Benchmark Dose Estimation for Cadmium-Induced Renal Effects Based on a Large Sample Population from Five Chinese Provinces.

A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium (UCd) for renal dysfunction as benchmark dose low (BMDL). The urinary N-acetyl-ß-D-glucosaminidase (UNAG) was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18 µg/g creatinine (cr) to 4.26 µg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses (BMR) of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 µg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males.

Role of voltage-gated potassium channels in pathogenesis of chronic pulmonary heart disease.

The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells (PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group (n=10), acute hypoxic group (n=10), and chronic hypoxic groups (n=60). The chronic hypoxic groups were randomly divided into 6 subgroups (n=10 each) according to the chronic hypoxic periods. The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia environmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and the current of voltage-gated potassium channel (I K) in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the I K in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak I K density at +60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density of I K (at +60 mV) and I-V relationship between control group and chronic hypoxic subgroup exposed to hypoxia for 5 days (P>0.05), but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days (P<0.05). Significant differences were noted in the I K density (at +60 mV) and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Compared with control rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days (P<0.05), which were further increased with prolongation of hypoxia exposure, and there were significant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Both the mPAP and the RVHI were negatively correlated with the density of I K (r=-0.89769 and -0.94476, respectively, both P<0.01). It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasoconstriction (HPV). Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease.

Congenital long QT syndrome caused by the F275S KCNQ1 mutation: mechanism of impaired channel function.

Congenital long QT syndrome is characterized by a prolongation of ventricular repolarization and recurrent episodes of life-threatening ventricular tachyarrhythmias, often leading to sudden death. We previously identified a missense mutation F275S located within the S5 transmembrane domain of the KCNQ1 ion channel in a Chinese family with long QT syndrome. We used oocyte expression of the KCNQ1 polypeptide to study the effects of the F275S mutation on channel properties. Expression of the F275 mutant, or co-expression with the wild-type S275 polypeptide, significantly decreased channel current amplitudes. Moreover, the F275S substitution decreased the rates of channel activation and deactivation. In transfected HEK293 cells fluorescence microscopy revealed that the F275S mutation perturbed the subcelluar localization of the ion channel. These results indicate that the F275S KCNQ1 mutation leads to impaired polypeptide trafficking that in turn leads to reduction of channel ion currents and altered gating kinetics.

Effects of platelet activating factor on action potentials and potassium channels in guinea-pig ventricular myocytes.

This study was designed to investigate the effects of platelet activating factor (PAF) on the action potential and potassium currents in guinea-pig ventricular myocytes. Whole cell patch clamp techniques were used. With 5 mmol/L ATP in the pipette electrode(mimic normal condition), 1 micromol/L PAF increased APD(90) from 225.8+/-23.3 to 352.8+/-29.8 ms (n=5, P<0.05), decreased I(K1) and I(K) tail currents from -6.1+/-1.3 to -5.6+/-1.1 nA (n=5, P<0.05) at -120 mV and from 173.5+/-16.7 to 152.1+/-11.5 pA (P<0.05, n=4) at +30 mV, respectively. But PAF had no effect on I(K1) at potentials within the normal range of membrane potentials (between -90 mV and +20 mV). In the contrary, without ATP in the pipette electrode by which I(K.ATP) was activated (mimic ischemic condition), 1 micro mol/L PAF shortened APD(90) from 153+/-24.6 to 88.2+/-19.4 ms (n=5, P<0.01). Incubation of myocytes with 1 micro mol/L glibenclamide, a blocker of I(K.ATP ) could restore prolongation of APD induced by PAF. In conclusion, in guinea-pig ventricular myocytes, with 5 mmol/L ATP in the pipette PAF could prolong APD partly due to the inhibition of I(K); while with 0 mmol/L ATP in the pipette, PAF could induce an activation of I(K.ATP), hence a decrease in APD. It is suggested that PAF may amplify the heterogeneity between ischemic and normal cardiac myocytes during ischemia /reperfusion, which may play a vital role in the pathogenesis of the arrhythmias induced by ischemia /reperfusion.