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PubMed1998

Origin and function of epoxyeicosatrienoic acids in vascular endothelial cells: more than just endothelium-derived hyperpolarizing factor?

1. In addition to their contribution to endothelium-derived hyperpolarization, our understanding of the physiological function of epoxyeicosatrienoic acids (EET) within the vascular wall and the actual enzymes involved in the formation of the EET in endothelial cells is very limited. In the present study, the expression of potential cytochrome P450 (CYP) mono/epoxygenases was assessed in endothelial cells isolated from porcine and bovine aortas as well as in the human umbilical vein-derived cell lines EA.hy926 and ECV304. 2. Expression of CYP2B1, CYP2E1 and CYP3A could be found. The latter were inducible by dexamethasone/clofibrate for 72 h, a procedure that also enhanced CYP epoxygenase activity in endothelial cells. 3. Enzyme induction yielded increases in capacitative Ca2+ entry and membrane hyperpolarization in response to autacoids, such as bradykinin and thapsigargin. Thiopentone sodium, an inhibitor of endothelial CYP mono/epoxygenase(s), diminished autacoid-induced capacitative Ca2+ entry and membrane hyperpolarization, while the effect of EET remained unchanged. 4. Epoxyeicosatrienoic acids activated endothelial tyrosine kinase activity in a concentration-dependent manner. Arachidonic acid, at 20-fold higher concentrations, also increased tyrosine kinase activity. Because only the effect of arachidonic acid was inhibited by thiopentone sodium, an inhibitor of CYP mono/epoxygenases, these data suggest that arachidonic acid needs to be converted to the EET in order to stimulate tyrosine kinase. 5. All these data provide clear evidence that the CYP epoxygenase-derived arachidonic acid metabolites (EET) not only serve as potential endothelium-derived hyperpolarizing factors but also constitute highly active intracellular messengers with a physiological role including the control of Ca2+ signalling, membrane potential and tyrosine kinase activity.

8,11,14-Eicosatrienoic Acid↗
PubMed1988

Differential role of extra- and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells.

1. The effects of extracellular Ca2+ on the release of endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2), and on the intracellular free calcium concentration [( Ca2+]i), were studied in cultured bovine aortic endothelial cells. 2. Receptor-mediated stimulation of endothelial cells with bradykinin (10 nM) elicited a transient release of EDRF (assayed by its stimulant effect on purified soluble guanylate cyclase) and of PGI2 (measured by radioimmunoassay for 6-keto prostaglandin F1 alpha). 3. Bradykinin (10 nM) also increased [Ca2+]i (measured with the fluorescent probe indo-1) from 125 +/- 11 nM to 631 +/- 59 nM, with the same time course as for autacoid release. 4. In Ca2+-free medium, [Ca2+]i was still increased by bradykinin but declined faster (within 1 min) to resting levels than in the presence of extracellular Ca2+. 5. PGI2 release was almost completely abolished in Ca2+-free medium. The intracellular calcium antagonist TMB-8 evoked a similar inhibition of PGI2 release. 6. In contrast, bradykinin-induced EDRF release was not significantly affected by TMB-8 but was completely abolished in Ca2+-free medium. 7. When endothelial cells were stimulated with the receptor-independent drug thimerosal (an inhibitor of the enzyme acyl-CoA-lysolecithin-acyl-transferase; 5 microM), a long-lasting release of EDRF (greater than 90 min) and PGI2 (greater than 20 min) was observed. 8. In contrast to bradykinin stimulation, thimerosal-induced autacoid release was associated with only a slight increase of [Ca2+]i to 201 +/- 13 nM after 40 min. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released. 9. After removal of extracellular Ca2 + from thimerosal-stimulated endothelial cells, [Ca2+] was little affected during the observation time of 90s. EDRF release was completely abolished within 90s whereas PGI2 release was unchanged. 10. We conclude that EDRF production is directly controlled by extracellular Ca2+ during both receptor-dependent and independent stimulation. This effect of extracellular Ca2 + is not mediated by changes in [Ca2+]i. In contrast, PGI2 release is closely correlated to [Ca2+]i in bradykininstimulated endothelial cells. However, the results obtained during thimerosal stimulation indicate that there is not necessarily a tight coupling between the absolute level of [Ca2+]i and the amount of PGI2 released.

Animals↗
PubMed2006

Electromechanical and pharmacomechanical signalling pathways for conducted vasodilatation along endothelium of hamster feed arteries.

Conducted vasodilatation (CVD) reflects the initiation and rapid (>mm s(-1)) spread of hyperpolarization along the endothelium and into smooth muscle. The ion channels that initiate CVD remain unclear as do signalling pathways that may complement electromechanical relaxation. Using isolated pressurized (75 mmHg; 37 degrees C) feed arteries (n=63; diameter: rest: 53 +/- 2 microm, maximal: 98 +/- 2 microm) from hamster retractor skeletal muscle, we investigated the contribution of calcium-activated potassium channels (KCa) and endothelium-derived autacoids to CVD. Local delivery (1 microm micropipette tip; 500-2000 ms pulse) of acetylcholine (ACh) at the downstream end initiated a local increase in endothelial cell [Ca2+]i (Fura-PE3; Deltaratio 340/380 nm = 0.215 +/- 0.032) that preceded CVD along the entire vessel. During local perifusion with KCa antagonists, iberiotoxin (5 microm) had no effect, but charybdotoxin (CTX, 5 microm) + apamin (APA, 10 microm) abolished CVD reversibly. Remarkably, this local inhibition of KCa unmasked a 'slow-conducted vasodilatation' (SCVD) that spread >1200 microm at approximately 21 microm s(-1) (n=27). Recorded 500 microm upstream from the ACh stimulus, a rise in endothelial cell [Ca2+]i (Deltaratio 340/380 nm) = 0.146 +/- 0.017; P<0.05) preceded SCVD (Deltadiameter = 14 +/- 3 microm) by approximately 10 s. Before KCa inhibition, antagonism of nitric oxide synthase (Nomega-nitro-L-arginine, 250 microm; l-NNA) and cyclooxygenase (indomethacin, 5 microm; INDO) had no effect on the amplitude of CVD yet response duration decreased by one-third (P<0.05). During local CTX + APA perifusion, L-NNA + INDO abolished SCVD while conducted [Ca2+]i responses remained intact. Thus, ACh triggers electromechanical relaxation of smooth muscle cells along the vessel initiated by local KCa, and the ensuing 'wave' of Ca2+ along the endothelium releases autacoids to promote pharmacomechanical relaxation.

Acetylcholine↗
PubMed1989

The search for the endogenous digitalis: an alternative hypothesis.

The universal presence of a binding site for cardiac glycosides on Na+-K+-ATPase has engendered speculation as to whether it also serves as a receptor for an endogenous digitalis-like hormone or autacoid. If such a hormone were to exist, it could play a role in sodium homeostasis and in the pathophysiology of primary hypertension and uremia. However, we believe that this hypothesis rests on unproven assumptions. Although typical of many toxins and drugs, binding to a single protein that acts as both its receptor and effector mechanism at the cell membrane, thereby directly affecting transmembrane ion flux, would be unusual for a hormone or autacoid. As an alternative hypothesis for the evolutionary conservation of the cardiac glycoside binding site, we suggest that its endogenous ligand may exist within the cell. After cotranslational insertion of the alpha- and beta-subunits into the membrane of the rough endoplasmic reticulum, Na+-K+-ATPase, like most integral membrane proteins, 1) must be targeted through a complex network of intracellular organelles to the correct plasmalemmal domain, 2) must be monitored for appropriate protein conformation and subunit assembly, and perhaps 3) could have its catalytic function regulated before insertion in the cell membrane. Because the lumina of the endoplasmic reticulum, Golgi, and other organelles and vesicles are topologically equivalent to the outside of the cell, all three functions could be subserved by an intraorganellar ligand for the cardiac glycoside binding site.

Animals↗
PubMed1997

Regulation of bFGF expression and ANG II secretion in cardiac myocytes and microvascular endothelial cells.

Basic fibroblast growth factor (bFGF; fibroblast growth factor-2) and angiotensin II (ANG II), among other peptide signaling autacoids (cytokines), are known to regulate the phenotypic adaptation of cardiac muscle to physiological stress. The cell type(s) in cardiac muscle responsible for ANG II synthesis and secretion and the role of endogenous cytokines in the regulation of bFGF induction remain unclear. With the use of confluent, serum-starved, low-passage cultures of cardiac microvascular endothelial cells (CMEC), ANG II could be detected in cellular lysates and in medium conditioned by these cells with the use of high-performance liquid chromatography followed by radioimmunoassay. The secretion of angiotensins by individual CMEC could be detected with a cell-blot assay technique. ANG II secretion was decreased by brefeldin A, an agent that interrupts constitutive and regulated secretory pathways for peptide autacoid/ hormone synthesis, suggesting de novo synthesis, activation, and secretion of angiotensins by CMEC. In primary isolates of adult rat ventricular myocytes (ARVM) and CMEC, ANG II, acting at ANG II type 1 receptors in both cell types, was found to increase bFGF mRNA levels measured by ribonuclease protection assay. Endothelin-1 (ET-1), which is known to be synthesized by CMEC, and bFGF itself, which has been detected in both ARVM and CMEC, increased bFGF transcript levels in both cell types. Interleukin-1beta (IL-1beta), which like ANG II and ET-1 is known to activate mitogen-activated protein kinases in both ARVM and CMEC, increased bFGF mRNA levels only in cardiac myocytes. Thus cytokines such as ANG II, ET-1, bFGF, and IL-1beta locally generated by cellular constituents of cardiac muscle, including CMEC, regulate bFGF mRNA levels in a cell type-specific manner.

Angiotensin II↗
PubMed1997

Hydrogen peroxide downregulates IL-1-driven mesangial iNOS activity: implications for glomerulonephritis.

In glomerulonephritides, autacoids such as nitric oxide (NO), reactive oxygen species, and prostanoids are produced in increased amounts in response to cytokines such as interleukin-1 (IL-1). These autacoids influence the expression of glomerular injury by their direct as well as interactive actions. We studied the effect of hydrogen peroxide (H2O2) on NO production in rat mesangial cells. We demonstrate that transient exposure of mesangial cells to H2O2 prior to sustained exposure to IL-1 decreased extracellular accumulation of NO2/NO3 and cellular guanosine 3,'5'-cyclic monophosphate (cGMP) content. H2O2 markedly impaired inducible nitric oxide synthase (iNOS) activity induced by IL-1 directly measured by the conversion of L-[14C]arginine to L-[14C]citrulline. Such impairment in iNOS activity was accompanied by a parallel reduction in iNOS protein abundance but not by a reduced expression of iNOS mRNA. The inhibitory effect of H2O2 on NOS activity was further supported by peroxide-induced impairment in IL-1-driven, NO-dependent synthesis of prostaglandin E2. Our studies thus provide the first direct evidence of a posttranscriptional inhibitory effect of H2O2 on iNOS activity. Additionally, our studies uncover the existence of a previously unrecognized effect of H2O2 on the production of NO that may exert influence on the severity of glomerular injury during glomerular inflammation.

Animals↗
PubMed2001

Multiple mechanisms of reflex bronchospasm in guinea pigs.

The mechanisms of histamine- and bradykinin-induced reflex bronchospasm were determined in anesthetized guinea pigs. With intravenous administration, both autacoids evoked dose-dependent increases in tracheal cholinergic tone. Vagotomy or atropine prevented these tracheal reflexes. When delivered as an aerosol, bradykinin readily increased tracheal cholinergic tone, whereas histamine aerosols were much less effective at inducing tracheal reflexes. Also, unlike histamine, bradykinin could evoke profound increases in cholinergic tone without directly or indirectly (e.g., prostanoid dependent) inducing measurable airway smooth muscle contraction resulting in bronchospasm. Neither autacoid required de novo synthesis of prostanoids or nitric oxide to induce reflex tracheal contractions. Combined cyclooxygenase inhibition and tachykinin-receptor antagonism did, however, abolish all effects of bradykinin in the airways, whereas responses to histamine were unaffected by these pretreatments. The data indicate that histamine and bradykinin initiate reflex bronchospasm by differential activation of vagal afferent nerve subtypes. We speculate that selective activation of either airway C fibers or airway rapid adapting receptors can initiate reflex bronchospasm.

Animals↗
PubMed1989

Effect of long-term administration of platelet-activating factor on pulmonary responsiveness and morphology in the guinea pig.

To further substantiate the possible role of platelet-activating factor (PAF) in the development of bronchial hyperreactivity, Alzet osmotic minipumps loaded with the autacoid or solvent alone were placed under the back skin of male Hartley guinea pigs and connected to the jugular vein for 15 days. As compared to the animals treated with solvent alone, guinea pigs receiving PAF (20 micrograms/kg/h, 15 days) exhibited a hyperresponsiveness to histamine that was not observed in those simultaneously treated with PAF and the PAF antagonist BN 52021. Lungs from PAF-treated animals were congestive in appearance, bronchi and bronchioli were contracted, Reisseisen muscles were markedly hypertrophied, and a muciparous metaplasia of the endothelium was observed. The number of eosinophils was significantly increased in the parenchyma, as was the number of mast cells in the peribronchial zones in the lungs from guinea pigs chronically treated with PAF. Lungs from control animals did not show morphologic alterations or eosinophil and mast cell infiltration. These data indicate that long-term treatment with PAF induces profound alterations in the respiratory system, resembling those observed in asthmatic patients. This result is in keeping with the possible role of this autacoid in the development of bronchial hyperreactivity.

Animals↗
PubMed1993

Serotonin-induced vasoconstriction in human placental chorionic veins: interaction with prostaglandin F2 alpha.

In vitro experiments using isolated rings and perfused segments of human chorionic veins, were designed to determine the effects of serotonin and their interaction with PGF2 alpha on vascular tension and perfusion pressure. These vessels responded vigorously with high sensitivity to the vasoconstrictor effects of serotonin in both experimental designs. Administration of PGF2 alpha also led to constriction of the veins, but this autacoid is at least 100 times less potent than serotonin. When adding PGF2 alpha previously to serotonin to the bathing fluid or to the perfusate, the serotonin response was significantly potentiated, increasing the maximal contractile response in 116 +/- 12% and the perfusion pressure in 180 +/- 25%. Both autacoids probably operate in this vascular bed interacting with each other and playing an important role in the regulation of placental blood flow in vivo.

Analysis of Variance↗
PubMed1991

Vasoactive effects of intra- and extravascular serotonin, PGE2 and PGF2 alpha in human umbilical arteries.

The effect of serotonin, PGE2 and PGF2 alpha on the vascular tension in human umbilical arteries has been investigated during in vitro perfusions. All autacoids induced dose-dependent biphasic pressure responses when added to the perfusate. When added to the extraumbilical fluid, serotonin induced monophasic vasoconstrictory responses, whereas PGE2 and PGF2 alpha did not elicit significant changes except for minor pressure oscillations in some experiments. The results obtained suggest a contributory role of the endothelial layer in the action of these autacoids on the smooth muscle tension.

Dinoprost↗
PubMed1997

Endothelium-derived hyperpolarizing factor, but not nitric oxide, is reversibly inhibited by brefeldin A.

The subcellular localization of the enzymes synthesizing endothelium-derived vasodilator autacoids has been proposed to play a role in determining the ability of endothelial cells to enhance autacoid production in response to stimulation. We therefore investigated the effects of brefeldin A-induced disruption of the Golgi apparatus and Golgi-plasma membrane trafficking on the production of nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor (EDHF) by native and cultured endothelial cells. In porcine coronary artery segments, brefeldin A (35 micromol/L, 90 minutes) did not affect relaxations to sodium nitroprusside or the K+ channel opener cromakalim but elicited a rightward shift in the concentration-response curve to bradykinin without altering the maximum vasodilator response (Rmax). Brefeldin A failed to attenuate the bradykinin-induced, NO-mediated relaxation under depolarizing conditions but inhibited the bradykinin response under conditions of combined cyclooxygenase/NO synthase blockade, suggesting that this agent selectively interferes with the production of EDHF. Indeed, incubation of porcine coronary arteries with brefeldin A, which did not affect the bradykinin-induced accumulation of either cyclic GMP or 6-keto-prostaglandin F1alpha, markedly and reversibly attenuated the EDHF-mediated hyperpolarization of detector smooth muscle cells in a patch-clamp bioassay system. The microtubule destabilizer nocodazole also affected both the EC50 and Rmax to bradykinin in porcine coronary arteries. Since EDHF is thought to be a cytochrome P450-derived metabolite of arachidonic acid and both brefeldin A and nocodazole are known to interfere with the targeting of cytochrome P450 from the Golgi apparatus to the plasma membrane, it is conceivable that brefeldin A inhibits EDHF formation by preventing the targeting of the EDHF-synthesizing enzymes to the plasma membrane.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

Inhibition of platelet-activating factor biosynthesis by adenosine and histamine in human neutrophils: involvement of cPLA2alpha and reversal by lyso-PAF.

Leukotrienes (LT) and platelet-activating factor (PAF) are important lipid mediators of inflammation. We and others reported previously that autacoids such as adenosine, histamine, prostaglandin E2, and beta-adrenergic agents inhibit LT biosynthesis in activated human polymorphonuclear leukocytes (PMN). In this study, we demonstrate that CGS-21680 (a selective agonist of the adenosine A2A receptor) and histamine also potently inhibit PAF biosynthesis in agonist [formyl Met-Leu-Phe (fMLP)]- and thapsigargin-activated human PMN. The observed inhibitions of PAF biosynthesis were reversed effectively by exogenous 1-O-alkyl-lyso-sn-glyceryl-3-phosphocholine (lyso-PAF), suggesting that these effects of CGS-21680 and histamine implicate the blockade of cytosolic phospholipase A2alpha (cPLA2alpha) activity and lyso-PAF release and that the acetyl-coenzyme A/lyso-PAF acetyl transferase is not inhibited by the autacoids. Accordingly, the cPLA2alpha inhibitor pyrrophenone completely blocked PAF formation, and lyso-PAF similarly prevented this effect of pyrrophenone. The inhibitory effects of CGS-21680 and histamine on PAF biosynthesis were prevented by the protein kinase A inhibitor H-89, supporting roles for the Gs -coupled receptors A2A and H2, respectively, and cyclic adenosine monophosphate in the inhibitory mechanism. The fMLP-induced phosphorylations of p38 and extracellular signal-regulated kinase 1/2 were not altered significantly by the CGS-21680, indicating that inhibition of these kinases is not involved in the inhibitory effect of the adenosine A2A receptor ligand on LT and PAF biosynthesis. These data further emphasize the multiple and potent inhibitory effects of adenosine and histamine on leukocyte functions, in particular, on the biosynthesis of two classes of important lipid mediators and their putative regulatory roles in immune processes in health and diseases.

Adenosine↗
PubMed1995

Decidual histamine release and amplification of prostaglandin F2 alpha production by histamine in interleukin-1 beta-primed decidual cells: potential interactive role for inflammatory mediators in uterine function at term.

Inflammatory cytokines such as interleukin-1 (IL-1) have been implicated as paracrine mediators of decidual prostaglandin (PG) production during preterm labor. The aim of the present in vitro study was to investigate a similar potential role for the inflammatory autacoid histamine. Histamine action on human primary decidual cell cultures was monitored by measuring both PGF2 alpha production and PG precursor release. Histamine release from decidual cell suspensions was measured in response to a variety of putative mast cell secretagogues. Histamine stimulated a dose-dependent increase in PGF2 alpha production and [14C]arachidonate release from prelabeled decidual cells, with ED50 values around 1 and 2 mumol/L, respectively. Pretreatment of cells with IL-1 beta enhanced maximal PGF2 alpha production in response to histamine by approximately 4-fold. Mepyramine, an H1 receptor antagonist, completely blocked this PGF2 alpha response. The mean histamine content of unpurified decidual cells was approximately 81 pmol/10(6) cells. Upon challenge with antihuman immunoglobulin E, these cells exhibited a dose-dependent release of histamine. Basal release from decidual cell suspensions and release in response to antiimmunoglobulin E (1:400) or A23187 (1 mumol/L) were 7.6 +/- 2.7%, 25.5 +/- 0.9%, and 63.5 +/- 5.6% of the total histamine content, respectively. No significant changes in histamine secretion were seen in response to compound 48/80, substance-P, phorbol ester, or bacterial endotoxin. These in vitro findings support a potential role for histamine as a local regulator of phospholipase-A2 and PGF2 alpha production in human term decidua. The interaction of this autacoid with other inflammatory mediators, such as IL-1, could play a role in the control of PG production during preterm labor.

Arachidonic Acid↗
PubMed1991

Blood viscosity measurement for screening of affecting blood circulation.

An in vitro screening test for drugs that decrease blood viscosity was carried out on many pharmacologically active compounds such as Ca-antagonists, alpha-antagonists, beta-antagonists, alpha, beta-antagonists, alpha-agonists, beta-agonists, alpha, beta-agonists, autacoids and others. The results revealed that various types of microcirculatory-improving drugs, vasodilators, and antagonists decreased blood viscosity, while the agonists and autacoids had no significant effect. These findings suggest that this assay is useful for screening compounds related to hemorheology.

Animals↗
PubMed1992

Cell surface receptors and ectoenzymes in mesangial cells.

Mesangial cells possess a variety of receptors for hormones and autacoids. They are also equipped with ectoenzymes whose function may be to control the availability of autacoids and hormones at their receptor sites. Several examples are considered. Receptors for angiotensin II (AII) are present both on murine and human mesangial cells. One single group of receptors has been demonstrated in each of these preparations. Mesangial cell AII receptors are linked to phospholipase C via a G protein. They belong to the AT1 subtype because (125I)AII is displaced from its binding sites preferentially by AT1 antagonists such as DUP 753 and EXP 3,174, whereas AT2 antagonists are much less potent. AT1 antagonists suppress the biological effects of AII in mesangial cells, including the stimulation of intracellular calcium concentration and the increase of prostaglandin synthesis and of (3H)leucine incorporation. Mesangial cells also have receptors for atrial natriuretic factor, but the distribution between B receptors with guanylate cyclase activity and clearance (C) receptors varies with the species. Both types are present in murine mesangial cells, whereas only C receptors are found in human mesangial cells. In contrast, human epithelial cells possess both B and C receptors. Ecto-5'-nucleotidase activity results in the production of adenosine, which acts on mesangial cells through A1 and A2 receptors. This enzyme is markedly induced in rat mesangial cells by interleukin-1, whose effect is mediated in part by prostaglandin E2 and cAMP. Various other cAMP-stimulating agents also induce 5'-nucleotidase expression in rat mesangial cells. Ectopeptidases are present in all glomerular cell types but essentially in epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

5'-Nucleotidase↗
PubMed2002

Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation.

Polymorphonuclear neutrophils (granulocytes; PMNs) are often the first blood cells to migrate toward inflammatory lesions to perform host defense functions. PMNs respond to specific stimuli by releasing several factors and generate lipid mediators of inflammation from the 5-lipoxygenase and the inducible cyclooxygenase (COX)-2 pathways. In view of adenosine's anti-inflammatory properties and suppressive impact on the 5-lipoxygenase pathway, we addressed in this study the impact of this autacoid on the COX-2 pathway. We observed that adenosine up-regulates the expression of the COX-2 enzyme and mRNA. Production of PGE(2) in response to exogenous arachidonic acid was also increased by adenosine and correlated with COX-2 protein levels. The potentiating effect of adenosine on COX-2 could be mimicked by pharmacological increases of intracellular cAMP levels, involving the latter as a putative second messenger for the up-regulation of COX-2 by adenosine. Specific COX-2 inhibitors were used to confirm the predominant role of the COX-2 isoform in the formation of prostanoids by stimulated PMNs. Withdrawal of extracellular adenosine strikingly emphasized the inhibitory potential of PGE(2) on leukotriene B(4) formation and involved the EP(2) receptor subtype in this process. Thus, adenosine may promote a self-limiting regulatory process through the increase of PGE(2) generation, which may result in the inhibition of PMN functions. This study identifies a new aspect of the anti-inflammatory properties of adenosine in leukocytes, introducing the concept that this autacoid may exert its immunomodulatory activities in part by modifying the balance of lipid mediators generated by PMNs.

Adenosine↗
PubMed2000

Attenuation of histamine-induced endothelial permeability responses after pacing-induced heart failure: role for endogenous catecholamines.

OBJECTIVE: After congestive heart failure (CHF), lung endothelial permeability responses to a number of perturbations, including acute barotrauma, angiotensin II, and thapsigargin are blunted. Our hypothesis was that similar attenuation of permeability responses occurs in peripheral vascular beds after CHF. We compared peripheral microvascular permeability responses to the autacoid histamine in control dogs and in dogs paced to heart failure (245 bpm for approximately 36 days). Since catecholamines attenuate autacoid-induced increases in microvascular permeability in skin and muscle in normal animals, we also tested whether the known elevation in catecholamines in CHF was involved in any downregulation of permeability responses in this group. METHODS: Control and paced dogs were anesthetized, intubated, and ventilated, and a hindpaw lymphatic cannulated. The reflection coefficient for total proteins (sigma) was measured at baseline and during one-hour, local intra-arterial histamine infusion. RESULTS: In controls, sigma fell from 0.83 +/- 0.02 to 0.73 +/- 0.04 after histamine (p < 0.05), while in the paced group sigma was no different from that at baseline (0.77 +/- 0.02). To test whether this difference was due to endogenous catecholamines, dogs were pretreated with propranolol (controls only) or the specific beta 2-antagonist ICI 118,551 prior to histamine infusion. After beta-blockade, histamine significantly reduced sigma in both control (0.83 +/- 0.01 to 0.55 +/- 0.05) and paced (0.83 +/- 0.01 to 0.57 +/- 0.07) groups (p < 0.05). CONCLUSION: We conclude that endogenous catecholamines, acting via beta 2-adrenergic receptors, attenuate the permeability response to histamine in pacing-induced heart failure.

Adrenergic beta-Antagonists↗
PubMed2001

[Increase of water permeability and recovery of water impermeability of the frog urinary bladder].

The experiments carried out on the urinary bladder of the frog Rana temporaria L. have shown that the period of recovery of water impermeability after an increase of osmotic water permeability induced by arginine-vasotocin, desmopressin, or cAMP depends on the degree of increase of the osmotic permeability but not on the nature of the substance stimulating the increase of osmotic water permeability. The removal of the hormone in the absence of autacoids fails to recover the water impermeability. After cessation of the vasotocin action the water permeability decrease is delayed if phospholipase A2 and cyclooxygenase are inhibited by qiunacrine and voltaren, respectively. An agonist of V1-receptors has no effect on dynamics of the recovery of water impermeability. This recovery has been shown to depend on PGE2 concentration in the serosal solution after the hormone removal. The obtained results indicate that decrease of water permeability depends not only on removal of vasotocin or cAMP but also on involvement of autacoids.

Animals↗