Urinary kallikrein activity in workers exposed to cadmium, lead, or mercury vapour

A significant reduction of kallikrein activity in urine (assayed by its amidolytic activity) was found in 64 normotensive workers who had been exposed to cadmium for 11 years on average and whose cadmium concentrations in urine ranged from 2.2 to 33.1 micrograms/g creatinine. The mean (geometric) urinary kallikrein activity (in U/g creatinine) amounted to 0.52 (range 0.11-1.90) in the control group (n = 193) against 0.39 (range 0.10-1.03) in the cadmium group, and the prevalence of abnormally low activity levels (less than or equal to 0.20 U/g creatinine) amounted to 17.2% in the cadmium group against 5.2% in the control group. A reduction of aldosterone release (aldosterone in urine) associated with an increased natriuresis was also observed. This might constitute a compensatory mechanism maintaining blood pressure in the normal range. These biological effects of cadmium were not reversible after removal from exposure. This study indicates that cadmium can induce an irreversible toxic effect in the distal nephron. It also suggests that an excessive cadmium body burden alone may not be sufficient to induce hypertension, but in individuals whose blood pressure regulation may be impaired by other factors cadmium could stimulate the development of hypertension. This study also supports the recommendation to prevent hypertensive subjects from being exposed to cadmium. There was no indication that moderate exposure to mercury vapour (n = 53; mercury in urine, range 11-224 micrograms/g creatinine; average duration of exposure: six years) or to inorganic lead (n = 23; lead in blood, range 40-67 micrograms/100 ml; average duration of exposure: eight years) was associated with a reduction of kallikrein production by the kidney.     

Effects of cadmium exposure on the cardiovascular system and on calcium metabolism: results of a cross-sectional population study.

This paper summarizes the findings of the Cadmibel Study, a cross-sectional population study of the health effects of cadmium, but only with respect to the cardiovascular system and calcium metabolism. The study disproved the hypothesis that exposure to cadmium would lead to an increase in blood pressure and in the prevalence of hypertension and other cardiovascular diseases. On the other hand, there was a positive relationship between urinary cadmium (Cd-U) and both serum alkaline phosphatase activity and urinary excretion of calcium. The regression coefficients obtained after adjustment for significant co-variates indicated that, when Cd-U increased two-fold, serum alkaline phosphatase and urinary calcium rose by 4% and 0.25 mmol/24 h, respectively. These findings suggest that calcium metabolism is gradually affected as cadmium accumulates in the body. The morbidity associated with the latter phenomenon is still unknown, and requires further investigation, preferably in a longitudinal prospective population study, in which the incidence of morbid events would be monitored in relation to the cadmium body burden.     

Dietary sodium variation, erythrocyte cationic transport and plasma renin-aldosterone in men

Erythrocyte concentrations and fluxes of sodium and potassium were investigated in normal white male subjects during dietary sodium restriction and repletion, each period lasting for 16 weeks. Intraerythrocyte sodium concentration decreased and red cell ouabain-sensitive 86Rubidium-uptake increased during dietary sodium restriction while no significant changes were observed in the total, furosemide-resistant and furosemide-sensitive sodium-efflux and the sodium, lithium-countertransport. The decrease in intraerythrocyte sodium concentration could have resulted from the observed increase in sodium, potassium-ATPase pump activity. The latter increase could have been secondary to the early decrease in a digitalis-like plasma inhibitor and the later increase could have been facilitated by the late rise in the intracellular adenosine triphosphate concentration, which is the energy supplier for this pump. During the subsequent first month of sodium repletion intraerythrocyte sodium concentration remained low. Red cell ouabain-sensitive 86Rubidium-uptake and adenosine triphosphate concentration remained elevated and returned to baseline only after 16 weeks. This long-term effect suggests either the involvement of a mechanism which can only be slowly reversible or a mechanism which is irreversible so that normalization takes place only when new red cells are released into the circulation.     

K1K2Pu, a recombinant t-PA/u-PA chimera with increased thrombolytic potency, consisting of amino acids 1 to 3 and 87 to 274 of human tissue-type plasminogen activator (t-PA) and amino acids 138 to 411 of human single chain urokinase-type plasminogen activator (scu-PA). Purification in centigram quantities and conditioning for use in man.

K1K2Pu, a recombinant t-PA/u-PA chimera with increased thrombolytic potency in animal models of venous and arterial thrombosis, which consists of amino acids 1 to 3 and 87 to 274 of human tissue-type plasminogen activator (t-PA) and amino acids 138 to 411 of human single chain urokinase-type plasminogen activator (scu-PA), was produced and conditioned for use in patients. Chinese hamster ovary cells were transfected with an expression plasmid containing the K1K2Pu cDNA, high producer cell lines were selected and scaled up in 800 cm2 roller bottles, and 350 ml conditioned cell culture medium was harvested 3 to 7 times at 2 to 5 day intervals. Batches of 21 +/- 4 liter (mean +/- SD, n = 28) containing 1.8 +/- 0.6 mg/l of K1K2Pu related antigen were purified by chromatography on Copper chelate-Sepharose and immunoadsorption on an insolubilized murine monoclonal antibody (MA-1C8). Yields were 8.6 +/- 3.4 mg K1K2Pu per batch with a specific activity of 83,000 +/- 44,000 IU/mg. The final material, obtained at a concentration of approximately 0.7 mg/ml, was dialyzed against 0.3 M NaCl, 0.02 M Tris-HCl buffer, pH 7.5, containing 0.01% Tween 80 and 10 KIU/ml aprotinin. It was homogeneous on SDS-PAGE, contained 6.5 +/- 6.9 percent two chain material and the contamination with murine monoclonal antibody was less than 0.1 percent. After filtration of pools of 3 to 5 selected batches on 0.22 microns Millipore filters the material was sterile and virus free by routine screening; it was obtained at a concentration of approximately 0.5 mg/ml with a specific activity of 110,000 +/- 16,000 IU/mg (mean +/- SD, n = 3) and an endotoxin content of 0.5 to 7 units/mg. Bolus injection at a dose of 1 mg/kg in mice did not produce weight loss within 8 days. Thus, this material appears to be suitable for the investigation on a pilot scale of the pharmacokinetic and thrombolytic properties of K1K2Pu in patients with thromboembolic disease.     

The plasminogen-activation system in ovarian tumors

We studied the plasminogen activation system in tumor tissue by measuring the antigen level of the 2 plasminogen activators, tissue-type (t-PA) and urokinase-type (U-PA) and their inhibitors, plasminogen-activator inhibitors type-1 (PAI-1) and type-2 (PAI-2) in the tissue extracts of 43 human benign and malignant ovarian tumors. U-PA levels were significantly higher in malignant than in benign tumors. In addition, U-PA antigen levels were higher in the metastatic tissue of advanced disease (FIGO stage III) than in the primary localized tumor (FIGO stage I/II). Also PAI-1 concentrations tended to be higher in malignant than in benign tumors, but this difference was not statistically significant. In contrast, t-PA levels were lower in metastatic than in non-metastatic tumors, whereas PAI-2 levels were unrelated to the stage of ovarian malignancy. These results were integrated in a plasminogen-activation-dependent malignancy index (U-PA × PAI-1/t-PA). This index distinguished the different groups of benign ovarian tumors, localized and metastatic ovarian carcinomas better than U-PA levels. It could be useful as a prognostic indicator in ovarian cancer © 1993 Wiley-Liss, Inc.     

Humoral and cellular effects of the K+-channel activator cromakalim in man

Summary The effect of cromakalim, a K⁺-channel activator, on the plasma renin-angiotensin-aldosterone system, catecholamines and -atrial natriuretic peptide, and on the intraerythrocyte concentration and transmembrane fluxes of Na⁺ and K⁺ has been investigated in 18 normal male subjects, in a double-blind parallel study. After a run-in period on placebo for 1 week, the subjects were treated either with placebo (n=6) or cromakalim (n=12) for 1 week.Plasma renin activity was significantly increased during cromakalim. No effect of cromakalim on plasma angiotensin II, aldosterone, adrenaline, noradrenaline and -atrial natriuretic peptide was demonstrated. The intra-erythrocyte K⁺ concentration was decreased during cromakalim administration and Ca²⁺-dependent K⁺-channels in red blood cells were increased.