Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers

Aim - The aim of the study was to determine the potential for KV1 potassium channel blockers as inhibitors of human neoinitimal hyperplasia. Methods and results - Blood vessels were obtained from patients or mice and studied in culture. Reverse transcriptasepolymerase chain reaction and immunocytochemistry were used to detect gene expression. Whole-cell patch-clamp, intracellular calcium measurement, cell migration assays, and organ culture were used to assess channel function.  KV1.3 was unique among the  KV1 channels in showing preserved and up-regulated expression when the vascular smooth muscle cells switched to the proliferating phenotype. There was strong expression in neointimal formations. Voltage-dependent potassium current in proliferating cells was sensitive to three different blockers of  KV1.3 channels. Calcium entry was also inhibited. All three blockers reduced vascular smooth muscle cell migration and the effects were non-additive. One of the blockers (margatoxin) was highly potent, suppressing cell migration with an IC of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia. Conclusion - KV1.3 potassium channels are functional in proliferating mouse and human vascular smooth muscle cells and have positive effects on cell migration. Blockers of the channels may be useful as inhibitors of neointimal hyperplasia and other unwanted vascular remodelling events. © 2010 The Author.

Microsegregation in nodular cast iron and its effect on mechanical properties

A review of the literature pertaining to the mechanical properties, solidification and segregation effects in nodular cast iron has been made. A series of investigations concerning the influence of microsegregation on mechanical properties of :pearlitic, ferritic and austenitic nodular cast iron have then been reported. The influence of section size on the tensile and impact properties of cornmercial purity and refined ferritic nodular cast iron has been studied. It has been shown. that an increase in section caused a decrease in impact transition temperature of the commercial purity material without greatly affecting the impact transition temperature of the purer material. This effect has been related to increased amounts of segregation effects such as cell boundary carbides in heavier sections of the commercial purity material. Microsegregation studies on the materials used in this thesis have been carried out using an electron probe microanalyser. This technique has shown that concentrations of chromium and manganese and depletions of nickel and silicon occurred at eutectic cell boundaries in nodular cast iron and were often associated with brittle carbides in these areas. These effects have been shown to be more prevalent in heavier sections. The nature of segregation during the solidification of nodular cast iron has been studied by quenching samples of nodular iron during the solidification process. Micro-analysis of such samples has shown that segregation of manganese and chromium occurs by a gradual build-up of these elements at the solid/liquid interface. The microstructures of the quenched specimens revealed carbide filaments connecting graphite nodules and areas of quenched liquid. These filaments have been used as evidence for a revised hypothesis for the solidification of nodular cast iron by a liquid diffusion mechanism. A similar series of experiments has been carried out on two high nickel austenitic irons containing 0.5 per cent manganese and 4 per cent manganese respectively. In both these materials a decrease in elongation was experienced with increasing section. This effect was more drastic in the 4 per cent manganese material which also contained much greater amounts of cell boundary carbide in heavy sections. Micro-analysis of samples of the 4 per cent manganese material quenched during solidification revealed that manganese concentrated in the liquid and that nickel concentrated in the solid during solidification. No segregation of silicon occurred in this material. Carbide filaments appeared in the microstructures of these specimens. A discussion of all the above effects in terms of current concepts is included.