Biomedical subjects

D de Chaffoy de Courcelles

Publications and source records attributed to D de Chaffoy de Courcelles.

29 records · Page 2Linked to original sources

PubMed1987

Serotonin-induced alterations in inositol phospholipid metabolism in human platelets.

When human platelets were incubated for 5 min with [32P]orthophosphate and then stimulated with serotonin, the 32P content of phosphatidylinositol (PI) increased within seconds, compared with the control. The 32P content of phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) only slightly increased during the first minute after addition of serotonin and became more apparent on prolonged stimulation. These changes were not caused by serotonin-induced change in the specific activity of ATP. Using inorganic phosphate determination for the chemical quantification of different inositol phospholipid pools, we found that the platelet PI content remained nearly constant; the amount of PIP increased while that of PIP2 decreased. When the platelets were first prelabeled for 80 min with [32P]orthophosphate, the changes in 32P-labeled inositol phospholipids after addition of serotonin were similar to their changes in mass. When the platelet inositol phospholipids were labeled with myo-[2-3H]inositol, serotonin induced an increase in [3H]inositol phosphates. From these data, it is concluded in addition to the earlier-reported effects on phospholipid metabolism (de Chaffoy de Courcelles, D. et al. (1985) J. Biol. Chem. 260, 7603-7608) that serotonin induces: a very rapid formation of PI; and alterations in inositol phospholipid interconversion that cannot be explained solely as a resynthesis process of PIP2.

Adenosine Triphosphate↗

PubMed1987

Opposite regulation of serotonin-S2 and dopamine-D2 receptors in rat brain following chronic receptor blockade.

Rats were chronically treated with setoperone, a mixed serotonin and dopamine antagonist. Alterations in serotonin-S2 and dopamine-D2 receptors in the brain and changes in behavioural responses to tryptamine and apomorphine were studied along with duration of treatment and drug withdrawal. As with neuroleptics, behavioural supersensitivity to apomorphine and increase in the number of striatal dopamine-D2 receptor sites were apparent after 2 days setoperone treatment, both effects were maximal with 14 days treatment and were maintained over more than 20 days drug withdrawal. In contrast to the changes in the dopaminergic system, the rats showed a decreased response to tryptamine and serotonin-S2 receptor sites in the frontal cortex were significantly reduced in numbers. Both effects developed in parallel over 14 days treatment and extinguished over 10 days drug withdrawal. KD-values of radioligand binding to dopamine-D2 and serotonin-S2 receptor sites were unchanged by the setoperone treatment. The concomitant development and extinction of the in vivo and in vitro effects suggests a causal relationship between them. Chronic treatment with a selective histamine-H1 antagonist (levocabastine) or the tranquilizer diazepam did not affect dopamine-D2 or serotonin-S2 receptor sites. These observations demonstrate that in contrast to the receptor regulation theory, serotonin-S2 receptors are down regulated following persistent receptor blockade. Implications for the clinical use of serotonin antagonists and possible molecular mechanisms involved in the receptor regulation have been discussed.

Animals↗

PubMed1986

Agents that elevate platelet cAMP stimulate the formation of phosphatidylinositol 4-phosphate in intact human platelets.

The present study investigates the effect of compounds that are known to elevate cAMP on the phospholipid metabolism of platelets. Prostaglandin E1, forskolin and isobutylmethylxanthine induce an increase in [32P]-phosphatidylinositol 4-phosphate (PIP) in platelets prelabelled with [32P]orthophosphate. Possible roles of this phenomenon are discussed in view of the inhibitory effect of cAMP elevation on platelet activation.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites.

Upon stimulation with serotonin of washed human platelets prelabeled with [32P]orthophosphate, we found an approximately 250% increase in [32P]phosphatidic acid (PA) formation, a small decrease in [32P]phosphatidylinositol 4,5-bisphosphate, and a concomitant increase in [32P]phosphatidylinositol 4-phosphate. Using [3H]arachidonate for prelabeling, [3H]diacylglycerol accumulated transiently at 10 s after addition of the agonist, [3H]PA increased but to a lower extent compared to 32P-labeled lipid, and the formation of both [3H]polyphosphoinositides increased. The serotonin-induced dose-dependent changes in [32P]PA correlate with its effect on the changes in slope of aggregation of platelets. The potency of 13 drugs to antagonize the serotonin-induced PA formation closely corresponds to both their potency to inhibit platelet aggregation and their binding affinity for serotonin-S2 receptor sites. It is suggested that at least part of the signal transducing system following activation of the serotonin-S2 receptors involves phospholipase C catalyzed inositol lipid breakdown yielding diacylglycerol which is subsequently phosphorylated to PA.

Arachidonic Acid↗

PubMed1984

1-Oleoyl-2-acetyl-glycerol (OAG) stimulates the formation of phosphatidylinositol 4-phosphate in intact human platelets.

Diacylglycerol (DAG) is one of the primary products formed upon activation of platelets with stimuli that induce inositol lipid turnover. Its synthetic analog, 1-oleoyl-2-acetyl-glycerol (OAG) is often used as a tool for studying the involvement of the lipid in platelet activation. We found that OAG induces a concomitant increase in [32P]-incorporation in phosphatidylinositol 4-phosphate (PIP) and in the 40K protein, the endogenous substrate for protein kinase C in human platelets. It is hypothesized that in receptor mediated platelet activation a metabolic link might exist between both processes.

Blood Platelets↗

PubMed1984

12-O-Tetradecanoylphorbol 13-acetate stimulates inositol lipid phosphorylation in intact human platelets.

The phorbol esters are among the most potent tumor promoters. On addition of 12-O-tetradecanoylphorbol 13-acetate (TPA) to isolated human platelets prelabelled with [32P]orthophosphate we found a rapid increase in 32P incorporation into phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. In view of similar findings with cells infected with the oncogene Rous sarcoma virus, it is suggested that inositol lipid phosphorylation might be a key event in the molecular action of phorbol esters.

Blood Platelets↗

PubMed1984

Stimulation by serotonin of 40 kDa and 20 kDa protein phosphorylation in human platelets.

In human platelets, serotonin is known to induce a shape change followed by (reversible) aggregation. Recently, it was found that the amine triggers the elevation of cytosolic free calcium and activates phospholipase C. On stimulation of human platelets with serotonin we found an immediate increase in protein kinase C activity, phosphorylating its 40 kDa substrate protein. A 20 kDa protein, most likely the myosin light chain, was phosphorylated to the same extent. Ketanserin, a highly selective serotonin-S2 antagonist inhibited both phosphorylation processes at subnanomolar concentrations.

Blood Platelets↗

PubMed1984

Serotonin-S2 receptor binding sites and functional correlates.

Serotonin-S2 receptor binding sites have been labelled with several ligands such as [3H]spiperone, [3H]lysergic acid diethylamide (LSD), [3H]mianserin and [3H]ketanserin, the latter being the most selective ligand. The greatest concentration of the sites occurs in frontal cortical tissue, but they were also detected in striatum, nucleus accumbens and tuberculum olfactorium as well as on membranes of cat and human platelets. The serotonin-S2 sites, labelled with different ligands in different tissues, revealed similar binding properties for drugs, but careful definition of specific binding is necessary because of marked variation in the non-specific binding of drugs in different tissues. Serotonin-S2 sites were demonstrated to have a role in serotonin-induced behavioural excitation in rodents and they probably mediate perception of subjective feelings elicited by serotonin mimetics. In vivo studies revealed involvement of the serotonin-S2 sites in impairment of microcirculation by serotonin and in inflammation provoked by serotonin. On isolated tissues, serotonin-S2 sites mediate serotonin-induced vasoconstriction in peripheral blood vessels (e.g. superficial, coronary, splanchnic vessels) and cerebral blood vessels from various species including man. Serotonin-S2 sites also have a role in serotonin-induced contractions in tracheal smooth muscle and serotonin-induced bronchoconstriction in vivo, but the sites are unrelated to "M"- and "D"-serotonin receptor subtypes, which have been functionally characterized in gastrointestinal smooth muscle. Platelets proved to be an integral model for studying serotonin-S2 sites. Binding, measured on platelet membranes, was shown to be directly related to serotonin-induced platelet aggregation or changes in shape.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1980

Lipovitellin from the crustacean, artemia salina. Biochemical analysis of lipovitellin complex from the yolk granules.

The polypeptide, lipid, and carbohydrate components of the lipovitellin complex from anostracan crustacean, Artemia salina, have been investigated. The lipovitellin isolated from the yolk granules is a carotenoid.lipoglycoprotein complex, containing 3.3% carbohydrate and 8.6% lipid. About half of the carbohydrate fraction is mannose and the rest consists of galactosamine, galactose, and glucosamine. The lipid fraction contained 67% phospholipid and 33% neutral lipid. Phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine are three major phospholipid components and their relative ratio changes by developmental stages. The neutral lipid fraction is composed of mainly triacylglycerol and cholesterol. Two polypeptide chains are identified as apoprotein components of the lipovitellin complex. Their molecular weights are estimated by sodium dodecyl sulfate gel electrophoresis to be 190,000 and 68,000, respectively. The third polypeptide with Mr = 85,000 is a very minor component and exists in nonstoichiometric levels in the lipovitellin complex. On the basis of an apparent molecular weight of the lipovitellin complex determined by gel filtration chromatography, the dimeric lipovitellin form is suggested, each monomer of which contains one set of Mr = 190,000 and one set of Mr = 68,000 apoproteins. Each dimeric lipovitellin complex contains approximately 70 associated lipid molecules, of which about 4 are attributed to canthaxantin, and 100 bound carbohydrate molecules.

Amino Acids↗

PubMedDate not supplied

Is there evidence of a role of the phosphoinositol-cycle in the myocardium?

The recent findings on a more general involvement of phospholipids in signal transduction and on the different roles of inositolphospholipids in particular, thoroughly complicate research in this field. It becomes increasingly evident that measuring [3H]inositolphosphate formation alone will never provide insight into the complex machinery of cellular signalling. Certainly for the heart in which the role(s) of the inositolphospholipids is far from clarified, the novel trends provide new directions for research.

Animals↗

PubMedDate not supplied

Cardiac and hemodynamic effects of intravenous R 80122, a new phosphodiesterase III inhibitor, in anesthetized and awake dogs.

R 80122 is a newly synthesized, selective phosphodiesterase III inhibitor. The cardiac and hemodynamic effects of this compound following intravenous administration were studied in closed-chest anesthetized as well as in conscious chronically instrumented dogs. The findings in the closed-chest anesthetized dogs indicate that R 80122 has positive inotropic and possibly moderate vasodilating properties [maximum increase in LV dp/dtmax/pd: 61%, and maximum decrease in systemic vascular resistance: 29% (a 12.5% decrease for the solvent)]. As a result, cardiac output maximally increased to 149% of the control value. The most striking effect of R 80122 was its positive lusitropic effect (maximal decrease in the time constant of relaxation [T] of 46%). This pronounced lusitropic effect of R 80122 can be regarded as beneficial, because of the increasing evidence that lusitropic defects play an important role in disorders related to heart failure. These effects of R 80122 were associated with only slight changes in arterial blood pressure. The effects of R 80122 lasted about 75 min after stopping the infusion. No ventricular arrhythmias were noted during and after infusion of the compound. The positive inotropic effects seen in anesthetized dogs were confirmed in conscious nonsedated dogs. It may be concluded that R 80122 has a clinically favorable cardiovascular profile for acute applications in heart failure, because its combined positive inotropic and positive lusitropic effects, and moderate vasodilating properties lead to a pronounced increase in cardiac output and only minimal changes in aortic blood pressure.

Anesthesia↗