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At least 793 records · Page 44Linked to original sources
PubMed1975

Prostaglandins in the rheumatic diseases.

The prostaglandins may participate in the pathogenesis of the inflammatory rheumatic diseases by acting as mediators of inflammation and in promoting bone resorption. Levels of PGB (presumed to arise from PGE) in synovial fluids are elevated in the majority of a group of patients with inflammatory rheumatic diseases, as compared to similar patients treated with aspirin and indomethacin and patients with osteoarthritis. Rheumatoid synovium produces large amounts of PGE2 in organ culture. In addition, fibroblast cell lines derived from rheumatoid synovia synthesize more PGE and more cAMP than do cells from normal synovia or skin. The media from rheumatoid synovial organ cultures contain large quantities of bone-resorbing activity toward mouse calvaria in vitro. The bone resorption can be accounted for by PGE2 produced by the synovia, because the activity and PG synthesis are inhibited by more than 90% by incubation of the tissue with indomethacin, because it is quantitatively extractable into ether, and because it bears a relationship to the concentrations of PGE2 present, as measured by radioimmunoassay.

Arthritis, Rheumatoid↗
PubMed1976

Subversive activity of syngeneic tumor cells as an escape mechanism from immune surveillance and the role of prostaglandins.

Mice bearing a syngeneic tumor become increasingly immunodepressed during growth of the tumor, being unable to develop both cellular and humoral immunity to a histoincompatible tumor allograft and to reject the allograft. This failure to reject a strongly antigenic tumor allograft suggests that immunodepression associated with growth of a weakly antigenic syngeneic tumor provides the syngeneic tumor with an escape mechanism. This immunodepression is also manifest by the suppression of the response of spleen cells to mitogen stimulation by syngeneic tumor cells, both in vivo and in vitro. T cells that are stimulated by PHA, a T-cell mitogen, are the primary targets, and their suppression is the result of the direct subversive activity of the tumor cells. Subversion of T cells by tumor cells seems to be mediated through the prostaglandin pathway, because the prostaglandin PGE2 is itself suppressive, and an antagonist of PGE2 and an inhibitor of prostaglandin synthetases both inhibit the subversive activity of tumor cells. Several tumor cell lines tested, of different etiology and histologic type, all were subversive. This suggests that this subversive activity may be a general property of tumor cells and may be a key element in their ability to thwart the immunological system of the host. For this reason, any therapeutic regimen of cancer, based on immunostimulating drugs, should include drugs that can inhibit active subversion of the immune system by the tumor itself. Antagonists of prostaglandins and inhibitors of prostaglandin synthetases show promise in this regard.

Animals↗
PubMed2005

Gain modulation by serotonin in pyramidal neurones of the rat prefrontal cortex.

Serotonin (5-HT) is widely implicated in brain functions and diseases. The vertebrate brain is extensively innervated by 5-HT fibres originating from the brain stem, and 5-HT axon terminals interact with other neurones in complex ways. The cellular mechanisms underlying 5-HT function in the brain are not well understood. The present study examined the effect of 5-HT on the responsiveness of neurones in the neocortex. Using patch-clamp recording in acute slices, we showed that 5-HT substantially increased the slope (gain) of the firing rate-current curve in layer 5 pyramidal neurones of the rat prefrontal cortex. The effect of 5-HT on gain is confined to the range of firing rate (0-10 Hz) that is known to be behaviourally relevant. 5-HT also changed current threshold for spike train generation, but this effect was inconsistent, and was independent of the effect on gain. The gain modulation by 5-HT was mediated by 5-HT2 receptors, and involved postsynaptic mechanisms. 5-HT2-mediated gain increase could not be attributed to changes in the membrane potential, the input resistance or the properties of action potentials, but was associated with a reduction of the afterhyperpolarization and an induction of the slow afterdepolarization. Blocking Ca2+ entry with Cd2+ increased the gain by itself and blocked 5-HT2- mediated gain increase. Buffering [Ca2+](i) with 25 mM EGTA also substantially reduced 5-HT2- mediated gain increase. Noradrenaline, which blocked the afterhyperpolarization, also induced a moderate increase in gain. Together, our results suggest that 5-HT may regulate the dynamics of cortical circuits through multiplicative scaling.

Action Potentials↗
PubMed2002

Anti-inflammatory fibrosis suppression in threatened trabeculectomy bleb failure produces good long term control of intraocular pressure without risk of sight threatening complications.

AIMS: To determine the long term outcome of systemic anti-inflammatory fibrosis suppression in cases of threatened trabeculectomy bleb failure in open angle glaucoma. METHODS: This prospective non-comparative case series followed 77 eyes of 63 patients which showed signs of threatened early bleb failure and were treated with oral anti-inflammatory fibrosis suppression of prednisone, a non-steroidal anti-inflammatory agent, and colchicine taken for a mean period of 6 weeks, in addition to standard postoperative topical treatment, for a mean follow up of 6 years. RESULTS: Trabeculectomy with anti-inflammatory fibrosis suppression controlled the IOP at < or =21 mm Hg with a probability of 0.91 (95% CI: 0.81 to 1.0) at 8 years and 0.89 (95% CI: 0.56 to 1.1) at 12 years. There were no reported cases of endophthalmitis, hypotonous maculopathy, late bleb leak, or serious systemic side effects. CONCLUSION: Anti-inflammatory fibrosis suppression provided good control of bleb fibrosis without risk of sight threatening complications in a patient group at high risk of bleb failure.

Adult↗
PubMed2002

TRPC6 is a candidate channel involved in receptor-stimulated cation currents in A7r5 smooth muscle cells.

To investigate the possible role of members of the mammalian transient receptor potential (TRP) channel family (TRPC1-7) in vasoconstrictor-induced Ca(2+) entry in vascular smooth muscle cells, we studied [Arg(8)]-vasopressin (AVP)-activated channels in A7r5 aortic smooth muscle cells. AVP induced an increase in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) consisting of Ca(2+) release and Ca(2+) influx. Whole cell recordings revealed the activation of a nonselective cation current with a doubly rectifying current-voltage relation strikingly similar to those described for some heterologously expressed TRPC isoforms. The current was also stimulated by direct activation of G proteins as well as by activation of the phospholipase Cgamma-coupled platelet-derived growth factor receptor. Currents were not activated by store depletion or increased [Ca(2+)](i). Application of 1-oleoyl-2-acetyl-sn-glycerol stimulated the current independently of protein kinase C, a characteristic property of the TRPC3/6/7 subfamily. Like TRPC6-mediated currents, cation currents in A7r5 cells were increased by flufenamate. Northern hybridization revealed mRNA coding for TRPC1 and TRPC6. We therefore suggest that TRPC6 is a molecular component of receptor-stimulated Ca(2+)-permeable cation channels in A7r5 smooth muscle cells.

Animals↗
PubMed2005

Fluid secretion and the Na+-K+-2Cl- cotransporter in mouse exorbital lacrimal gland.

We have previously suggested that fluid flow in the mouse exorbital lacrimal gland is driven by the opening of apical Cl- and K+ channels. These ions move into the lumen of the gland and water follows by osmosis. In many tissues, the Na+-K+-2Cl- cotransporter (NKCC1) replaces the Cl- and K+ ions that move into the lumen. We hypothesize that mouse exorbital lacrimal glands would have NKCC1 co-transporters and that they would be important in fluid transport by this gland. We used immunocytochemistry to localize NKCC1-like immunoreactivity to the membranes of the acinar cells as well as to the basolateral membranes of the duct cells. We developed a method to measure tear flow and its composition from mouse glands in situ. Stimulation with the acetylcholine agonist carbachol produced a peak flow followed by a plateau. Ion concentration measurements of this stimulated fluid showed it was high in K+ and Cl-. Treatment of the gland with furosemide, a blocker of the NKCC1 cotransporter, reduced the plateau phase of fluid flow by approximately 30%. Isolated cells exposed to a hypertonic shock shrank by approximately 20% and then showed a regulatory volume increase (RVI). Both the RVI and swelling were blocked by treatment with furosemide. Cells isolated from these glands shrink by approximately 10% in the presence of carbachol. Blocking NKCC1 with furosemide reduced the amount of shrinkage by approximately 50%. These data suggest that NKCC1 plays an important role in fluid secretion by the exorbital gland of mice.

Animals↗
PubMed1995

The iodide channel of the thyroid. II. Selective iodide conductance inserted into liposomes.

An iodide channel has been previously identified in the plasma membrane of bovine throcytes [Golstein et al., Am. J. Physiol. 263 (Cell Physiol. 32): C590-C597, 1992]. The plasma membrane proteins were solubilized and ultrafiltered, and the protein fraction collected above 100 kDa was inserted in liposomes. Voltage-sensitive uptake of radiolabeled I- by these proteoliposomes was studied. To this end, an outward I- gradient was set up by loading the proteoliposomes with KI and removing extraliposomal I-. I- exit from the proteoliposome induces an inside positive membrane potential, which leads to the uptake of 125I- added to the incubation medium. This uptake was abolished by valinomycin, which in the presence of K+ short circuits the liposomal membrane potential, demonstrating the conductive nature of this uptake. A double reciprocal plot of I- influx over I- concentration suggests the existence of a single population of channels in these proteoliposomes with a Michaelis-Menten constant for I- of approximately 9 microM. When the proteoliposomes were loaded with KCl or KSCN instead of I-, no conductive uptake occurred anymore, suggesting that these anions are unable to diffuse through the I- conductance, hence do not generate a diffusion potential. I- uptake by KI-loaded proteoliposomes was not inhibited in the presence of a 1,000-fold excess of extraliposomal Cl- but was completely inhibited by a 1,000-fold excess of extraliposomal SCN-, indicating that Cl- does not permeate the I- channel, whereas SCN- inhibits it. SCN- and flufenamate were both shown to be competitive inhibitors of the I- channel with an inhibitor constant of approximately 10 and 750 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

A cationic nonselective stretch-activated channel in the Reissner's membrane of the guinea pig cochlea.

The Reissner's membrane (RM) separates in the mammalian cochlea the K(+)-rich endolymph from the Na(+)-rich perilymph. The patch-clamp technique was used to investigate the transport mechanisms in epithelial cells of RM freshly dissected from the guinea pig cochlea. This study shows a stretch-activated nonselective cationic channel (SA channel) with a linear current-voltage relationship (23 pS) highly selective for cations over anions [K+ approximately Na+ (1) > Ba2+ (0.65) > Ca2+ (0.32) >> Cl- (0.14)] and activated by the intrapipette gradient pressure. The open probability-pressure relationship is best fitted by a Boltzmann distribution (half-maximal pressure = 37.8 mmHg, slope constant = 8.2 mmHg). SA channels exhibit a strong voltage dependency and are insensitive to internal Ca2+, ATP, and fenamates but are blocked by 1 microM GdCl3 in the pipette. They are reversibly activated by in situ superfusion of the cell with hyposmotic solutions. Kinetic studies show that depolarization and mechanical or osmotic stretch modify the closed and open time constants probably by a different mechanism. These channels could participate in pressure-induced modifications of ionic permeability of the RM.

Animals↗
PubMed1987

Evidence for cAMP as a mediator of gonadotropin secretion from male pituitaries.

The purpose of this study was to use sodium flufenamate, a compound that inhibits gonadotropin-releasing hormone (GnRH)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production in the pituitary, to evaluate the potential role of cAMP as a mediator of GnRH-stimulated gonadotropin secretion from male pituitaries. Quartered male pituitaries were perifused at 37 degrees C and sequential effluent fractions collected every 10 min. Infusions of GnRH resulted in a twofold increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Cycloheximide, 5 microM, completely inhibited the GnRH-stimulated LH and FSH secretion. Infusions of 0.1 mM flufenamate had similar effects on gonadotropin secretion as cycloheximide, whereas the administration of 5 mM dibutyryl cAMP in combination with GnRH and flufenamate restored the secretory responses of both hormones. The flufenamate-inhibited GnRH stimulated LH and FSH release, which was restored by DBcAMP and appeared to be protein synthesis dependent and specific for cAMP. These results suggest an indirect role for cAMP as a mediator of gonadotropin secretion from male pituitaries. However, in contrast to female pituitaries, the secretion of these hormones from male pituitaries is completely dependent on cAMP and de novo protein synthesis.

Animals↗