Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction

Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Nitric oxide is the major endothelium-derived relaxing factor (EDRF), and it is thought to relax smooth muscle cells by stimulation of guanylate cyclase, accumulation of its product cyclic GMP, and cGMP-dependent modification of several intracellular processes, including activation of potassium channels through cGMP-dependent protein kinase. Here we present evidence that both exogenous nitric oxide and native EDRF can directly activate single Ca(2+)-dependent K+ channels (K+Ca) in cell-free membrane patches without requiring cGMP. Under conditions when guanylate cyclase was inhibited by methylene blue, considerable relaxation of rabbit aorta to nitric oxide persisted which was blocked by charybdotoxin, a specific inhibitor of K+Ca channels. These studies demonstrate a novel direct action of nitric oxide on K+Ca channels.

Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle

An attempt is made to elucidate the cellular mechanisms which may account for the well-documented correlation between sodium metabolism and peripheral vascular resistance. As a starting point, the ...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.1977.232.5.C165

Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis

Calcium antagonism and calcium entry blockade.

Alison Abbott Eric A. Barnard Tom I. Bonner Phillip B. Bradley George J. Cosmides B. N. Dhawan C. T. Dollery C. R. Ganellin T. Godfraind J. P. Green M. Hamon P. P. A. Humphrey D. H. Jenkinson T. Kenakin S. Z. Langer T. Masaki R. Paoletti M. Spedding (Secretary) U. G. Trendelenburg P. M. Vanhoutte (Chairman) M#{252}nchen, Germany London, United Kingdom Bethesda, Maryland, USA Birmingham, United Kingdom Bethesda, Maryland, USA Lucknow, India London, United Kingdom London, United Kingdom Bruxelles, Belgium New York, USA Paris, France Cambridge, United Kingdom London, United Kingdom North Carolina, USA Paris, France Kyoto, Japan Milano, Italy Suresnes, France Tubingen, Germany Courbevoie, France

https://pharmrev.aspetjournals.org/content/pharmrev/46/2/111.full.pdf

International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification.

With the endothelium present, the maximum response of rat isolated aorta to clonidine was much lower than that to noradrenaline. Removal of endothelium enhanced the response to both adrenoceptor agonists and the clonidine-induced maximum contraction became almost equal to that produced by noradrenaline, although it was much more sensitive to inhibition by flunarizine and nifedipine. These results indicate that clonidine and noradrenaline activate receptors present in the endothelial cells and that these receptors are highly sensitive to clonidine.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1984.tb10736.x

Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cells.

1. The Na, K, Ca and Mg content and the 45Ca uptake and loss were determined in rat aortae incubated in physiological solution or in solution containing LaCl3 instead of CaCl2. 2. Aortae washed in La-solution contained less Ca and Na than controls in physiological solution, the K content was not modified and the Mg content was slightly decreased. 3. In 50 mM-La solution the 45Ca diffusion space was intermediate between the values found for the [14C]sorbitol space and the [14C]inulin space, indicating that there was no Ca entry within the cell nor Ca binding at superficial sites. 45Ca loss from the tissue was directly related to the La concentration. 4. Noradrenaline increased the rate of uptake of 45Ca into the Ca fraction resistant to displacement by La. This increase was dose dependent, a response of 50% of the maximum being produced by 2 x 10(-8) noradrenaline as for the contraction. In the presence of phentolamine, the dose-effect curves for the action of noradrenaline on 45Ca uptake were displaced in a manner characteristic of competitive antagonism. The rhoA2 for phentolamine was 7-8. 5. In physiological solution, the rate of loss of 45Ca, from the Ca fraction resistant to displacement by La, was increased by noradrenaline the ED50 was 2 x 10(-8) M, and the effect was abolished by phentolamine. 6. In view of the similarity of phentolamine rhoA2 estimated by measuring noradrenaline sensitive 45Ca uptake or noradrenaline evoked contraction, it is likely that the activation of alpha-adrenergic receptors is responsible for both effects.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1976.sp011501

Calcium exchange in vascular smooth muscle, action of noradrenaline and lanthanum.

1. Mesenteric arteries immersed in a depolarizing solution contract in the presence of calcium. These contractions are proportional to the calcium concentration and are reversible.

2. Mesenteric arteries immersed in a calcium-free depolarizing solution contract in the presence of adrenaline. Under the experimental conditions reported here, this response develops only about one-third of the contractile tension developed in polarizing solution (modified Krebs bicarbonate).

3. Cinnarizine and chlorpromazine inhibit the contractile response to calcium and induce relaxation of depolarized muscle previously contracted by calcium; cinnarizine was 4 times more potent than chlorpromazine in such activity.

4. Chlorpromazine inhibits the response to adrenaline in both polarizing and calcium-free depolarizing solutions, whereas cinnarizine inhibits the response in polarizing solution but not that in calcium-free depolarizing solution.

5. The significance of these results is discussed.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1969.tb08010.x

Theophile Godfraind

Papers

Calcium antagonism and calcium entry blockade.

International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification.

Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cells.

Calcium exchange in vascular smooth muscle, action of noradrenaline and lanthanum.

Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle.