Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model
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We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS(-/-)) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10(-9)-10(-6) mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS(-/-) mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 μg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS(-/-) mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS(-/-) mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS(-/-) mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy.Keywords:
Iohexol
Proinflammatory cytokine
The nonionic iodinated contrast medium, iohexol, introduced for clinical urography, is eliminated from the human organism mainly by glomerular filtration. The aim of this study was to analyze the applicability of iohexol for glomerular filtration rate (GFR) measurement by comparing the plasma clearance of iohexol to the plasma clearance of the traditionally employed substances, chromium-51-EDTA and technetium-99m-DTPA. Iohexol concentration was measured by x-ray fluorescence. To analyze for possible acute effect of iohexol on renal function, additional measurements of 99mTc-DTPA clearance were made prior to the injection of iohexol. In 15 patients having clearance values between 30 and 130 ml/min per 1.73 m2, there were close correlations (r=0.95-0.98) among iohexol, 51Cr-EDTA, and 99mTc-DTPA clearance. No significant acute renal effect of iohexol was demonstrated. It is concluded that measurement of iohexol clearance provides information about GFR that is as valid as measurements of 51Cr-EDTA and99mTc-DTPA clearance. Thus, it is possible to perform urography and a determination of GFR using a single injection of iohexol.
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Iohexol was used on 62 patients who had had side effects or adverse reactions to conventional ionic contrast medium. No side effects were observed. Iohexol provided better nephrographic and pyelographic effects, but in one case a diagnosis could not be made using 20 ml of Iohexol 300. Iohexol 350, 20 ml, was thought to be more suitable contrast medium than Iohexol 300, 20 ml, for ordinary intravenous pyelography. Iohexol could be used safely in patients with previous adverse reactions to ionic contrast media.
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Abstract Background Recently, Gong et al. (Gong et al. 2022) showed, in nine heathy subjects, that plasma clearance of high doses of iohexol given as contrast enhanced computed tomography (CT) could be used for determination of glomerular filtration rate (GFR). We utilized high doses of iohexol from angiographic or other contrast enhanced CT given to critical ill patients for calculation of GFR iohexol and compared these data with standard low dose iohexol GFR determinations. Method Patients at intensive care units (ICUs) in Southeast Sweden intended for radiographic investigations that included injection of 45-120 ml of iohexol (Omnipaque) were included, and the concentration of iohexol in plasma was measured by HPLC. Iohexol clearance was calculated by the method of Bröchner-Mortensen. The following days was iohexol clearance determined using the standard low dose of 5 mL of iohexol. Sixteen patients admitted to ICUs were included in this pilot study. Results GFR after high dosing of iohexol at contrast enhanced CT could be measured for all sixteen critically ill patients. Patients with normal or increased renal function had neglectable iohexol concentrations the day following the CT scan. There was excellent correlation between GFR determination with high and standard low iohexol dosing among these 6 patients. Ten patients had decreased renal function and delayed elimination of iohexol, thus was not GFR measurement with low dose iohexol possible to analyse the day after CT scan with high dose iohexol. Conclusion This pilot study showed that GFR can be measured after high doses of iohexol at enhanced CT and compare well with the standard low dose of iohexol clearance determinations.
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Evaluation and treatment of acute ischemic syndromes, in the heart and brain, require vessel visualization by iodinated X-ray contrast agents. However, these contrast agents can induce injury, in both the kidneys and target organs themselves. Sulfobutylether beta cyclodextrin (SBECD) added to iohexol (SBECD-iohexol) (Captisol Enabled-iohexol, Ligand Pharmaceuticals, Inc, San Diego, CA) is currently in clinical trials in cardiovascular procedures, to determine its relative renal safety in high-risk patients. Preclinical studies showed that SBECD-iohexol reduced contrast-induced acute kidney injury in rodent models by blocking apoptosis. The current study was undertaken to determine whether SBECD-iohexol is also cardioprotective, in the male rat ischemia-reperfusion model, compared to iohexol alone.After anesthesia, the left coronary artery was ligated for 30 min and the ligation released and reperfusion followed for 2 h prior to sacrifice. Groups 1-4 were injected in the tail vein 10 min prior to ischemia with: (1) vehicle; (2) iohexol; (3) SBECD; and (4) SBECD-iohexol. Infarct size, hemodynamics, and serum markers were measured.An eight-fold increase in serum creatine kinase in the iohexol-alone group was observed, compared with no increase in the SBECD-iohexol group. The mean arterial pressure and rate pressure product were depressed in the iohexol-alone group, but not in the SBECD-iohexol group, or controls. No difference in infarct size or serum creatinine among the groups was observed.The results of this study suggest that SBECD-iohexol is superior to iohexol alone, for both the preservation of cardiomyocyte integrity and preservation of myocardial function in myocardial ischemia.
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Previous studies have demonstrated that the polyphenolic compound, reseveratrol (RSV), from the skin of red grapes increases endothelial nitric oxide synthase (eNOS) activity. However, the mechanism by which RSV increases eNOS activity is unknown. Therefore, we have investigated changes in eNOS phosphorylation at Ser1179, Ser635, Thr495 as well as changes in eNOS association with Hsp90, Akt, and cdc37 in bovine aortic endothelial cells (BAECs) treated with varying doses of RSV for 0, 20, 60 min as well as 72 h. Acute RSV treatment (less than 1) resulted in no significant ( P >0.05) changes in eNOS phosphorylation or changes in eNOS association with Hsp90, Akt or cdc37. In contrast, 72h treatment of BAECs at higher concentrations of RSV significantly ( P <0.05) increased eNOS phosphorylation and protein association that was consistent with the increase in eNOS expression. In conclusion, these data suggest that RSV‐induced eNOS activity is primarily due to increased eNOS expression and that acute (less than 1 h) RSV treatment does not alter post‐translational eNOS regulatory mechanisms. Supported by AHA SDG 0430157N (MBH) and William & Mary HHMI Undergraduate Research Program Student Grant (KNS)
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The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 (51Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The 51Cr-EDTA clearance was the same when injected separately and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media.
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Injections of iohexol in two series of volunteers, 20 in 1980 and 16 in 1982 are briefly reported. Intravenous injections of iohexol in doses from 125 to 1500 mg I/kg body weight were well tolerated. Iohexol was completely excreted in unchanged form. The results indicate that iohexol may safely be used in clinical trials.
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Iohexol (350 mg I/ml) has been compared with meglumine-Na-Ca metrizoate (370 mg I/ml) in selective coronary angiography in 37 adult patients. Iohexol was very well tolerated and resulted in only minor changes in blood pressure and ECG parameters. Changes in blood pressure and R-R interval were significantly more marked following injections of metrizoate than after injections of iohexol. Arrhythmias were not observed following injections of iohexol, while two patients had AV block II after injection of metrizoate. Both contrast media gave similar and adequate demonstration of the coronary vessels. The findings suggest that iohexol has distinct advantages over metrizoate in selective coronary angiography.
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Two strains of endothelial nitric oxide synthase (eNOS)-deficient (−/−) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS −/− mice in an in vivo model of MI/R. Harvard (Har) eNOS −/− mice ( n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls ( P < 0.05). University of North Carolina (UNC) eNOS −/− ( n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls ( P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant ( P < 0.05) increase in the UNC eNOS −/− mice compared with wild-type mice, and there was no significant difference between the Har eNOS −/− and wild-type mice. UNC eNOS −/− mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS −/− did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS −/− mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS −/− mouse may result from compensatory increases in iNOS, other genes may be involved.
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