Ca2+ channel antagonist actions in bladder smooth muscle: comparative pharmacologic and [3H]nitrendipine binding studies

The actions of a series of 15 Ca2+ channel antagonists including D-600, nifedipine, and diltiazem were examined against K+ depolarization and muscarinic receptor induced responses in guinea pig bladder smooth muscle. Responses of bladder are very dependent upon extracellular Ca2+ and sensitive to the Ca2+ channel antagonists, the tonic component more than the phasic component of response. Regardless of stimulant, K+ or methylfurmethide (MF), or component of response, the same rank order of antagonist activities is expressed, suggestive of a single structure-activity relationship and the existence of a single category of binding site which may, however, exist in several affinity states. High affinity binding of [3H]nitrendipine (KD = 1.1 X 10(-10) M) occurs in bladder membranes, and similar high affinity binding was found in microsomal preparations from other smooth muscles including guinea pig and rat lung, rat vas deferens, uterus, and stomach. [3H]nitrendipine binding in the bladder was sensitive to displacement by other 1,4-dihydropyridines, paralleling their pharmacologic activities and showing excellent agreement with binding data previously obtained for guinea pig ileal smooth muscle. Comparison of pharmacologic data for inhibition of K+- and MF-induced responses by a common series of Ca2+ channel antagonists in bladder and ileum revealed excellent correlations. Neither pharmacologic nor binding studies suggest significant differences in Ca2+ channel antagonist properties in smooth muscle from bladder and intestine.     

Arginine auxotrophs of Candida albicans deficient in argininosuccinate lyase

Auxotrophic mutants of Candida albicans FC18 were induced by a combination of treatments with nitrous acid and UV irradiation. Arginine (Arg-), histidine (His-) and methionine/cysteine (MetA-) auxotrophs were recovered by this means. The Arg- auxotrophs lacked active argininosuccinate lyase (EC 4.3.2.1), the enzyme catalysing the final step in arginine biosynthesis. Thus the locus may be designated arg-4. The mutant strains bearing this mutation did not form germ tubes unless the germination medium contained arginine.     

Habenular modulation of raphe indoleamine metabolism

Anatomical and neurophysiological findings have demonstrated neuronal connections between the diencephalic habenular nuclei and brain stem serotonergic raphe nuclei. Therefore we examined some neurochemical consequences of habenular lesions. Sixteen hours and one week after bilateral lesions serotonin metabolism (as reflected by concentrations of its metabolite, 5-hydroxyindoleacetic acid) was significantly increased in the dorsal but not the median raphe nuclei. Unilateral lesions produced a proportionally smaller augmentation. Motron locomotor activity was enhanced during the light and dark illumination phases in lesioned animals but only attained statistical significance during the day.     

Structural transformations of arabinogalactan from the Siberian larch during mechanochemical processing and the biological properties of the products

It has been found by gel-penetrating chromatography and quantitative ¹³C NMR spectroscopy that mechanochemical processing of arabinogalactan isolated from the wood of the Siberian larch changes the molecular mass distribution, monosaccharide composition, and the degree of branching of its macromolecules. This is due to the partial destruction of polysaccharide macromolecules and subsequent recombination of resulting fragments. The intensity of these processes depends on the conditions of mechanochemical processing. Based on the data of IR and ¹³C NMR spectra, the conclusion has been drawn that no functionalization of arabinogalactan macromolecules occurs under these conditions. The toxicopharmacological properties of mechanically processed arabinogalactan have been studied. Its acute toxicity is >5000 mg/kg.     

Maleylated-BSA suppresses IFN-gamma-mediated Ia expression in murine peritoneal macrophages

Maleylated bovine serum albumin (maleyl-BSA) and other polyanionic polymers that are recognized by cell surface receptors on macrophages have been shown to induce chemotaxis, protease secretion, and tumoricidal function in this cell type. In this paper the effect of maleyl-BSA on Ia antigen expression has been evaluated. In a fashion similar to LPS, maleyl-BSA suppressed IFN-gamma-induced expression of Ia in a time- and dose-dependent manner. Also like LPS, maleyl-BSA stimulated the production and secretion of substantial amounts of PGE2 over a 24-hr period. This did not, however, appear to be the primary mechanism by which expression of Ia was suppressed, because co-treatment of the cells with indomethacin, which totally inhibited the production of PGE2, only minimally affected the suppressive activity. Surprisingly, the suppressive activity of both maleyl-BSA and LPS could be largely abrogated by co-treatment of the cells with cyclohexamide during the time period when Ia expression was sensitive to suppression. This effect was selective in that PGE2- or dibutyryl cyclic AMP-induced suppression of Ia expression was not affected by cyclohexamide treatment. The data support the concept that there are multiple molecular mechanisms involved in the negative regulation of IFN-gamma-induced Ia expression in macrophages. Such mechanisms may include, in addition to the synthesis of PGE2 and consequent elevation in intracellular levels of cyclic AMP, one or more proteins made early after treatment with either maleyl-BSA or LPS. Thus the function of some of these early gene products may be to regulate expression of functional genes such as that encoding Ia antigen.     

Interrelation of the changes in the blood rheological properties and the microcirculatory disorders in the early and late stages of experimental hyperlipoproteinemia

Experiments were made on rabbit fed an atherogenic diet (0.5 g/kg cholesterol) singly for 15 and 24 h and repeatedly for 3, 9 and 30 days. At early stages of lipid metabolism distress the interrelationship was established between blood rheological disorders and microcirculatory abnormalities. The dependence of the initial reaction of some rheological characteristics on their initial level was marked.     

Changes in the ultrastructure of the adrenal medulla and cortex during endotoxic shock

Electron microscopy of the adrenal medulla and cortex during the intermediate period of endotoxin shock has revealed severe destructive changes in parenchymal cells. These changes are the reason for synthetic, secretory and trophic disturbances of glandular functions. Ultrastructural lesions indicate that stress exposure exceeds the adaptive capacity of cells, the majority of which are exhausted and killed.     

Osteoarthritis of the hip: an occupational disease in farmers.

OBJECTIVE--To test the hypothesis that farmers are at high risk of hip osteoarthritis and to investigate possible causes for such a hazard. DESIGN--Cross sectional survey. SETTING--Five rural general practices. SUBJECTS--167 male farmers aged 60-76 and 83 controls from mainly sedentary jobs. All those without previous hip replacement underwent radiography of the hip. MAIN OUTCOME MEASURES--Hip replacement for osteoarthritis or radiological evidence of hip osteoarthritis. RESULTS--Prevalence of hip osteoarthritis was higher in farmers than controls and especially in those who had farmed for over 10 years (odds ratio 9.3, 95% confidence interval 1.9 to 44.5). The excess could not be attributed to any one type of farming, and heavy lifting seems the likely explanation. CONCLUSIONS--Manual handling in agriculture should be limited where possible. Consideration should be given to making hip osteoarthritis a prescribed industrial disease in farmers. There may be wider implications for the prevention of hip osteoarthritis in the general population.