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Background: Prior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts., Methods: To fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time., Results: Observed CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories., Conclusions: These data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.

Objectives: Radiocontrast agents are one of the most common causes of acute renal failure in the world. These agents are required for both diagnostic and therapeutic modalities of medical intervention, including computed tomography (CT), angiography and cardiac catheterization. Publications over the past 40 years support three potential mechanisms of toxicity: oxidative stress, haemodynamics and hyperosmolar effects. An in vitro model provides a rapid evaluation of cellular toxicity without the complications of haemodynamics. This study evaluated the renal toxicity of radiocontrast agents at clinically relevant concentrations., Methods: This study investigated the toxicity of two radiocontrast agents, diatrizoic acid (DA) and iothalamic acid (IA), using an in vitro model. Renal cortical slices isolated from F344 rats were incubated with 0-111 mg I/ml DA or IA., Results: Renal slices exposed to DA and IA showed toxicity as measured by increased lactate dehydrogenase (LDH) leakage at concentrations lower than previously published using isolated cell models. These data indicate that DA and IA are toxic to renal cortical slices, and this is a more sensitive model than previously used cell culture systems. DA and IA treatment failed to cause a significant decrease in total cellular glutathione or increase in percent glutathione disulphide (GSSG), implying that oxidative stress may not be an initial mechanism of toxicity. Finally, the addition of exogenous glutathione did provide complete protection from DA- and IA-induced LDH leakage., Conclusion: These data validate the renal cortical slice in vitro model for investigation of radiocontrast nephrotoxicity. These studies further showed that glutathione was cytoprotective. Future research using this model is aimed at further characterization of radiocontrast nephrotoxicity, which may allow for improved prevention and treatment of radiocontrast-induced acute renal failure.

Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.

Background: Several markers are available to estimate the glomerular filtration rate (GFR) in patients. Cystatin C is a relatively new marker and has been suggested as an alternative for creatinine. Numerous studies have been performed to evaluate the usefulness of cystatin C to estimate GFR. The aim of this study is to compare the renal extraction of cystatin C with that of 125I-iothalamate in hypertensive patients., Methods: Forty hypertensive patients with unilateral renal artery stenosis, and who used at least two antihypertensive agents, were studied. For the determination of the renal extraction ratio, blood samples were drawn simultaneously from the renal vein and the abdominal aorta. The renal extraction ratio was calculated as ([A]-[V])/[A], in which A is the plasma concentration of the compound from the abdominal aorta, and V is the plasma concentration of the compound from the renal vein., Results: The mean difference between the renal extraction ratio of cystatin C and that of 125I-iothalamate was 0.002. The 95% confidence interval (CI) for the mean difference was -0.036 to 0.032, which was not statistically significant. However, the limits of agreement were large (-0.271 and 0.267)., Conclusions: Despite a lower reported glomerular sieving coefficient of cystatin C, the mean renal extraction of cystatin C was equal to the mean renal extraction of 125I-iothalamate in hypertensive patients, suggesting tubular secretion of cystatin C. Combined with the large variation in the renal extraction of cystatin C, these findings cast doubts on its usefulness as a glomerular filtration marker.

Purpose: To evaluate controversial results regarding the effect of the contrast medium (CM) iothalamate on renal medullary blood flow by applying two different methods simultaneously., Material and Methods: The outer medullary blood flow (OMBF) response was estimated using laser-Doppler flowmetry and hydrogen gas wash-out (microelectrodes) simultaneously. Outer medullary oxygen tension (PO2) was measured using Clark type microelectrodes. Iothalamate was injected i.v. at 1600 mg I/kg body weight for 2 min., Results: CM induced a transient 28% decrease in OMBF as measured with the laser Doppler. The hydrogen gas wash-out rate was reduced by 50%, indicating a reduced perfusion. CM induced a transient 60% reduction in PO2, while renal fluid and electrolyte excretion increased several fold., Conclusion: The CM iothalamate reduces outer medullary perfusion as estimated by two different techniques applied simultaneously. The PO2 in the same region was also reduced. Previous controversies regarding the effect of iothalamate on OMBF can be explained by extreme dosage and injection rates greatly exceeding clinical relevance.

Background: Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease., Methods: A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury., Results: Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia., Conclusion: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.

Background: Radiocontrast agents (RC), substances largely used in diagnostic procedures, present the nephrotoxicity as one of its major side effects, which could be due to an altered synthesis of vasodilators. The aim of the present study was to evaluate the nitric oxide (NO) production in rat renal artery smooth muscle cells primary culture (rVSMC) exposed to RC., Methods: The cells were treated for 72 hours with mannitol at 10% (MT10; 600 mOsm/kg H2O) or 35% (MT35; 2100 mOsm/kg H2O), with the nonionic iobitridol (IBT), the low-osmolality ioxaglate (IXG), the high-osmolality ioxitalamate (IXT), the nonionic, iso-osmolar iodixanol (IDX), and with lipopolysaccharide (LPS). We determined the NO and osmolality in the cell culture media and the cellular viability., Results: By the Griess and chemiluminescence methods, the NO was not different in MT10 and IDX, but decreased in MT35, IBT, IXG, and IXT when compared with the control; it was increased in LPS and also decreased in all RC+LPS when compared with LPS. MT35, IXT, and IXT+LPS decreased the cellular viability, and the media osmolality was increased in MT35 and IXT compared with the control., Conclusion: The RC (except IDX) significantly reduced NO in rVSMC, which was more pronounced after IXT treatment (57.3%). This was not related to the reduced cell viability (15.8%) or to its high osmolality, because in MT35, with similar osmolality as IXT, NO decreased only 11.0% relatively to the control. Neither the media osmolality nor the cell viability was altered by IXG or IBT. The decreased NO could explain the vasoconstriction and, therefore, the acute renal failure by RC.

The radiopaque contrast medium diatrizoate, has a vasodilator effect so that it is used in sudden-deafness secondary ischemic injury. However, ischemic problems are encountered, especially when longer flaps are elevated. A longer flap also has ischemic and relatively ischemic tissue, and may obtain some benefit from contrast media. Forty male Sprague-Dawley rats, weighing about 350-400 g, were used, and randomly divided into four groups (n = 10 rats each group): group 1 was the control, group 2 the diatrizoate, group 3 the iopamidol, and group 4 the iothalamate group. A rectangular 3 x 10 cm caudally based dorsal skin flap was elevated, and sutured back to its original place. In the control group, no pharmacologic agent was administered. Sodium-meglumine-diatrizoate 10 mg/kg/day was administered parenterally in the first experimental group (diatrizoate group); iopamidol 10 mg/kg/day in the second experimental group (iopamidol group); and iothalamate sodium 10 mg/kg/day in the third experimental group (iothalamate group) for 7 postoperative days. On postoperative day 7, all flaps were photographed, and the area of flap survival was measured by using a polar planimeter. The results were statistically evaluated with the Kruskal-Wallis test and Mann-Whitney U-test (P = 0.05). The mean flap survival ranged from 79% in the iopamidol group to 83% in the diatrizoate group, and was significantly greater in all experimental groups (P < 0.05) compared to the control group (59%). There was no significant difference between experimental groups (P < 0.05). We believe that radiopaque contrast media have a beneficial effect in improving skin flap viability when distal flap necrosis is a potential complication of longer flaps., (Copyright 2003 Wiley-Liss, Inc.)

Objective: To compare the effects of diuresis induced by a loop diuretic (frusemide), an osmotic diuretic (mannitol) and a high-osmolar radio-contrast medium (sodium iothalamate) on the intrarenal resistive index (RI) in dogs with chronic unilateral partial ureteric obstruction (UPUO)., Materials and Methods: The split renal clearance and intrarenal RI were estimated in 11 dogs with chronic UPUO. Doppler ultrasonography measurements of the interlobar arteries were obtained before and 10 min after the intravenous infusion of 1 mg/kg frusemide, 1 g/kg mannitol or 20 mL 60% sodium iothalamate. The same experimental protocol was repeated with another drug at 1-week intervals., Results: There was a significant difference between the intrarenal RI of obstructed and unobstructed kidneys in the chronic phase of UPUO. While mannitol and sodium iothalamate significantly increased the RI in both kidneys, differences in RI between the kidneys decreased after infusing the two drugs. However, while frusemide insignificantly increased the RI in the obstructed kidney, it decreased the RI in unobstructed one. Consequently, the difference in RI between the kidneys increased significantly after administering frusemide. There were no significant differences in urinary volume after administering each of the drugs., Conclusions: As there were no significant differences in the diuretic effects of the drugs, frusemide may have additional effects on the RI of unobstructed kidneys other than diuresis. Frusemide increased the difference between the intrarenal RI of the kidneys and therefore may improve the detection of unilateral urinary obstruction in humans.

Background/aims: Contrast media (CM) induce a biphasic renal hemodynamic response, with late prominent cortical vasoconstriction and marked outer medullary vasodilation. The objective of the study was to explore a possible role for altered nitric oxide (NO) production or bioavailability in these hemodynamic responses., Methods: We explored the impact of CM (sodium iothalamate) upon rat renal NO synthase (NOS) activity (citrulline recovery) and NO (using a NO electrode)., Results: The cortical NOS activity following CM was 11.5 +/- 1.0 versus 13.8 +/- 1.1 nmol/gww/min (gww = gram wet weight) in controls (p = 0.16, NS). In rats pretreated with the nonselective endothelin antagonist bosentan, CM reduced the cortical NOS activity to 8.5 +/- 1.2 nmol/gww/min (p < 0.005 vs. controls). Cortial NO readings declined over 30 min following CM by 13 +/- 8% (p < 0.05, Anova), in parallel with the decline in cortical blood flow. The outer medullary NOS activity was not affected by CM (5.2 +/- 1.5 vs. 5.5 +/- 1.3) nmol/gww/min in controls) or bosentan. Nevertheless, the outer medullary NO reading increased by 36 +/- 23% (p < 0.05), with a concomitant increase in regional blood flow., Conclusion: In the cortex, CM might reduce the NOS activity (an effect blunted by endothelin release). This may potentiate the effect of endothelin to induce regional vasoconstriction. In the outer medulla, the vasodilatory response to CM does not seem to be mediated by enhanced NOS activity and might reflect increased local NO bioavailability as the result of regional hypoxia.

Cardiac output is effectively redistributed to each part of the body by regional changes in vascular resistance. Thallium-201 distribution reflects the fractional distribution of cardiac output and parallels regional blood flow. The side effects of iodinated contrast media in different organs have been well documented in animal experiments and clinical studies. However, no simultaneous assessment of regional blood flow change in each part of the body after the administration of contrast media has been reported. Using a double-dose thallium-201 method, we investigated the effect of contrast media on the regional distribution of thallium-201 in each organ as an estimate of regional blood flow change in rabbits. The distribution of 201T1 and 99mTc-MAA was similar in the heart, spleen, kidneys, and leg muscles in the control animals (r = 0.99). The regional distribution of thallium-201 significantly increased in the heart and leg muscle, but decreased in the liver in the nonionic (Iohexol) and ionic (Iothalamate) contrast medium groups as compared with the control group. There were no significant changes in the kidneys or intestine in these three groups in our study. The intravenous infusion of contrast media in rabbits causes uneven redistribution of regional blood flow in the heart, leg muscle and liver. These changes are more prominent in the ionic contrast medium group.

Infusion of radiocontrast agents in vivo results in renal artery constriction and subsequent renal hypoperfusion. To examine the role of endothelin and of prostaglandins in radiocontrast-mediated renal vasoconstriction, rats were treated with an endothelin receptor antagonist, CP170687, and with indomethacin. The dose of CP170687 utilized was sufficient to reverse endothelin1-mediated constriction of isolated aortic rings and of renal blood flow in intact rats. In normal rats there was a transient drop in renal blood flow to 80% of baseline following sodium iothalamate injection, an effect which was not prevented by CP170687. In rats first given indomethacin, the drop in renal blood flow was more pronounced (to 63% of baseline) and was sustained. In this instance, CP170687 fully reversed the sustained decrease of renal perfusion. CP170687 also diminished the rise in systemic blood pressure seen following iothalamate injection. In the absence of indomethacin, iothalamate increased urinary prostaglandin E2 to a maximum of sevenfold above baseline values. In summary, injection of radiocontrast results in an immediate decrease in renal blood flow that is counteracted by an increase in renal prostaglandin formation. When prostaglandin synthesis is inhibited, prolonged endothelin-mediated renal vasoconstriction is observed that is reversed by an endothelin receptor antagonist.

To evaluate the effect of ionic contrast medium on plasma atrial natriuretic peptide (ANP) and its contributing factors, we measured plasma ANP, serum osmolality, pulmonary capillary wedge pressure (PCWP), femoral artery systolic pressure (FASP), and heart rate before and after left ventriculography with Rayvist in 13 patients suspected of coronary artery disease. The control values of plasma ANP, serum osmolality, and PCWP were 20.3 +/- 5.1 pg/ml, 293.5 +/- 1.5 mosm/kg, 6.6 +/- 0.8 mm Hg, respectively. Rayvist produced a significant increase in plasma ANP, serum osmolality, and PCWP at 1 minute (26.0 +/- 6.3 pg/ml, p < 0.05; 300.7 +/- 1.9 mosm/Kg, p < 0.001; 10.7 +/- 1.3 mm Hg, p < 0.001) and 5 minutes (27.3 +/- 6.3 pg/ml, p < 0.01; 296.8 +/- 1.9 mosm/Kg, p < 0.001; 10.4 +/- 1.7 mm Hg, p < 0.01) post left ventriculography. The FASP decreased significantly at 1 minute, followed by an insignificant increase at 5 minutes. The heart rate increased significantly at 1 minute but no significant change was noted at 5 minutes. We conclude that plasma ANP increases significantly after left ventriculography with Rayvist and its response may be related to left ventricular filling pressure and serum osmolality, but not to FASP or heart rate.

The effects of low-osmolality contrast media (CM) on red blood cell (RBC) filterability were investigated using a recently developed nickel mesh filtration method. The conventional hypertonic CM iothalamate, low-osmolality iohexol, and the recently synthesized iomeprol were studied. Among them, the osmolality of iomeprol was the lowest. The impact of CM osmolality, viscosity, and iodine content on the RBC filterability was analyzed. Under equal iodine content or viscosity condition, the filterability order of RBCs suspended in CM was iomeprol > iohexol >> iothalamate, because of the osmolality of CM. Iomeprol caused small echinocytic changes but these had a negligible influence on RBC filterability. In conclusion, the osmotic effect of CM on RBC filterability is more predominant than the other CM effects, and iomeprol is the preferred CM for RBC filterability.

Rationale and Objectives: It is known that ionic contrast media (CM) bind magnesium and that patients with asthma often benefit from magnesium injections. Similarly, asthmatics have a higher incidence of CM reactions. This work tests the hypothesis that ionic CM alter serum magnesium more than nonionic CM., Methods: Ten patients were divided into two groups; one group received iothalamate and the other received iohexol., Results and Conclusions: The total magnesium level changed significantly from baseline in the iothalamate-treated group (P less than .01). Iothalamate produced a significant decrease in protein-bound magnesium (P less than .01) with a significant increase in filterable magnesium (P less than .01). Iohexol did not produce significant changes for any of the magnesium fractions. The patient with the most clinically significant adverse reaction (though minor) had the lowest baseline magnesium level. Further studies with larger groups including patients with asthma are needed.

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.

Water soluble ionic contrast media (CM) and glucose 5% were administered to Sprague-Dawley rats 36 hours after bilateral warm renal ischemia for 45 min. In all animals (n = 28) the renal ischemia caused a decrease of the absolute urinary creatinine output. Intra-arterial injection of glucose 5% or CM did not produce different patterns of absolute urinary creatinine output. The serum creatinine increased after 36 hours of reflow. When compared by means of a Mann-Whitney U-test to a normal median serum creatinine obtained in a separate group of 22 normal rats, the increase was statistically significant (p less than or equal to 0.01). The serum creatinine medians returned to a normal level after 24 hours. It seems therefore that 45 min of warm renal ischemia and 36 hours of reflow is an insufficient challenge to the rat kidney for the detection of the nephrotoxic properties of CM as opposed to when CM are injected during ischemia.

Routine clinical use of radiographic contrast media (RCM) causes adverse reactions in some patients. To elucidate the mechanisms of these reactions both in vitro and in vivo studies are necessary. In this study, RCM-induced histamine release from isolated mast cells was compared with the in vivo release of histamine and cardiovascular symptoms using a porcine model. The 2 non-ionic preparations examined (Solutrast and Ultravist) released little or no histamine from the 4 cell types tested (porcine pulmonary, cardiac, hepatic, and renal mast cells). The 4 ionic preparations (Angiographin, Hexabrix Rayvist, and Telebrix) caused histamine release from most of the cell suspensions. In almost all cases, the cardiac mast cells were the most sensitive followed by the hepatic mast cells. All 4 RCM tested in vivo produced elevated plasma histamine levels in some animals. The highest incidence was observed using the ionic, high osmolal Rayvist (6 of 12 animals), followed by the non-ionic RCM with the lowest osmolality Ultravist (4 of 12 animals). In vivo, mechanisms in addition to direct histamine release may also be involved in RCM-induced adverse reactions, since low osmolal, non-ionic RCM can cause elevated plasma histamine levels without in vitro release. The susceptibility of cardiac mast cells to RCM-induced histamine release suggests that patients undergoing e.g. coronary angiography may be especially at risk for an adverse reaction.

It has been suggested (Fisher and al., Rainiko and al.) that contrast media could interfere with a red blood cell aggregation, low-osmolarity and non ionic contrast media leading to red blood cell aggregates in vitro. Clinical significance of this phenomenon is not known. We have studied 21 consecutive patients admitted in X ray department for pyelography. Sodium and meglumine ioxitalamate (Telebrix 38 R; Guerbet) osmolarity 2 100 mOsm kg--viscosity 8.5 cp at 37 degrees C is used for contrast. Red blood cell aggregation is studied by erythraggregometer Sefam. Samples are collected before (T0), 10 and 30 minutes (T10, T30) after contrast infusion. Hemogram and coagulation parameters are measured in parallel. Results show a significant increase of aggregation times at T10, with a trend towards baseline at T30. Dissociation shear rates follow the same fluctuations. We note a concomitant diminution of both fibrinogen and hematocrit levels, well-correlated with red blood cell aggregation. These results suggest a process of hemodilution which could explain the diminution of red blood cell aggregation with this type of contrast medium.

The direct effects of sodium iothalamate on renal vascular resistance (RVR) were examined using the isolated perfused rat kidney experimental model. A concentration-dependent biphasic change in RVR was produced with the hyperosmolar solution of sodium iothalamate [(Conray 420), 420 mgI/ml, 2500 mOsmol/kg/H2O]. The response characterized by an initial fall followed by a prolonged increase in RVR on discontinuation of the iothalamate infusion. No significant change in RVR was observed when iothalamate was infused as an iso-osmotic solution (60 mgI/ml, 280 mOsmol/kg/H2O) at a rate of 0.525 ml/min. to produce a concentration of 4.2 mgI/ml in the renal perfusate. We conclude that sodium iothalamate can exert direct biphasic effects on RVR which are mediated by its hyperosmolality rather than its chemical content.

Amiodarone, an iodine-containing antiarrhythmic drug, has been reported to interfere with thyroid function and thyroid hormone metabolism. We studied the effects of amiodarone on basal and agonist [thyroid-stimulating hormone (TSH), phorbol ester, or carbachol]-stimulated glucose oxidation, 32PO4 incorporation into phospholipids, and adenosine 3',5'-cyclic monophosphate (cAMP) concentration in dog thyroid slices. Slices were preincubated with amiodarone at 37 degrees C for 1 h before the addition of agonist and the appropriate radioisotope. cAMP stimulation was measured after 20 min, glucose oxidation for 45 min, and 32PO4 incorporation into phospholipids for 2 h. Amiodarone (0.5 mM) had no effect on basal 14CO2 formation or 32PO4 incorporation into phospholipids but significantly inhibited TSH, phorbol ester, and carbachol stimulation of these parameters. It also inhibited cAMP stimulation by TSH. Inhibition of TSH-stimulated [14C]glucose oxidation was also obtained with another iodide-containing compound, iopanoic acid (0.5 mM), but not with iothalamate (up to 10 mM). Inhibition by amiodarone was still present, but to a lesser extent, when it was added at the same time as the agonist. Inhibition of stimulated [14C]glucose oxidation persisted even after the slices were incubated without amiodarone for 6 h. Inhibition by amiodarone, in contrast to that by inorganic iodide, was not prevented by 1 mM methimazole added at the same time as amiodarone. These results indicate that the inhibitory effects of amiodarone on thyroid function are not due to dissociation of iodide from the molecule.

There is increasing evidence that activation of the plasma contact system that results in the production of bradykinin plays an important role in contrast material systemic reactions. The effects of bradykinin in anaphylaxis depend on its rate of destruction and its rate of production. The highest percentage of contrast material reactions occur after intravenous injections, and the major enzyme hydrolyzing bradykinin (kininase II; angiotensin-converting enzyme) is found on pulmonary vascular endothelial surfaces. The inhibitory effects of numerous ionic and nonionic contrast material solutions on the enzyme have been determined. Additionally, the role in this inhibition of the chelators found in all commercial contrast material vials has been studied. In vitro, all such preparations combined with their chelators inhibit angiotensin-converting enzyme. Whether this inhibition plays a role in vivo remains to be established.

It has been suggested that contrast media could interfere with red blood cell aggregation, hyperosmolar media leading to an inhibition of red blood cell aggregation whereas non ionic products might induce a sludge phenomenon. We present an in vitro study accompanying two contrast media: 1) Ioxitalamate of sodium and meglumin (ionic, hyperosmolar). 2) Iopaminol (non ionic). In their effect on hemorheological parameters of red blood cell aggregation. Blood samples have been obtained from 7 healthy donors. Contrast media have been tested at increased contrast media (O.1, 1, 2, 10, 100 mg/ml of Iodine in final concentration). The following parameters have been studied: hematocrit, fibrinogen level, erythrocyte aggregation using the Erythro-aggregometer*, whole blood viscosity at 3 different shear rates (0.87, 18.74, 118 sec.-1) using Low Shear 30*. Deformability of red blood cell was assessed by ektacytometry. Osmolarity was controlled in each sample. Results show an inhibition effect of both contrasts media on red blood cell aggregation. There is a concomitant decrease of blood viscosity at low shear rates. On the contrary, apparent viscosity increases at high shear rates in parallel with the contrast media concentration. This effect is more pronounced with ioxitalamate above a concentration of 10 mg/ml. Ektacytometric parameters are not modified by contrast media and this could indicate a complete reversibility of the media-induced alteration on red blood cell. In order to precise the prothrombotic effect on contrast media, hemorheological studies have to be completed by the assessment of their effect on hemostatic parameters.

The effect of ingestion of 60 ml sodium iothalamate (Gastro-Conray; Maybaker)--a radiographic contrast medium--on resting lower oesophageal sphincter (LOS) pressure was studied in 10 normal human volunteers. Compared with a barium meal, which does cause a fall in LOS pressure, Gastro-Conray did not affect the sphincter tone. The importance of this is discussed.

Prior to the formation of an intravenous digital subtraction angiography (IV-DSA) image, contrast medium passes through the lesser circulation and is diluted by the blood volume of the heart and lungs. If the contrast medium alone influences central blood volume or cardiac output, the shape of the resultant time-concentration curve may be degraded. To the extent that contrast medium tonicity reduces curve peak or increases width, image quality for mask mode IV-DSA will suffer. To quantify the effect of contrast medium tonicity upon curve shape, contrast medium (1) at increasing iodine concentration and increasing osmolality and (2) at constant iodine concentration and increasing osmolality was injected into the right atria of mongrel dogs. In both experiments, increasing osmolality was associated with an increase in central blood volume (CBV) and cardiac output. With an increase in CBV, curve peak fell. With an increase in both CBV and cardiac output, curve width was not influenced by increasing osmolality. The effect of osmolality upon CBV was highly variable; in these experiments CBV was influenced more by subject-to-subject variability. However, on the average, higher tonicity contrast media produced curves with lower peaks. These studies suggest that isotonic contrast medium does not increase CBV and that isotonic contrast medium is preferable to hypertonic contrast medium for IV-DSA image formation.

In the arterial wall, ATP:creatine N-phosphotransferase (E.C.2.7.3.2) is present in the form of its three isoenzymes, MM, MB, and BB, the latter being predominant. Six iodinated contrast agents in routine angiographic use were examined from the point of view of their effects in vitro on the isoenzymes of ATP:creatine N-phosphotransferase from the arterial wall, compared with their effects on the same isoenzymes in other organs. There is a clear inhibitory effect from the contrast agents on all organs, but it is least marked for the arterial wall. Furthermore, nonionic compounds have far less enzyme-inhibitory effect than ionic compounds.

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.

The effect of iopamidol on the leptomeninges was tested and compared with that of metrizamide and normal saline solution in 18 dogs. Pathologic and clinical effects were evaluated at 24 hours and 14 days after cisternal injection of iopamidol, metrizamide, or normal saline solution. Pathologic changes were evaluated by microscopic examination of serial CSF samples and of sections of brain and spinal cord with the leptomeninges intact. Clinical changes were subjectively evaluated. Electromyograms and EEG were performed on each dog after physical and neurologic examination. There were no changes seen in neurologic status, electromyogram, or EEG in any of the dogs immediately after subarachnoid injection nor at 24 hours or 14 days later. Pathologic changes were limited to mild, moderate, or severe patchy hemorrhagic leptomeningitis seen at 24 hours after iopamidol or metrizamide was injected. The severity of changes were judged to be similar with both these agents. The CSF analysis and histologic evaluation of brain and spinal cord sections revealed a neutrophilic response to iopamidol and a mononuclear response to metrizamide. These findings indicate that iopamidol has minimal neurotoxicologic effect on the leptomeninges and therefore has merit as a myelographic agent.

Thirty-two mongrel dogs were used in a comparative study to assess the effect of normal saline solution, metrizamide and Cardioconray on serum osmolality, haematocrit and cardiac output. The study demonstrated that the higher the osmolality of the test substance, the greater the reduction in haematocrit and the higher the increase in cardiac output.

The neurotoxic effects in cerebral angiography of three iodinated ionic contrast media, nonionic iopamidol, 25% mannitol, and saline controls were compared in 25 rabbits. Diatrizoate sodium meglumine was the most toxic agent, followed by diatrizoate and meglumine, iothalamate meglumine, and mannitol in terms of blood-brain barrier (BBB) disruption and coupled perfusion decline. HIPDm distribution was more sensitive than trypan blue extravasation for monitoring brain dysfunction. Iopamidol and saline controls exhibited no visual BBB breakdown or alteration in regional uptake of I-125 HIPDm, confirming the safety of nonionic iopamidol as compared with presently used ionic contrast media.

The effects of LV dynamics of the intracoronary administration of three new contrast materials with reduced osmolality were compared with those of a monomeric ionic material, sodium iothalamate, and the nonionic material, metrizamide. In eight anesthetized dogs, the monacid dimer, P286, caused increases in LV dimensions and decreases in LV systolic pressure and parameters of the contractile state. The changes were less than those caused by sodium iothalamte. The alterations in LV function tended to be greater, but not significantly so, during systemic hypoxemia compared to the normal state. The nonionic materials, P297 and iopamidol, like metrizamide, caused no deleterious effects on LV dynamics in either the normal or hypoxemic state. Nonionic materials actually caused a slight increase in parameters of the LV contractile state.

The attenuation coefficients of cerebral parenchyma and systemic blood were simultaneously measured at varying times after injection of two contrast agents with differing osmolarities. Cerebral parenchyma was in fact denser than the theory would predict. The osmolarity of the iodinated contrast agents seems to play only a very minor part. However, liposolubility could perhaps explain the leakage of iodine across the BBB and thus the increase in the attenuation coefficient of cerebral parenchyma.

The inhibition of enzymes by radiological contrast agents has been invoked to explain some of their clinical effects. In a previous paper, in-vitro studies of the inhibition of the enzyme acetylcholinesterase were presented and some clinical correlations were discussed. More detailed studies, described here, have now shed new light on the mechanisms involved in this important phenomenon. Because the findings restore the iodine atoms to a central role, they have important general implications for contrast agent pharmacology.

The effects of the iodine-containing radiocontrast agents ipodate, iopanoic acid, and iothalamate on the secretion of T4, T3, and rT3 were studied using perfused canine thyroid lobes. The experiments were performed as paired comparisons, with one thyroid lobe acting as a control. At 10(-5) M, the two agents used for cholecystography (ipodate and iopanoic acid) inhibited the TSH-stimulated secretion of T3 [ipodate, 69 +/- 8% of control (P less than 0.05); mean +/- SE; n =4] and rT2 [iopanoic acid 59 +/- 9% (P less than 0.01); iopanoic acid, 61 +/- 9% (P less than 0.05)], whereas T4 secretion was not significantly altered. Iothalamate (10(-3)M), an agent predominantly excreted through the kidneys, did not alter T4, T3, or rT3 secretion. This pattern is compatible with an inhibitory effect on intrathyroidal T4 deiodination to T3 and rT3 by ipodate and iopanoic acid, similar to the inhibition of T3 deiodinases in peripheral tissues by these compounds. At a concentration of 10(-3) M, ipodate induced a hitherto unrecognized pattern of thyroid hormone secretion: a very rapid, sustained and reversible inhibition of the secretion of all three iodothyronines. The mechanism behind this response remains to be elucidated.

We demonstrate that salts of diatrizoate and iothalamate, radiographic contrast agents, depress the active transport of sodium in the urinary bladder of the Columbian toad, Bufo marinus. Isolated toad bladders were incubated in isotonic Ringer's solutions with isosmolar displacement of sodium chloride by contrast media in experimental solutions. Sodium transport as measured both by short-circuit current (SCC) and by isotopic sodium flux was significantly depressed in the presence of sodium diatrizoate. Sodium transport measured by SCC was significantly depressed with sodium iothalamate and meglumine iothalamate. Equimolar methylsulfate Ringer's solution did not depress SCC. Although contrast media in isotonic Ringer's solutions depressed basal SCC, the vasopressin-stimulated increment in SCC was not depressed by contrast media. Separate experiments with hyperosmolar solutions (786 mM, as utilized in angiography) demonstrated equivalent suppression of SCC by contrast media and by other solutions made hyperosmolar with glucose or sodium methylsulfate, implying a general or nonspecific effect of hyperosomolarity. Inhibition of SCC by contrast media was reversible when the agents were removed by serial changes with standard Ringer's solution. Inhibition of sodium transport by contrast media might provide a basis for studies on some of the clinical toxicities of these agents.

Using a canine model, the effect of intracarotid injections of the ionic contrast medium methylglucamine iothalamate was compared with that of the nonionic contrast medium iopamidol of similar iodine concentration (280 mg 1/ml). The degree and distribution of blood-brain barrier disruption was assessed using Evans blue stain as a visual marker and by contrast enhancement measured by a computed tomographic (CT) scanner. In all studies with methylglucamine iothalamate, Evans blue staining was demonstrated, and CT enhancement demonstrated a significant mean difference (p less than 0.01) between the control and injected hemispheres. The absence of blood-brain barrier disruption with iopamidol is probably related to its lower osmolality (570 mosmol/kg) compared with methylglucamine iothalamate (1,424 mosmol/kg) and the absence of any cation.

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.

In an attempt to study the role of prostaglandins in the renal vascular response to contrast media in mongrel dogs, renal arterial injections of 6 ml of either the non-ionic contrast medium Iopamidol or the ionic medium diatrizoate meglumine/Na+ were performed, before and after intravenous injection of a buffered solution of acetylsalicylic acid (10 mg/kg) (ASA). Renal blood flow was recorded using non-occluding electromagnetic flow probes. The resting renal blood flow was significantly reduced after ASA. The usual biphasic response to contrast injection was observed both before and after ASA, and using either contrast medium. Analysis of the results failed to show any difference in degree of vasodilation or vasoconstriction after ASA. We conclude that prostaglandins may affect the resting level of renal blood flow but are not mediators of the instantaneous changes in response to contrast injection.

A representative selection of X-ray contrast media was tested for their effects on the action of chymopapain on cartilage proteoglycan in an in-vitro test system. Inhibition of the action of chymopapain was detected only at high concentrations of contrast media, and was more marked with ionic contrast media than with non-ionic media. A dose-response curve for the release of glycosaminoglycan by chymopapain was linear when the amount of enzyme was plotted on a logarithmic scale against glycosaminoglycan release. In view of our results, we suggest that there is no need for a delay between injection of contrast medium and enzyme, contrary to the instructions of the distributors of chymopapain, if small amounts of a non-ionic contrast medium are used.

Contrast media having high osmolality (methylglucamine diatrizoate; 1,510 mOsm/kg) and low osmolality (triiodoisophthaldiamide, 616 mOsm/kg) were compared in 15 functionally immature rabbits 2-3 weeks of age. Renal function was assessed with a gamma camera and whole-body counter, using excretion of technetium-99m-tin-DTPA as an index of glomerular filtration rate. Both DTPA and the contrast agent (2 ml/kg) were injected as a single intravenous bolus in 15 seconds. After 40 minutes, per cent DTPA excreted was 33.0 +/- 2.3 for triiodoisophthaldiamide and 28.2 +/- 1.5 (p less than 0.01) for methylglucamine diatrizoate. Excretion of DTPA was reduced with the latter (p less than 0.005) but not the former agent (p greater than 0.6). Thus contrast materials with high osmolality depress renal function in immature rabbits, suggesting that agents with low osmolality are preferable for use in newborns.