Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0432222 (SEM)
47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human microvascular anastomosis represents a localized environment with strongly thrombotic tendencies. In previous studies, an increase in initial platelet deposition at a human ex vivo anastomosis was measured. It is postulated that this increase in anastomotic platelet deposition was due to a reduction in anastomotic prostacyclin production as a consequence of local endothelial cell injury or loss. Instead, in this study, an increase in anastomotic prostacyclin production over unsutured controls (control 1093 +/- 222 pg/ml of 6-keto prostaglandin F (PGF) 1-alpha, n=21; anastomosis 2494 +/- 414, n=21, mean +/- 1 SEM, p=0.005) is demonstrated. Anastomotic prostacyclin production was augmented by addition of arachidonic acid (0.1 mM) (39,000 +/- 11,300 pg/ml of 6-keto PGF 1-alpha, n=7, p<0.001) and suppressed by the preincubation of vessel segments with aspirin in a dose-dependent fashion (1mM) (83+/-22 pg/ml of 6-keto PGF 1-alpha, n=21, p<0.001); aspirin (0.1 mM) (312 +/- 56 pg/ml of 6-keto PGF 1-alpha, n=7, p<0.001). In further studies using a perfusion apparatus of human blood pumped through human placental artery segments, suppression of prostacyclin production did not augment initial platelet deposition (control anastomosis 4.9 +/- 2.2 x10(6) platelets per cm2, aspirin treatment 6.0 +/- 2.8 x 10(6) platelets per cm2, n=5, mean +/- 1 SEM, p>0.05). Suppression of platelet function with aspirin (0.1 mM) also did not decrease initial platelet deposition onto the anastomosis (5.8 +/- 2.8 x 10(6) platelets per cm2, n=r, p>0.05). In this model system, initial platelet deposition at the anastomosis may not be dependent upon cyclooxygenase pathways.
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PMID:Prostacyclin production at the human microvascular anastomosis: its effect on initial platelet deposition. 862 73

The maintenance of endothelial barrier function is important in the regulation of fluid and solute balance between the vascular space and the surrounding tissue. Since fluid flow across endothelial cells stimulates a wide variety of endothelial responses, the effect of shear stress on barrier function was investigated. Bovine pulmonary artery endothelial cells were cultured on permeable microcarrier beads, placed in a chromatography column, and perfused. Indicator-dilution techniques were used to estimate the permeability of the cell-covered beads to low molecular weight tracers (sodium fluorescein-NaFlsc; cyanocobalamin-B12) as a function of flow rate through the column. Permeability values for both tracers were significantly increased (9.3 +/- 0.6 to 19.3 +/- 1.7 for NaFlsc; 8.2 +/- 0.5 to 20.4 +/- 3.1 for B12; mean+/-SEM, x 10(-5) cm/s, P < .05) when the flow rate was increased from 0.9 ml/min to 3.2 ml/min (corresponding to average shear stresses of 4.7 and 16.8 dynes/cm2). The permeability increase occurred within minutes of the flow increase, and was reversed by decreasing the flow rate to 0.9 ml/min. In the presence of cytochalasin D, the flow-induced permeability increase was not reversible. Neither inhibition of nitric oxide synthase (with NG-monomethyl-L-arginine) nor inhibition of cyclooxygenase (with indomethacin) was capable of blocking the flow-induced permeability increase. These results indicate that the rapid modulation of endothelial barrier by flow in vitro is probably not due to prostacyclin or nitric oxide.
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PMID:Flow-induced modulation of the permeability of endothelial cells cultured on microcarrier beads. 870 76

5-Hydroxyeicosatetraenoic acid (5-HETE) is an arachidonic acid (AA) metabolite derived from the lipoxygenase pathway which is capable of inducing uterine contractions. The purpose of this study was to determine a). whether 5-HETE concentrations in amniotic fluid increase before or after the onset of labor and b). whether acetylsalicylic acid (ASA) could modulate the production of 5-HETE by human amnion cells. 5-HETE concentrations are increased in amniotic fluid before the onset of labor. Furthermore, ASA treatment as expected inhibited PGE2, but also significantly increased 5-HETE production by amnion cells. 5-HETE concentrations on average increased by greater than 2.5 fold (p < 0.001) in amniotic fluid prior to spontaneous labor when compared with samples obtained from the same patients earlier in gestation and therefore may be important in mechanisms regulating the onset of labor. ASA provokes an increase in 5-HETE biosynthesis by amnion cells: control media 2.60 +/- 1.5, ASA treatment alone 5.17 +/- 0.20, IL-1 beta alone 6.39 +/- 2.1, and ASA + IL-1 beta 8.95 +/- 1.2 (mean +/- SEM) picograms per microgram protein per 16 hours. These findings may explain in part why cyclooxygenase inhibitors are not always successful in treating women with preterm labor.
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PMID:5-Hydroxyeicosatetraenoic acid and human parturition. 887 35

Stimulated release of vasodilator prostaglandins and nitric oxide by angiotensin II may counteract the vasoconstrictor effects of this octapeptide. We investigated the effects of inhibition of prostaglandin synthesis by indomethacin and of nitric oxide formation by NG-monomethyl-L-arginine (L-NMMA) on baseline forearm blood flow (FBF) and on angiotensin II-induced vasoconstriction in healthy subjects. For comparison, the effects of the AT1-receptor antagonist losartan on these parameters were determined. FBF was measured by venous occlusion plethysmography. Angiotensin II (0.01-10 ng/kg/min) was infused into the brachial artery, in the absence and presence of indomethacin (0.65 micrograms/kg/min; n = 8), L-NMMA (30 micrograms/kg/min; n = 5), and losartan (3 micrograms/kg/min; n = 12), respectively. Sodium nitroprusside was used to submaximally predilate the forearm vascular system. Baseline FBF remained unchanged with indomethacin and losartan, but was significantly decreased by -42 +/- 6% (mean +/- SEM) by L-NMMA. The dose-dependent angiotensin II-induced vasoconstriction was unaffected by indomethacin and L-NMMA, but was inhibited by losartan. Emax was -78 +/- 2% during control conditions, -84 +/- 3% during indomethacin (n.s.), -74 +/- 4% during L-NMMA (n.s.), and -17 +/- 6% during losartan infusion (p < 0.05). None of the interventions significantly changed the EC50 value of angiotensin II of -9.4 +/- 0.14 log M. In conclusion, in the human forearm of healthy subjects, neither endogenous angiotensin II nor cyclooxygenase-dependent prostaglandin synthesis plays a role in the genesis of vascular tone, whereas endogenous nitric oxide production does. The constrictor effects of angiotensin II are counteracted by neither stimulated release of prostaglandins nor by that of nitric oxide.
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PMID:Influence of indomethacin and L-NMMA on vascular tone and angiotensin II-induced vasoconstriction in the human forearm. 935 98

The effects of protopine on human platelet aggregation and arachidonic acid (AA) metabolism via cyclooxygenase (COX) and lipoxygenase (LOP) enzymes were examined. Platelet aggregation induced by various platelet agonists (AA, ADP, collagen and PAF) was strongly inhibited by protopine in a concentration-related manner. The IC50 values (microM) of protopine (mean +/- SEM) against: AA; 12 +/- 2: ADP; 9 +/- 2: collagen; 16 +/- 2 and PAF; 11 +/- 1, were much less than those observed for aspirin. In addition, protopine selectively inhibited the synthesis of thromboxane A2 (TXA2) via COX pathway and had no effect on the LOP pathway in platelets. In vivo, pretreatment with protopine (50-100 mg kg-1) protected rabbits from the lethal effects of AA (2 mg kg-1) or PAF (11 micrograms kg-1) in dose-dependent fashion. Protopine (50-100 mg kg-1) also inhibited carrageenan-induced rat paw oedema with a potency of three-fold as compared to aspirin. These results are suggestive that protopine acts as a potent inhibitor of thromboxane synthesis and PAF with anti-inflammatory properties.
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PMID:Anti-thrombotic and anti-inflammatory activities of protopine. 936 8

Historically, catecholamine-producing chromaffin cells and steroid-producing adrenocortical cells have been regarded as two independent endocrine systems that are united under a common capsule to form the adrenal gland. There is increasing evidence for bidirectional interactions, with regulatory influences of adrenocortical secretory products on adrenomedullary functions and vice versa. However, the direct involvement of chromaffin cells on the regulation and maintenance of cortical function has not yet been demonstrated. Therefore, we analyzed glucocorticoid secretion and P450 messenger RNA (mRNA) expression in bovine adrenocortical cells in cocultures with chromaffin cells compared with those in pure cortical cell cultures. Cortisol release from cortical cells in coculture with chromaffin cells was 10 times as high (mean +/- SEM, 1035 +/- 119%) as that from the same number of isolated cortical cells (100 +/- 11%). By a [3H]thymidine incorporation assay, it was demonstrated that this effect was not due to a higher proliferation rate. Northern analysis revealed an increasing expression of P450(17alpha) mRNA in the coculture from days 1-5, whereas in isolated cortical cells, P450(17alpha) mRNA decreased, leading to a 6-fold difference on day 5. Inhibitors of protein (cycloheximide) or RNA (actinomycin D) synthesis completely annulled the observed increase in cortisol release, indicating that de novo protein synthesis is required for this activation of adrenocortical steroidogenesis. Addition of the cyclooxygenase inhibitor indomethacin reduced the stimulatory effect, suggesting that this stimulation is in part mediated by PGs. Locally produced ACTH, catecholamines, and interleukin-1 accounted for 43% of the effect. Secretory products of chromaffin cells that act in concert are believed to be responsible for the stimulation of steroidogenesis in the coculture. The coculture system is an in vitro model that corresponds to the in vivo situation in the intact adrenal gland, where both endocrine cell systems are in close contact. Our data demonstrate the requirement of intraadrenal cellular communication for the full strength of the adrenocortical hormonal response.
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PMID:Basal steroidogenic activity of adrenocortical cells is increased 10-fold by coculture with chromaffin cells. 944 52

The mechanism of the ocular hypotensive effect of bunazosin hydrochloride (an alpha1-adrenergic antagonist) and the possible intermediary role of prostaglandins were studied in New Zealand albino rabbits. Aqueous flow, outflow facility and uveoscleral outflow were determined by fluorophotometry, and intraocular pressure (IOP) was measured by pneumatonometry on the fourth day of twice daily topical treatment with 0.1% bunazosin. Uveoscleral outflow was measured with a tracer infusion technique at 1 to 2 hours after one dose of 0.1% bunazosin. Total outflow facility was measured by a two-level constant-pressure infusion method before and at one hour after one dose of 0.1% bunazosin. The effect of topically applied cyclooxygenase inhibitors, including 0.25% indomethacin and 0.03% flurbiprofen, on the IOP reduction after bunazosin was evaluated. At 3 hours after the seventh consecutive dose given twice-daily, bunazosin significantly (P<0.001) reduced IOP to 13.4+/-0.8 mm Hg (mean +/- SEM) from a baseline of 19.6+/-1.1 mm Hg. Indomethacin significantly inhibited the IOP reduction after one dose of bunazosin, whereas flurbiprofen did not (repeated measures ANOVA). Bunazosin significantly increased uveoscleral outflow (P<0.05) and total outflow facility (P<0.02), but not fluorophotometric outflow facility or aqueous flow. It is concluded that, in rabbits, 0.1% bunazosin reduces IOP predominantly by increasing uveoscleral outflow. The role of prostaglandins in this effect is equivocal.
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PMID:Bunazosin reduces intraocular pressure in rabbits by increasing uveoscleral outflow. 967 29

The contribution of diacylglycerol (DAG) and protein kinase C (PKC) to diabetic complications has been the subject of debate. In vascular tissues, diabetes increases DAG content, which activates PKC and causes abnormal tissue perfusion. Reduced nerve blood flow has been implicated in the development of neuropathy. However, nerve DAG/PKC activity is not increased and may even be reduced by diabetes, which has also been implicated in neuropathy. The aim was to test whether 2 weeks of treatment with cremophor, an agent that complexes DAG and prevents PKC activation, could correct nerve-conduction velocity (NCV) deficits in rats with 6 weeks of untreated diabetes, as predicted on a vascular hypothesis, or whether this worsened the deficits, as predicted for a direct effect on nerve fibers. Diabetes caused 17.9 +/- 0.9% (+/- SEM) and 15.5 +/- 1.6% reductions in sciatic motor and saphenous sensory NCV, respectively, that were largely (79.6 +/- 6.3% and 57.8 +/- 11.5%) corrected by 100 mg x kg(-1) x day(-1) cremophor treatment. The effects of cremophor on motor and sensory NCV were completely attenuated by co-treatment with the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine. In contrast, co-treatment with the cyclooxygenase inhibitor, flurbiprofen, had no effect on NCV. Sciatic nutritive and total endoneurial perfusion were 49.7 +/- 3.4% and 51.8 +/- 4.2% reduced by diabetes, respectively, and these deficits were 69.5 +/- 7.4% and 79.0 +/- 11.6% corrected by cremophor treatment. Thus the data suggest that an increased DAG/PKC vascular mechanism, perhaps linked to the nitric oxide system, contributes to the etiology of diabetic nerve dysfunction.
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PMID:Effects of the diacylglycerol complexing agent, cremophor, on nerve-conduction velocity and perfusion in diabetic rats. 1023 3

It is well established that many cell types produce inflammatory cytokines and we were interested to see whether cells in the neurohypophysis had this ability. This study examines the effect of lipopolysaccharide (LPS) on cytokine production in cultured murine neural lobe (NL) cells. Cells were cultured from the neurohypophysis of mice not older than 5 days and the experiments were performed after 12 days in culture. The majority of cells in culture were immunoreactive for glial fibrillary acidic protein, indicating that the cells were pituicytes. Cytokines were measured in 24-hour samples using commercial ELISA kits. Cells growing in a medium free of endotoxin released 94.3 +/- 6.6 pg IL-6/NL/24 h (mean +/- SEM, n = 21). The release of interleukin-6 (IL-6) was reversible and increased concentration dependently with LPS in the concentration range of 0.1-1 ng/ml. The addition of 1 ng/ml LPS increased the IL-6 release 12-fold to a maximum value of 1,134 +/- 85.5 pg IL-6/NL/24 h (mean +/- SEM, n = 6). No trace of interleukin-1beta (IL-1beta) (<3 pg/NL/24 h) or tumor necrosis factor-alpha (<10 pg/NL/24 h) was detected after LPS stimulation. We examined the effect of dexamethasone (10(-6) M) and indomethacin (10(-4) M) on the release of IL-6 in submaximally stimulated cells. Dexamethasone inhibited the unstimulated and the LPS-stimulated release of IL-6 by 70 and 81%, respectively. Indomethacin had no influence on the release, and it is concluded that cyclooxygenase is not involved in the response. A close association exists between the membrane of the neurosecretory endings and the pituicytes in the neurohypophysis. This naturally raises the question as to whether IL-6 might reflect a physiological connection between the two cell types.
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PMID:Endotoxin-stimulated release of cytokines by cultured cells from the murine neurohypophysis: role of dexamethasone and indomethacin. 1047 51

The renal vascular response to vasopressin and its modulation were evaluated in vivo by infusing the peptide directly into the renal artery of anaesthetized rats. The intra-renal artery (i.r.a) infusion of vasopressin induced a dose-dependent decrease in renal blood flow. Vasoconstriction was obvious at a dose of 3 ng/kg per min and reached a maximum at 100 ng/kg per min. The dose required for a half-maximal response (ED50) was 24+/-4 ng/kg per min (mean+/-SEM, n=8), corresponding to an estimated concentration in renal arterial blood required for a half-maximal response (EC50) of 1.9+/-0.6 nM. Thiobutabarbitone anaesthesia markedly increased plasma vasopressin concentration. This increase was prevented partially by hypotonic hydration of the rats without any change in the renal vascular response to exogenous vasopressin. Vasopressin-induced vasoconstriction dose/response curves were similar in homozygous and heterozygous Brattleboro rats. Infusion of desmopressin (1-1000 ng/kg per min, i.r.a.), a vasopressin V2 receptor-selective agonist, failed to induce renal vasodilation or vasoconstriction. In the presence of SR 49059 (1 mg/kg i.v.), a vasopressin V1A receptor antagonist that completely abolished the vasopressin-induced renal vasoconstriction, desmopressin again failed to induce vasodilation. Inhibition of nitric oxide synthase by N(omega)-nitro-L-arginine (L-NNA, 100 microg/kg for 10 min and 7.5 microg/kg per min, i.r.a.) enhanced vasopressin-induced renal vasoconstriction (EC50 0.6+/-0.1 nM, P<0.05). In contrast, cyclooxygenase blockade by indomethacin (5 mg/kg, i.v.) neither modified the vasopressin-induced decrease in renal blood flow nor altered the potentiation of vasoconstriction by L-NNA. These results show that the constrictor response of the rat renal vascular bed in vivo is observed only with high local concentrations of vasopressin. This hyporeactivity in vivo was not explained by an anaesthesia-elicited increase in endogenous vasopressin, nor by a modulatory effect linked to V2 receptor activation or prostanoid release. In contrast, NO release contributed to the attenuation of vasopressin-induced renal vasoconstriction.
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PMID:Nitric oxide, but not vasopressin V2 receptor-mediated vasodilation, modulates vasopressin-induced renal vasoconstriction in rats. 1073 Oct 46


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