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P Falardeau

Publications and source records attributed to P Falardeau.

At least 73 records · Page 4Linked to original sources
PubMed1985

The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form.

In order to determine whether the high affinity state or the low affinity state of the dopamine receptor mediated the inhibition of release of PRL by dopamine agonists, a large number of dopaminergic agonists (n = 31) and antagonists (n = 24) were tested for their potencies to inhibit the binding of [3H] spiperone to porcine anterior pituitary tissue, and for their potencies to affect the release of PRL from rat anterior pituitary cells in culture. All agonists (except bromocriptine, ergocryptine, and dihydroergocryptine) inhibited [3H]spiperone binding in two phases: one phase occurred at nanomolar or subnanomolar concentrations (representing the high affinity state of the dopamine receptor) and the other phase occurred at much higher concentrations of agonist (the low affinity state of the dopamine receptor). The dissociation constants (K) for each drug at each state were derived by computer, with the program LIGAND. It was observed that the agonist K values for the high affinity state were virtually identical with those agonist concentrations inhibiting PRL release; the K values for the low affinity state were about 2 orders higher. These data suggest that the high affinity state of the D2 dopamine receptor is the functional state which mediates the inhibition of PRL release.

Animals↗
PubMed1984

Dopamine receptors in rat pituitary and estradiol-induced pituitary tumor: effect of chronic treatment with bromocriptine.

We have investigated dopamine (DA) receptors in estradiol-induced PRL-secreting pituitary tumors and intact pituitary tissue. Female rats were injected at 3-week intervals with 2 mg estradiol valerate (EV) or with diluent. After 21 weeks, adenomatous changes in the pituitary gland of EV-treated rats were seen and plasma PRL concentrations reached 2 micrograms/ml. Bromocriptine (2.5 mg/kg) was then administered for 1 month to half of the control rats and half of the rats bearing tumors. Anterior pituitary weight was increased in EV-treated rats compared to controls while the affinity and the density of DA receptors as assessed by [3H]spiperone binding remained unchanged. Bromocriptine (CB-154) induced a 70% decrease in the density of DA receptors without any change in affinity both in normal pituitaries and in tumors. Concurrently, the elevated plasma concentrations of PRL in the tumor bearing rats were decreased to control values following the CB-154 treatment. Our data suggest that rats with primary estrogen-induced PRL secreting tumors have normal pituitary DA receptors.

Adenoma↗
PubMed1984

[Prostaglandins and thromboxanes].

Prostaglandins and thromboxanes are 20-carbon-atom-chain fatty acids which contain a cyclopentane or oxane nucleus respectively. They belong to a family of icosanoids whose main intracellular precursor is arachidonic acid. These icosanoids are synthetized in all tissues (except red cells). Enzymatic hydrolysis of the arachidonic acid of lipids is the first step of their biosynthesis. This step, which is limitative, is usually catalyzed by phospholipase A2 and may be indirectly inhibited by glucocorticoids. Once released, arachidonic acid is promptly transformed into an endoperoxide intermediary through the action of an enzymatic complex called "cyclooxygenase". This intermediary is the precursor of both prostaglandins and thromboxane. Non-steroidal antiinflammatory agents such as acetylsalicylic acid and indomethacin have an inhibitory action on cyclooxygenase. The mechanisms of action of prostaglandins and thromboxane are still poorly understood. In certain tissues (platelets, adipose cells) their effect seems to involve stimulation of adenyl-cyclase and/or guanyl-cyclase. In other tissues (smooth muscle) their biological action is associated with changes in transcellular flows of calcium. Prostaglandins and thromboxane have many biological properties. Their effects are local, as they are produced in small quantities and promptly metabolized. They act more often as cell function modulators than as essential mediators. The often conflicting biological actions of these icosanoids involve: a) smooth muscles (stimulation or relaxation of blood vessel, respiratory tract, digestive tract and genitourinary tract musculatures); b) platelets (induction or inhibition of aggregation); c) the inflammatory reaction; d) the cellular fluid and electrolyte transports; e) and certain metabolic functions (lipolysis, insulin release, renin release, mobilization of bone calcium...). The advances achieved over the last decade now provide some insight into the significance of the physiologic role of icosanoids. Several prostaglandins, as well as some of their analogues, are already being used as therapeutic agents. In the future, rational manipulation of dietary fatty acids and development of selective inhibitors can be expected to provide the necessary tools for better controlling the icosanoid system in medicine.

Animals↗
PubMed1984

Behavioral and biochemical evidence of apomorphine-induced supersensitivity of the striatal dopamine receptors.

The effect of repeated administration of apomorphine was studied behaviorally and biochemically in rats bearing either a unilateral lesion of the substantia nigra with 6-OHDA or an electrolytic lesion of the entopeduncular nucleus. Rats with the nigral lesion displayed a progressive increase in contralateral circling rate. In animals with the entopeduncular lesion, the ipsiversive circling response was unchanged after the eight injection of apomorphine. [3H] Spiroperidol binding to striatal membranes did not appear modified by the apomorphine treatment on the intact side. It was however increased on the side of the 6-OHDA lesion. We propose that a denervated striatum responds to repeated stimulation by dopamine agonists with a paradoxical increase in sensitivity. This may explain in part the appearance of dyskinesia in treated parkinsonian patients.

Animals↗
PubMed1984

5-Hydroxytryptamine synthesis, storage, and secretion from rat pancreatic acinar cells.

Pancreatic acinar cells are known to synthesize serotonin and dopamine from extracellular precursors. In this study, we found that small amounts of serotonin, alone, were preferentially stored in zymogen granules of acinar cells. Serotonin was apparently incorporated into mature rather than newly formed granules. This was based on the fact that the amine, rather than the newly synthesized zymogen protein, appeared first in the purified granule fraction; additionally, concentrations of cycloheximide, which markedly inhibited de novo synthesis of zymogen protein, did not affect the incorporation of serotonin into the granule fraction. Serotonin, synthesized by the acinar cells, can be secreted along with amylase in a time- and concentration-dependent manner following stimulation of acinar cells by a variety of pancreatic secretagogues. Whether serotonin secreted into pancreatic juice has a biological function remains unknown.

Amylases↗
PubMed1983

Fatty acid composition of tissue phospholipids and prostaglandin excretion in hyperlipidemia induced in rats by implantation of the mammotropic pituitary tumor MtT-F4.

A mammotropic pituitary tumor, MtT-F4, was implanted into male Fisher 344 rats for a period of 4 weeks. This tumor induced growth retardation, hyperlipidemia, hepatic hypertrophy and adrenal hyperplasia. Lipids were extracted from various tissues. In tumor-bearing rats, phospholipid concentration was found to be increased in plasma, spleen and testis. Distribution among the various phospholipid classes was similar to that of controls except in liver and heart, where phosphatidylcholine was increased at the expense of phosphatidylinositol and phosphatidylserine. The main difference was in the fatty acid composition of major phospholipids. The proportion of omega 6 fatty acids was lower and that of docosahexaenoic acid of the omega 3 series (22:6 omega 3) was higher in most tissues, especially in plasma, liver, heart and kidney. Concurrently, the urinary excretion of two endogenous metabolites of PGI2 (2,3-dinor-6-keto-PGF1 alpha and 6,15-diketo-13,14-dihydro-2,3-dinor-PGF1 alpha) was found to be increased significantly in tumor-bearing rats. The results raise the hypothesis that hormonal changes induced by the MtT-F4 tumor accelerate the conversion of arachidonic acid (20:4 omega 6) to prostaglandins. This effect, perhaps coupled with a diversion of linoleic acid (18:2 omega 6) towards other metabolic processes, would account for a partial depletion of membrane phospholipids in 18:2 omega 6 and for the reduced production of longer chain omega 6 unsaturated acids from 20:4 omega 6, creating a state of "relative essential fatty acid deficiency." As a result, the metabolism of omega 3 fatty acids is altered towards an enhanced production of 22:6 omega 3 which accumulates in the lipids of cell membranes to compensate for the depletion of unsaturated acids of the omega 6 series.

Animals↗
PubMed1981

Estimated rate of prostacyclin secretion into the circulation of normal man.

The rate of secretion of prostacyclin (PGI2) into the circulation of normal man was estimated by measurement of the 2,3-dinor-6-keto-PGF1 alpha (D) and 15-keto-13,14-dihydro-2,3-dinor-6-keto-PGF1 alpha (KDD) urinary metabolites of PGI2. Subjects received 6-h intravenous infusions of vehicle alone and PGI2 at 0.1, 0.4, and 2.0 ng/kg per min in random order. The fractional elimination of the metabolites was independent of the rate of PGI2 infusion. 6.8 +/- 0.3% of the infused PGI2 appeared as D and 4.1 +/- 0.4% as KDD. The regression of infused PGI2 upon the quantities of the two metabolites excreted in excess of control values permitted estimation of the rate of entry of endogenous PGI2 into the circulation corresponding to a given quantity of metabolite excreted. Using the quantities excreted in the 24 h from commencement of the infusions the estimated rates were 0.08 +/- 0.02 ng/kg per min from D and 0.10 +/- 0.03 from KDD. Studies with exogenous PGI2 suggest that infusion rates 2--4 ng/kg per min are required to achieve the threshold for inhibition of platelet function (ex vivo) in man. Although not precluding a role for PGI2 in local platelet-vessel wall interactions, the much lower estimates obtained in this study suggest that endogenous PGI2 is unlikely to act as a circulating antiplatelet agent in healthy man.

Adult↗
PubMed1977

Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets.

Thromboxane synthase was localized to the microsomes of human platelets. The enzyme was insensitive to sulfhydryl reagents and thiols but was inhibited by 12L-hydroperoxy-5, 8, 10, 14-eicosatetraenoic acid (concentration for 50% inhibition = 0.1 mM). Treatment of microsomes with Triton X-100 solubilized the enzymes that catalyze the conversion of arachidonic acid to thromboxane B2. The solubilized material was resolved by DEAE-cellulose chromatography into two components, one converting arachidonic acid to prostaglandins G2 and H2 and the other converting prostaglandin H2 to thromboxane B2.

Blood Platelets↗
PubMed1976

Metabolism of 8,11,14-eicosatrienoic acid in human platelets.

The following labeled compounds were isolated and identified after incubation of 8,11,14-eicosatrien [1-14C] oic acid with human platelets: 12-L-hydroxy-8,10,14-eicosatrienoic acid, 8,11,12-trihydroxy-9,14-eicosadienoic acid, 8,9,12-trihydroxy-10,14-eicosadienoic acid, 12-L-hydroxy-8,10-heptadecadienoic acid, prostaglandin E1, prostaglandin D1, and 8-(1-hydroxy-3-oxopropyl)-9,12-dihydroxy-10-heptadecenoic acid (thromboxane B1).

8,11,14-Eicosatrienoic Acid↗
PubMed1975

Evidence of an enzymatic 17alpha leads to 21 hydroxyl transfer in the biosynthesis of cortexolone from 17alpha-hydroperoxyprogesterone by adrenal cortex microsomes.

The concept of a possible biogenetic intramolecular relationship between several pairs of hydroxylated positions of corticosteroids, in particular between positions 17alpha and 21, has been proposed by us some time ago. We now present evidence that to a certain extent such a relationship can indeed exist. 18O-labelled 17alpha-hydroperoxyprogesterone was incubated under ordinary oxygen atmosphere with the microsomal fractions of bovine adrenal cortex. Following extensive purifications by thin-layer chromatography, we have isolated a metabolite with mobility characteristics corresponding to those of authentic 17,21-dihydroxy-4-pregnene-3,20-dione (cortexolone). According to its mass spectrum, this metabolite has a molecular weight of 350, i.e. 4 atomic mass units higher than the molecular weight of non-labelled cortexolone. No conversion of 17alpha-hydroperoxyprogesterone to cortexolone was observed with a previously heat-inactivated preparation. The presence of 4 additional mass units in the cortexolone metabolite means that the latter has preserved two 18O-labels in the molecule, one at position 17alpha and the other one at position 21. This can only be explained by a rearrangement reaction of the hydroperoxide group in such a way that it is accompanied by a C-17alpha to C-21 hydroxyl transfer. In the inverse case, when non-labelled 17alpha-hydroperoxyprogesterone was incubated under 99% 18O2-atmosphere, non-labelled cortexolone of molecular weight 346 was also found.

17-Hydroxycorticosteroids↗