Suppression of immune complex vasculitis in rats by prostaglandin.
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Immune complex-induced vascular damage can be markedly suppressed by treatment of rats with either prostaglandin (PG)E1 or its stable derivative, 15-(S)-15-methyl PGE1, but not with PGF2 alpha. In addition, PGD2 and PGE2 also show suppressive effects. The PGE1 derivative is considerably more effective than PGE1 and shows potent anti-inflammatory activity even after oral administration. Suppression of the vasculitis reaction is reflected by a greatly diminished increase in vasopermeability, indicating little or no vascular damage. In suppressed animals, the infiltration of neutrophils is greatly reduced, and those leukocytes that have appeared at tissue sites fail to show phagocytic uptake of immune complexes. In suppressed animals, the skin sites nevertheless show deposits of immune complexes and C3 fixation in vascular walls. Neutrophils harvested from the blood of rats treated with PGE1 show depressed responsiveness in chemotaxis and in enzyme secretion after incubation with chemotactic peptide. These studies indicate that certain PG have potent anti-inflammatory activity, which may be related to their effects on leukocytes. (+info)
Effects of antiglaucoma drops on MMP and TIMP balance in conjunctival and subconjunctival tissue.
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PURPOSE: To study the effects of antiglaucoma drugs on metabolism within the extracellular matrix (ECM) of the ocular surface, including corneal, conjunctival, and subconjunctival tissue. METHOD: Several antiglaucoma drugs--including beta-blockers, alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative-were topically administrated to rat eyes daily for 2 weeks or were incubated with human corneal cells or human fibroblasts for 72 hours. Thereafter, expression and enzymatic activity of the matrix metalloproteinases (MMPs), a group of enzymes proteolyzing ECM and their inhibitors, called tissue inhibitors of metalloproteinase (TIMPs), were evaluated. RESULTS: Quantitative RT-PCR revealed significantly upregulated and downregulated expression of MMPs and TIMPs, respectively, in rat conjunctival and subconjunctival tissue on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, suggesting that these drugs may enhance ECM degradation. However, in contrast, beta-blocker administration caused reverse effects--that is, upregulation and downregulation of TIMPs and MMPs, respectively. Enzymatic activity of MMPs in rat conjunctival and subconjunctival tissue analyzed by biochemical assay and zymography was markedly enhanced on the administration of alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative, but not of beta-blockers. Similar effects of these antiglaucoma drugs were observed in cultured human corneal cells and human fibroblast cells. CONCLUSIONS: The present experimental observations suggest that some alpha/beta-blockers, alpha1-blocker, alpha2-agonist, and prostaglandin derivative stimulate ECM degradation of ocular surface tissue by modulating the balance between MMPs and TIMPs. (+info)
Chemical transformation of prostaglandin-A2: a novel series of C-10 halogenated, C-12 hydroxylated prostaglandin-A2 analogues.
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[reaction: see text] Synthesis of a novel class of C-10 halogenated and C-12 oxygenated prostaglandin-A(2) derivatives (6a-6c) has been accomplished. (15S)-Prostaglandin-A(2) (1), from the gorgonian Plexaura homomalla, served as the starting material for the synthesis. The absolute configuration was determined using NMR. (+info)
Low doses of superoxide dismutase and a stable prostacyclin analogue protect in myocardial ischemia and reperfusion.
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The effects of low dose human superoxide dismutase and low dose taprostene, a stable analogue of prostacyclin, were investigated separately and together in a model of myocardial ischemia (1.5 h) with reperfusion (4.5 h) in open chest, anesthetized cats. Taprostene (60 ng/kg per min), human superoxide dismutase (0.25 mg/kg per h), both agents together, or their vehicle, were infused intravenously in cats starting 0.5 h after occlusion of the left anterior descending coronary artery. Neither low dose taprostene nor low dose human superoxide dismutase exerted any endothelial or myocardial protection in this model. However, the two agents together showed a significant endothelial and myocardial protection in cats with myocardial ischemia and reperfusion. Compared with cats that were untreated or received only taprostene or human superoxide dismutase, cats receiving both agents exhibited a lower plasma creatine kinase activity at every time point observed after reperfusion, a reduced area of cardiac necrosis (7 +/- 2% vs. 21 +/- 5% area at risk, p less than 0.001), lower myeloperoxidase activity in the ischemic region (p less than 0.01) and a significant preservation of vasorelaxant responses of left anterior descending coronary rings to endothelium-dependent vasodilators, acetylcholine (p less than 0.001) and A-23187 (p less than 0.001). Taprostene appears to act additively with human superoxide dismutase to inhibit neutrophil adherence and activation and to inactivate superoxide radicals, and thus reduce cellular injury 4.5 h after reperfusion of the ischemic heart. Use of this agent may allow low doses of superoxide dismutase to be used more effectively in early myocardial ischemia. (+info)
Mechano- and chemosensitivity of rat nodose neurones--selective excitatory effects of prostacyclin.
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Nodose ganglion sensory neurones exert a significant reflex autonomic influence. We contrasted their mechanosensitivity, excitability and chemosensitivity in response to the stable prostacyclin (PGI2) analogue carbacyclin (cPGI) in culture. Under current clamp conditions we measured changes in membrane potential (DeltamV) and action potential (AP) responses to mechanically induced depolarizations and depolarizing current injections before and after superfusion of cPGI (1 microM and 10 microM). Chemosensitivity was indicated by augmentation of AP firing frequency and increased maximum gain of AP frequency (max. dAP/dDeltamV), during superfusion with cPGI. Results indicate that two groups of neurones, A and B, are mechanosensitive (MS) and one group, C, is mechanoinsensitive (MI). Group A shows modest depolarization without AP generation during mechanical stimulation, and no increase in max. dAP/dDeltamV, despite a marked increase in electrical depolarization with cPGI. Group B shows pronounced mechanical depolarization accompanied by enhanced AP discharge with cPGI, and an increase in max. dAP/dDeltamV. Group C remains MI after cPGI but is more excitable and markedly chemosensitive (CS) with a pronounced enhancement of max. dAP/dDeltamV with cPGI. The effect of cPGI on ionic conductances indicates that it does not sensitize the mechanically gated depolarizing degenerin/epithelial Na+ channels (DEG/ENaC), but it inhibits two voltage-gated K+ currents, Maxi-K and M-current, causing enhanced AP firing frequency and depolarization, respectively. We conclude that MS nodose neurones may be unimodal MS or bimodal MS/CS, and that MI neurones are unimodal CS, and much more CS to cPGI than MS/CS neurones. We suggest that the known excitatory effect of PGI2 on baroreceptor and vagal afferent fibres is mediated by inhibition of voltage-gated K+ channels (Maxi-K and M-current) and not by an effect on mechanically gated DEG/ENaC channels. (+info)
Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits.
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1. Sodium arachidonate, the prostaglandin precursor substance, when injected intraventricularly into rabbits, results in dose-dependent hyperthermia, which is rapid in onset and of several hours duration. 2. Arachidonate fever was inhibited by intraventricular injection of indomethacin, but not by the simultaneous intraventricular injection of either of the two prostaglandin antagonists SC 19220 or HR 546. 3. Both antagonists effectively inhibited the fever induced by the intraventricular injection of an equipotent dose of PGE1. 4. Our results show that a derivative of arachidonic acid other than prostaglandin is pyrogenic. (+info)
Conjunctival changes induced by prostaglandin analogues and timolol maleate: a histomorphometric study.
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PURPOSE: To compare histological changes induced by antiglaucoma medications in the rabbit conjunctiva. METHODS: Fifty New Zealand rabbits were divided in 5 groups of 10 animals. The left eyes were treated daily with one drop of bimatoprost 0.03%, travoprost 0.004%, latanoprost 0.005%, timolol maleate 0.5% or artificial tears containing benzalkonium chloride (BAK) for 30 days. The right eyes served as controls. Superior limbic conjunctival biopsies were performed at the 8th and 30th day in 5 rabbits of each group. The conjunctiva was fixed with 10% formaldehyde, followed by HE and PAS staining. Morphohistometric quantitative analyses were performed to evaluate the following parameters: inflammatory infiltrate, epithelial thickness, number of goblet cells, diameter and number of blood vessels. RESULTS: At the 8th and 30th posttreatment days, all groups, except one that received artificial tears, exhibited a diffuse inflammatory infiltrate, composed by lymphocytes and neutrophils, which was denser in the timolol group than in the prostaglandin (PG) analogues groups. At the 30th day, the timolol group also showed an increased subepithelial collagen density and a significant increase in epithelial thickness (p=0.0035). The goblet cell density was significantly increased at the 8th day in the group treated with travoprost (p=0.0006), and at the 30th day in those treated with bimatoprost (p=0.0021) and latanoprost (p=0.009). CONCLUSIONS: Although a moderate, diffuse inflammatory infiltrate was observed in PG-treated eyes, no changes in conjunctival epithelial thickness or subconjunctival collagen density were observed with these medications, suggesting that these drugs induce fewer changes than timolol maleate in the rabbit conjunctiva. (+info)
The effects of thromboxane receptor antagonists on oestrogen-induced uterotrophic responses in the spontaneously hypertensive rat.
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1. The possible role of thromboxane in the uterotrophic response to oestrogen, in the spontaneously hypertensive rat was investigated by use of the thromboxane receptor antagonists EP092, AH23848 and BM 13.505. 2. The parameters studied were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights and the concentrations of cytosolic and nuclear oestrogen receptors. 3. The antagonists attenuated oestradiol-induced uterine blood flow and significantly reduced both wet and dry uterine weight. These changes were accompanied by decreases in nuclear oestrogen receptor levels. 4. The results suggest a supportive role for thromboxane in oestradiol-induced uterine growth. (+info)