. EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis. Am J Physiol Heart Circ Physiol 289: H99 -H107, 2005. First published February 25, 2005 doi:10.1152/ajpheart.00901.2004.-Arsenic exposure is associated with an increased risk of atherosclerosis and vascular diseases. Although endothelial cells have long been considered to be the primary targets of arsenic toxicity, the underlying molecular mechanism remains largely unknown. In this study, we sought to explore the signaling pathway triggered by sodium arsenite and its implication for endothelial phenotype. We found that sodium arsenite produced timeand dose-dependent decreases in human umbilical vein endothelial cell viability. This effect correlated with the induction of p21Cip1/Waf1 (up to 10-fold), a regulatory protein of cell cycle and apoptosis. We also found that arsenite-stimulated EGF (ErbB1) and ErbB2 receptor transactivation, manifest as receptor tyrosine phosphorylation, appeared to be a proximal signaling event leading to p21Cip1/Waf1 induction, because both pharmacological inhibitors and knockdown of receptors by RNA interference blocked arsenite-induced p21Cip1/Waf1 upregulation. Arsenite-induced activation of JNK and p38 MAPK was distinct, with only JNK as a downstream target of the EGF receptor. Moreover, inhibition of JNK with SP-600125 or dominant negative MKK7 inhibited only p21Cip1/Waf1

(Text-figs. I and 2) 161 Combined inorganic nitrogen occurs in sea water principally as nitrate, nitrite and ammonium ions, the concentrations of which lie in the ranges I-600 mg N03--Njm3, 0'1-5°mg N02--Njm3 and 5-50 mg NH4LNjm3 respectively. Nitrogen occurring in any of these forms is readily assimilable by marine organisms, and its exhaustion in sea water is frequently a growthlimiting factor in the water. This paper describes a method for the determination of the total ionic inorganic nitrogen in sea water, based on preliminary reduction to ammonia followed by separation and estimation of the latter colorimetrically.Riley (1953) has discussed the determination of ammonia in sea water, and has concluded that ammonia is best separated from the water, adjusted to pH 9'2, by distillation under reduced pressure in a current of air as described by Krogh (1934). The distillation process is rather time-consuming and requires a special apparatus. Experiments were therefore carried out to separate the ammonia by diffusion. It was found that the capacity of the concentric microdiffusion cells employed by Conway (1950, p. 8) was too small for the volume of sea water which was necessary if low concentrations of ammonia were to be determined. When diffusion was carried out in the flasks (Fig. I) described by Cavett (1937) for the microdetermination of alcohol in blood, reproducible recoveries of approximately 73 % of added ammonium salt were obtained from 50 ml. of sea water after diffusion at 70°C for 24 h at pH 9'2 (Table I).

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