The chronic administration of CyA to animals and humans to prevent graft rejection may induce renal arteriolar damage resembling hemolytic uremic syndrome (HUS). This is a syndrome of vascular damage with thrombotic occlusions of the microcirculation. Endothelial damage is considered the first event in the pathogenetic cascade leading to HUS. We have used bovine aortic endothelial cells in culture to address the issue of CyA-induced arteriolar damage. CyA-induced a time (1-24 hours) and dose (1-50 μM) dependent cell damage. CyA-induced injury was characterized by an early cell detachment followed by lysis as documented by the increase in LDH and Cr release. 1 μM CyA did not induce cell detachment and lysis was evident only after prolonged incubations. 10 and 50 μM CyA both induced marked cell detachment and lysis: lysis started 3 hours after incubation of endothelial cells with CyA and was maximal at the end of 24 hour incubation (LDH release, percent specific increase over control values: 10 μM CyA, 47%; 50 μM CyA, 70%; 51 Cr release, percent specific increase over control values: 10 μM CyA, 28%; 50 μM CyA, 34%). CyA-induced injury was associated with dose- and time-depedent increase in prostacyclin (PGI2) and thromboxane A2 (TxA2) release by endothelial cells exposed to 10 and 50 μM CyA. CyA-induced generation of PGI2 and TxA2 was inhibited when the incubations were carried-on in the presence of acetyl salicilic acid (500 μM). These studies indicate that CyA exerts a direct toxic effect on endothelial cells and might help to understand the pathogenesis of CyA-induced vascular damage.
In vivo ethylenebisdithiocarbamates and ETU are toxic to the thyroid gland. Since the molecular target of these compounds is thought to be thyroid peroxidase (TPO) which catalyzes the transfer of iodine to thyroglobulin, we examined the effect of these compounds on peroxidative activity in Chinese hamster ovary (CHO) cells transfected with the human TPO gene. The activity was inhibited by 50 microM ETU, 5 microM ziram and 5 microM zineb, the last-mentioned effect being irreversible in the absence of iodide. Thiram had no effect. By contrast, the iodinating activity of TPO was blocked only by 5 microM ETU and 50 microM zineb but not by the other compounds. The effect on TPO-catalysed iodination could explain the differences in thyrotoxicity of these compounds in vivo.
Summary The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been linked to endothelial dysfunction. We investigated the relation between ADMA, symmetric dimethylarginine (SDMA) and L‐arginine concentrations and erectile dysfunction. We compared plasma levels of ADMA, SDMA and L‐arginine in 61 men in good health with erectile dysfunction of arteriogenic and non‐arteriogenic origin. Diagnosis of erectile dysfunction was based on the International Index of Erectile Function Score and its aetiology was classified with penile echo‐colour‐Doppler in basal condition and after intracavernous injection of prostaglandin E1. The ADMA and SDMA concentrations were significantly higher in men with arteriogenic erectile dysfunction compared with those with erectile dysfunction of non‐arteriogenic origin (p < 0.05) and the concentrations in both subgroups were significantly higher than in controls (p < 0.001). There was a negative correlation between ADMA and International Index of Erectile Function Score only in arteriogenic erectile dysfunction subgroup. L‐arginine did not differ significantly neither between the two erectile dysfunction subgroups (p > 0.05) nor between each of the two erectile dysfunction subgroups and controls (p > 0.05). The L‐arginine/ADMA and the L‐arginine/SDMA ratios in arteriogenic erectile dysfunction subgroups were significantly lower than both in controls (p < 0.05) and in non‐arteriogenic erectile dysfunction patients (p < 0.05); the two ratios in non‐arteriogenic erectile dysfunction patients did not differ from those in the controls (p > 0.05). We conclude that ADMA and SDMA concentrations are significantly higher and L‐arginine/ADMA ratio lower in patients who have arteriogenic erectile dysfunction compared with both patients with non‐arteriogenic erectile dysfunction and controls. The negative correlation between ADMA and severity of erectile dysfunction is present only in patients with arteriogenic erectile dysfunction. This study supports the importance to always distinguish arteriogenic from non‐arteriogenic erectile dysfunction patients to study the complicate erectogenic mechanisms that lead to erectile dysfunction and also to provide potential therapeutic agents for patients with arteriogenic erectile dysfunction.
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