Edwin D. Bransome

Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline

The mechanism of action of the negative inotropic (relaxing) effect of the methylxanthine theophylline on respiratory smooth muscle is generally assumed to involve inhibition of cyclic nucleotide phosphodiesterase. When guinea pig tracheal rings or dog tracheal muscle strips were incubated with low concentrations of theophylline capable of producing a significant negative inotropic effect in vivo and in vitro, there was no alteration of cyclic 3′,5′-adenosine monophosphate (cAMP) or cyclic 3′,5′-guanosine monophosphate (cGMP) levels.45Ca uptake increased however, and there was a subcellular redistribution of elemental calcium consistent with a sequestration of calcium in mitochondria and a decrease of myoplasmic calcium ion (Ca++) concentration.

Ureterosigmoidostomy and Cancer: New Observations

Excerpt During the past years there has been an increasing number of reports of colonic cancer arising at the sites of implantation of the ureters into the colon (1). Tank, Karsch, and Lapides (2),...

Structure — activity relationships of some unique estrogens related to estradiol are predicted by fit into dna

The estrogenic activity of 11 beta-acetoxy estradiol, 11 beta-hydroxy estradiol, 11 alpha-hydroxy estradiol and 9 beta-estradiol was compared to estradiol using the restoration of uterine weight and prevention of LH rise in immature ovariectomized rats as endpoints of the assay. There was a good correlation between results using the two methods and estrogenic activity was found to be in the following order: 11 beta-acetoxy estradiol greater than estradiol greater than 9 beta-estradiol greater than 11 beta-hydroxy estradiol greater than 11 alpha-hydroxy estradiol. The biological activities of these compounds could be explained on the basis of stereochemical complementarity to the structure of DNA.

The ligand insertion hypothesis in the genomic action of steroid hormones

Gene regulation by steroids is tightly coupled to hormone concentration and stereochemistry. A key step is binding of hormones to receptors which interact with consensus DNA sequences known as hormone response elements (HREs). The specificity and strength of hormone binding do not correlate well with hormonal activity suggesting an additional step involving recognition of ligand by the gene. Stereospecific fit of hormones between base pairs and correlation of fit with hormonal activity led to the proposal that such recognition involves insertion of hormone into DNA. Here, the feasibility of insertion was investigated using computer models of the glucocorticoid receptor DNA binding domain bound to its HRE. The site reported to accommodate glucocorticoids was found in the HRE and was exposed to permit unwinding at this locus. The resulting cavity in the unwound DNA/receptor interface fit cortisol remarkably well; cortisol formed hydrogen bonds to both the receptor and DNA. Current experimental evidence is generally consistent with ligand binding domains of receptors undergoing a conformational change which facilitates transfer of the ligand into the unwound DNA/receptor interface. We propose this step is rate limiting and alterations in receptor, DNA or hormone which attenuate insertion impair hormonal regulation of gene function.

Hypoglycemia caused by selegiline, an antiparkinsonian drug: can such side effects be predicted?

Treatment with selegiline produced profound hypoglycemia in a 70‐year‐old man with Parkinsons disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959–1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.

Apparent stereochemical complementarity of estrogens and helical cavities between DNA base pairs: Implications for the mechanism of action of steroids

The shape of the space occupied by a model of the estrogenic steroid hormone estradiol-17 beta conforms closely to a helical cavity between neighboring base pairs in partially coiled B-DNA. The orientation of estradiol-17 beta when fitted into DNA allows stereochemically complementary hydrogen bonding of both the 3- and 17 beta-hydroxyl groups to phosphate oxygens of the deoxyribose-phosphate backbone on adjacent strands. Changes in the chirality (handedness) of the steroid skeleton or in the absolute stereochemistry of hydrogen bonding groups prevent formation of complementary fits in the DNA. Synthetic estrogens can also adopt conformations which are stereochemically complementary to the cavities between base pairs. The complementary relationships between active estrogens and nucleic acids may be related to constraints on the evolution of the structure and the biological function of steroids.

Primary culture and maintenance of steroid-secreting human placental monolayers

SummaryA simple method is described for primary culture and for maintenance of hormone-producing cells from normal human placenta. A consistent yield of cells was obtained and an average survival of 3 to 4 months in culture using 1 mm3 explants from the most vascular area of the placentas. These explants were placed in a variety of culture media in 30 ml flasks and incubated at 37°C in an atmosphere of 5% CO2 and 95% air. The best yields in terms of cell growth were observed with Eagle’s MEM (minimum essential medium) with supplements of horse serum and fetal calf serum or human cord serum. (Ham’s F-10 with supplement of horse serum and fetal calf serum supports growth for the longest period and media containing human cord serum had the best yield of steroids.)

Are there structural analogies between amino acids and nucleic acids

Space-filling molecular models have been used to examine structural analogies between amino acids and nucleic acids. The three-dimensional structures of amino acidR groups appear to be stereochemically related to cavities formed by removal of single bases in double helical nucleic acids. The common L amino acids may thus be complementary to their codons.

Alkalotic disequilibrium in patients with solid tumors: Rediscovery of an old finding

Abstract Acid-base equilibrium in two groups of cancer patients, one with newly diagnosed bronchogenic cancer and one with various solid tumors, was compared to that of a group of normal volunteers and a group of hospitalized patients with diverse diseases. A consistent tendency toward alkalosis was found in both groups of cancer patients. Similar findings reported in the literature of 40–70 years ago are discussed and the possible biochemical implications of these findings considered. It is our hope that this report of findings obtained with modern technology will encourage studies of the effects of alkalinity in the pathogenesis and progression of cancer.

Crown ethers which influence cardiac and respiratory muscle contractility

Guinea-pig tracheal smooth muscle and heart muscle demonstrated a variety of in vitro positive and negative inotropic responses to concentrations of crown ethers in the nmole/l to μmole/l range. It is suggested that these ionophoretic compounds have potential as therapeutic agents.