Substituted piperidin-2-one biphenyltetrazoles as angiotensin II antagonists

A novel series of substituted piperidine-2-ones has been identified as antagonists of angiotensin II. These compounds showed high affinity for the receptor in bovine adrenal cortex binding assays with IC₅₀'s as low as 20nM. They are potent inhibitors of angiotensin II induced contractions in rabbit aortic rings, with pA₂ values as high as 9. A number of these compounds are also orally active as antihypertensives in spontaneously hypertensive rat preparations.     

Maturation-related changes in mass and elemental contents of secretory granules as measured by electron-microprobe

Summary The relationship between granule density, protein content, and Ca and S contents were studied in two secretory granule fractions, from parotid glands of the rat, previously shown to constitute different stages in granule maturation. The density of the lighter fraction was between 1.133 and 1.142 g/ml, while that of the heavier fraction was greater than 1.142 g/ml. The mean protein content of the denser granules was 12% greater than that of the lighter granules (P<0.03), while the dry-mass elemental concentrations in the two granule fractions were unchanged. These results indicate that protein is added to granules during the maturation process (presumably by vesicular traffic), and that the resulting increase in granule density is not driven simply by decrease in water content and/or increased concentrations of inorganic Ca or S in the granules. The elemental concentration values also indicate that the diffusible elements permeate the granule membrane during the fractionation procedures.     

Role of tumour necrosis factor in the tumour-necrotizing activity of agents with diverging toxicity

Summary We investigated the ability of various tumournecrotizing agents with diverging toxicity to induce tumour necrosis factor (TNF) and cytostatic activity inPropionibacterium-acnes-primed Swiss and tumour-bearing BALB/c mice, and the capacity of anti-TNF antibodies to inhibit induction of tumour necrosis by the agents. Lipid A and especially its combination with muramyl dipeptide induced high TNF levels in Swiss mice, as measured in the serum. Lower levels were induced by detoxified lipid A and the nontoxic dsRNA, polyadenylic polyuridylic acid, either alone or combined with muramyl dipeptide. The toxic agents also appeared the strongest inducers of mediators with cytostatic activity against cultured endothelial cells and MethA tumour cells. Anti-TNF antibodies partially reduced the cytostatic activity of the sera against MethA cells. Tumour-bearing BALB/c mice produced only low levels of TNF and cytostatic factors in response to all agents. Recombinant mouse TNF hardly reduced the DNA synthesis of MethA cells, unless normal mouse serum was added. Serum fromP.-acnes-treated Swiss mice and tumour-bearing BALB/c mice, that were inhibitory on their own, failed to potentiate the action of TNF. Serum from Swiss mice treated with toxic, but not detoxified, lipid A caused extensive tumour necrosis upon injection into MethA-bearing BALB/c mice. This activity was completely abolished by pre-incubation of the serum with anti-TNF. The tumour-necrotizing activity of the agents could be partially reduced by prior injection of these antibodies. Results show that the capacity of the agents to induce TNF and cytostatic activity is not related to their antitumour potential. Although TNF is likely to be a crucial mediator of the tumour-necrotizing action of the toxic as well as the nontoxic agents, it is probably not the sole mediator. Data also indicate that induction of tumour necrosis does not require induction of high and, thus toxic, TNF levels in the serum.     

Habitat selection and subsequent reproductive success in the beaugregory damselfish

Synopsis Male beaugregory damselfish,Stegastes leucostictus, were provided with three types of artificial breeding structures to determine if they change habitats based on past or future reproductive payoffs. All three site types quickly lured males away from their natural sites. In comparison to those living on natural sites, those using artificial sites were less likely to move to different areas and had a higher reproductive success. When given no choice, male reproductive success was correlated to structural type. A second experiment provided males with an additional structure after using the intermediate quality type for 2 months. Males would often initially use both sites but would eventually shift their spawning activity to the new site if it was of the same quality or better than the old one. However, males would not move if the new site was of inferior quality. When given a new site identical to the initial one, approximately half of the males shifted to the new site. There was no evidence that reproductive performance influenced a male's decision to use a new site.     

Characterization of the morphological, growth, and steroidogenic effect of TPA on mouse Y-1 adrenal cortical tumor cells in culture

The tumor-promoting agent 12-0-tetradecanoyl-phorbol-13-acetate (TPA) caused a time- and dose-dependent morphological change in Y-1 adrenocortical tumor cells. The morphological alteration was apparent 2 hr following addition of 1 microgram/ml TPA to cell cultures and became more striking with longer treatment times. Smaller doses of TPA took a longer time to produce an effect. Cultures grown in the presence of TPA exhibited more rounding and piling up of cells than similar cultures maintained in medium lacking TPA. These TPA-stimulated morphological changes were reversible, and after 24 hr in TPA-free media, the cultured cells began to flatten. After 96 hr in TPA-free media they resembled the control cultures. The reversibility of the morphological change was also dose dependent: cells treated with 1 microgram/ml TPA took a longer time to resume the typical control morphology than did cultures treated with 0.01 microgram/ml TPA. In addition, TPA treatment resulted in a decrease in cell growth rate, an increase in steroid production, and an increase in the localization of free catalytic units of cAMP-dependent protein kinase in the cytoplasm. The steroidogenic effect of ACTH on the cell population was inhibited in cultures maintained in TPA. The results of this study indicate that TPA induces morphological changes in the Y-1 adrenocortical tumor cell population while increasing steroidogenesis and the activation of cAMP-dependent protein kinase and decreasing cell growth rate.     

Structure of an S layer on a pathogenic strain of Aeromonas hydrophila.

Negative staining revealed a tetragonal surface array (S layer) on all the members of a serogroup of Aeromonas hydrophila which possess high virulence for fish. The S layers were similar on all the strains examined, with unit cell dimensions of approximately 12 nm. A single representative strain, strain TF7, was selected for further analysis. Freeze-cleaved and etched preparations and sections for electron microscopy showed that the S layer was the outermost component of the cell envelope. This was confirmed by observation of thin sections. Computer-generated enhancements of the negatively stained micrographs showed the subunit organization to a resolution of less than 4 nm. Two structural units of identical lattice constants alternated in the array in both axes, and one of them was apparently dominant as the center of mass. The lesser unit was rotated 20 degrees from the dominant axes of symmetry and was formed by the junction of linker projections from a corner of the four components of the dominant unit. This interpretation was supported by finding that the array consists of a single polypeptide (molecular weight, 52,000). The unit cell as defined showed p4 symmetry, and a = b = 12.2 nm.