidance was used when necessary to facilitate contrast agent delivery. CT and radiographic images were obtained prior to contrast administration and at 4 hr, 24 hr, and 7 days postcontrast injection. Postmortem examinations were then conducted. RESULTS: CT images showed enhancement of regional lymph nodes draining the various injection sites. The mean attenuation of opacified nodes was 678 +/- 463 Hounsfield units 24 hr after injection and remained elevated 7 days later. Lymph node opacification on CT images correlated well with the node location observed on postmortem examinations. CONCLUSION: Subdiaphragmatic lymph nodes can be effectively opacified using an iodinated nanoparticle contrast agent for indirect CT lymphography.

Pharmacological action of radiographic contrast media reduced cerebrospinal fluid production in the dog.

Intravenous administration of radiographic contrast media (CM) significantly decreases cerebrospinal fluid (CSF) production as measured by negative pressure collection from a lateral ventricle of the anesthetized dog. This effect has been shown with the conventional ionic CM, sodium diatrizoate, and is now reported for the new nonionic agent, iohexol. Continuous infusion of either agent maintains the decrease. The magnitude of the CM-induced decreased CSF production is proportional to the dose in the range of 1 to 4 ml/kg. This action of CM cannot be explained by an osmotic mechanism. Two enzymes involved in the elaboration of CSF, carbonic anhydrase and sodium, potassium-adenosine triphosphatase, are not inhibited by sodium diatrizoate sufficiently in vitro to explain this action of CM. These results indicate a pharmacological action by i.v. CM that may require special attention when reduced CSF production would be deleterious.

Radiologic diagnosis of diethylstilbestrol induced teratogenesis in rats.

Radiographs were used for the assessment of diethylstilbestrol-induced teratogenesis of the urogenital system of rats. Lesions such as female hypospadias were demonstrable with a 4:1 magnification of radiographs that were not observed using subgross dissection and histologic step sections.