Trace elemental analysis was carried out in the tissue samples of normal, benign hypertrophic and carcinoma prostate using the particle-induced X-ray emission technique. A proton beam of 3 MeV energy was used to excite the samples. The elements Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, Se, and Br were identified and their concentrations were estimated. It is observed that in benign tissues the concentrations of Cl, K, Zn, and Se are lower (P<0.05) and those of Cr, Fe, Ni, and Cu are higher (P<0.05 ) than in normal tissues. The concentrations of K, Ca, Zn, Se, and Br are lower (P<0.01) and those of Ti, Cr, Mn, Fe, Ni, and Cu are significantly higher (P<0.0005) in cancerous tissues than in normal tissues. Free radicals generated by elevated levels of Cr, Fe, Ni, and Cu possibly initiate and promote prostate cancer by oxidative DNA damage. The excess Cu levels in cancerous tissues support the fact that Cu promotes cancer through angiogenesis. The higher levels of Fe observed in cancerous tissues might be a consequence of tumor growth through angiogenesis. Significantly higher levels of Ni and Cr observed in carcinoma tissues support the well-established role of Ni and Cr as carcinogens. It is likely that the observed low levels of Zn and Se in cancerous tissues lead to the development of prostate cancer owing to a decrease in antioxidative defense capacity and impaired immune function of cells and also suggest that the inability to retain high levels of Zn and Se may possibly be an important factor in the development and progression of malignant prostate cells. In order to substantiate the observed elevated or deficient levels of trace elements in initiating, promoting, and inhibiting prostate cancer, several cellular and molecular studies are required.

Studies in rat and rabbit outer medullary collecting duct of inner stripe origin (OMCDis) suggest that both H(+)-ATPase and H(+)-K(+)-ATPase participate in H+ secretion. However, the relative contributions of these transporters, and, in particular, that of H(+)-K(+)-ATPase to K+ absorption have not been defined precisely. The present study was designed to delineate more clearly the response of these two transporters to hypokalemia and acidosis in a newly developed mouse OMCD1 cell line. In cells grown in normal K+ (5 mM) media, intracellular pH (pHi) recovery was similar either in the presence or absence of K+ in the perfusate (delta pHi/min = 0.014 +/- 0.001 vs. 0.017 +/- 0.003, not significant). The inhibitory effects of Sch-28080 (10 microM) and bafilomycin A1 (10 nM) on pHi recovery were evident only in the presence and absence of K+ in the perfusate, respectively. In cells grown in low-K+ (2.5 mM) media to simulate chronic hypokalemia, pHi recovery was significantly faster than in cells grown in normal K+ media (delta pHi/min = 0.045 +/- 0.01 vs. 0.014 +/- 0.001, P < 0.01) and was inhibited specifically by Sch-28080, not by bafilomycin A1. In contrast, in cells preconditioned to low pH (7.0) to simulate chronic acidosis, the enhanced pHi recovery was abolished by bafilomycin A1 but not by Sch-28080. 86Rb+ uptake, when used as a K+ congener, was inhibited by Sch-28080. The K(m) for 86Rb+ uptake (H(+)-K(+)-ATPase activity) and the 50% inhibitory concentration for Sch-28080 were 270 and 5.0 microM, respectively. These studies provide evidence that, in morphologically homogeneous OMCD1 cells, 1) both H(+)-K(+)-ATPase and H(+)-ATPase participate in pHi regulation, 2) the H(+)-K(+)-ATPase is selectively upregulated by preconditioning in low-K+ media, and 3) conversely, preconditioning in low-pH media stimulates only the H(+)-ATPase. Thus, in OMCDis, the H(+)-K(+)-ATPase and H(+)-ATPase respond selectively and independently to chronic hypokalemia and acidosis, respectively.

Studies in inner medullary collecting duct (IMCD) cells in primary culture have proposed two mechanisms for Na(+)-independent hydrogen ion transport: an H(+)-adenosinetriphosphatase (H(+)-ATPase) and an H(+)-K(+)-ATPase. In the present study, we have employed two sources of IMCD cells, cells in primary culture derived from the terminal papilla of the Munich-Wistar rat (IMCDp) and an established murine cell line (mIMCD-3), to define the predominant mechanism(s) of Na(+)-independent intracellular pH (pHi) recovery in the IMCD. In confluent monolayers of IMCDp and mIMCD-3 cells, pHi was measured using the pH-sensitive dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) following addition and withdrawal of NH4Cl. Removal of K+ completely abolished Na(+)-independent pHi recovery in both IMCDp (delta pHi/min = 0.039 +/- 0.006 to 0.005 +/- 0.003; P < 0.001) and in mIMCD-3 (delta pHi/min = 0.055 +/- 0.009 to -0.003 +/- 0.002; P < 0.001) cells, respectively. In mIMCD-3 cells, K(+)-dependent pHi recovery was abolished by either of two specific inhibitors of the H(+)-K(+)-ATPase, Sch-28080 (5 or 10 microM) or A-80915A (10 microM). In contrast, bafilomycin A1 (2.5 and 10 nM), an inhibitor of the H(+)-ATPase, failed to attenuate K(+)-dependent pHi recovery. Moreover, sequence verified mouse gastric and colonic alpha-H(+)-K(+)-ATPase probes hybridized to total RNA from mIMCD-3 cells. Based on these findings, we conclude that Na(+)-independent pHi recovery from an acid load in both IMCDp and mIMCD-3 cells in critically dependent on extracellular K(+)-That K(+)-dependent pHi recovery was inhibited by both Sch-28080 and A-80915A but not by bafilomycin A1 suggests that the predominant mechanism by which Na(+)-independent pHi recovery is accomplished in IMCD is through the H(+)-K(+)-ATPase. Expression of both gastric and colonic alpha-H(+)-K(+)-ATPase mRNA in mIMCD-3 cells suggests that one or both of these H(+)-K(+)-ATPases may be responsible for proton secretion in the IMCD.

The effects of metabolic acidosis on renal PO4 handling are controversial. Clearance experiments, therefore, were performed in fasted parathyroidectomized rats 1) to test the thesis that NH4Cl per se alters PO4 reabsorption, 2) to characterize the mechanisms responsible for these changes, and 3) to define the interaction of NH4Cl with parathyroid hormone (PTH) in PO4 deprivation. NH4Cl increased the clearance and fractional excretion of PO4 (FEPO4) without altering plasma PO4. Lactic acid and HCl, but not saline loading. NH4HCO3, or glutamine, produced similar effects. At steady-state phosphaturic effects of NH4Cl, neutralization of the acidemia by NaHCO3 abolished the increment. PTH (3.3 U.kg-1.h-1), superimposed on the maximal effective dose of NH4Cl (5.7 mmol.kg-1.h-1), further augmented FEPO4 (from 24.3 to 46.9%). The effects of NH4Cl (delta FEPO4 = 23 vs. 21%) and the synergism with PTH were not affected by PO4 deprivation. In both PO4 repletion and deprivation, NH4Cl increased basal and PTH-stimulated cAMP excretion, but the changes were poorly correlated with FEPO4. We conclude that NH4Cl inhibits PO4 reabsorption independent of PTH, extracellular fluid volume, natriuresis, NH4+ ion, plasma PO4, or the status of PO4 balance. The effects are mediated by mechanisms dependent on acidemia but are quite distinct from those of PTH. Our findings on cAMP are most compatible with the hypothesis that biochemical events beyond cAMP generation mediate both the phosphaturia of NH4Cl and its ability to restore PTH sensitivity in PO4 deprivation.

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