No steroids or STITCH for CPB?
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Animals↗
Biomedical subjects
H Kan
Publications and source records attributed to H Kan.
Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NO production by rat cardiac myocytes.
The effect of norepinephrine (NE) on cytokine-stimulated nitric oxide (NO) production by cardiac myocytes has not been previously reported. NE alone caused no significant increase in NO-2 levels over vehicle. Addition of NE to interleukin-1beta (IL-1beta) significantly increased inducible NO synthase (iNOS) mRNA expression, iNOS protein, and NO-2 production vs. IL-1beta alone. Addition of the alpha-adrenergic blocker prazosin or the beta-adrenergic blocker propranolol partially reduced the NE-mediated increase in iNOS mRNA expression and NO-2 production. Addition of prazosin and propranolol together completely abolished the NE-induced increase in iNOS mRNA expression and NO-2 production. NE significantly enhanced mitogen-activated protein (MAP) kinase activity that was reduced by prazosin, propranolol, and PD-98059, a selective MAP kinase kinase inhibitor. Addition of PD-98059 reduced the NE-mediated increase in iNOS mRNA expression and NO-2 production. We report for the first time that NE enhances IL-1beta-stimulated NO production by activation of alpha- and beta-adrenergic receptors through a novel MAP kinase mechanism.
Adrenergic alpha-Agonists↗
Effects of cytokines and nitric oxide on myocardial E-C coupling.
Compelling evidence now exists that pro-inflammatory cytokines and nitric oxide (NO) are newly identified endogenous regulators of myocardial contractility. The mechanism(s) responsible for the inotropic and chronotropic effects of these novel mediators can be explained on the basis of recently established principles of myocardial excitation contraction coupling (E-C). A novel hypothesis is proposed that cytokines and NO-mediated alterations in E-C coupling contribute to the reversible myocardial depression and beta-adrenergic desensitization observed in a diverse group of clinical conditions that activate host inflammatory responses, including congestive heart failure. The results of in vitro studies indicate that cytokines and NO have both immediate, short-term, as well as long-term effects on cardiac performance. Basic studies into these cytokine signaling pathways in cardiac myocytes have the potential to provide important new insights relevant to the design of new management strategies for the treatment of congestive heart failure patients.
Animals↗
Cytokines, cardiopulmonary bypass, and NO STITCH?
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Cardiopulmonary Bypass↗
Fighting fire with fire.
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Angiotensin II↗
Alpha-1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in rat-1 fibroblasts: inhibition by protein kinase A.
This study was conducted to determine the mechanism of arachidonic acid (AA) release elicited by phenylephrine (PHE) stimulation of alpha adrenergic receptor (AR), and its modulation by cyclic adenosine 3',5'-monophosphate (cAMP) in Rat-1 fibroblasts (R-1Fs) transfected with the alpha-1A, alpha-1B or alpha-1D AR. PHE increased AA release and also caused a marked accumulation of cAMP in R-1Fs expressing the alpha-1 AR subtypes, but not in those transfected with vector alone. PHE also enhanced phospholipase D (PLD), but not phospholipase A2 (PLA2) activity. The increase in PHE-induced AA release, PLD activity and cAMP accumulation differed among the various alpha AR subtypes with: alpha-1A > alpha-1B > alpha-1D AR. The effect of PHE to increase AA release was attenuated by C2-ceramide, an inhibitor of PLD; propranolol, a phosphatidate phosphohydrolase inhibitor; and RHC-80267, a diacylglycerol lipase inhibitor in R-1Fs expressing the alpha-1A AR. Forskolin, which activates adenylyl cyclase, increased cAMP accumulation and inhibited PHE-induced AA release and PLD activity in alpha-1A-AR-expressing R-1Fs. 8-(4-chlorophenyl-thio)-cAMP, a nonhydrolyzable analog of cAMP, also attenuated the rise in AA release and PLD activity elicited by PHE in these cells. In contrast, SQ 22536, an adenylyl cyclase inhibitor, and KT 5720, a protein kinase A inhibitor, increased PHE-induced AA release and PLD activity in R-1Fs expressing the alpha-1A AR. These data suggest that the alpha-1A, alpha-1B and alpha-1D ARs are coupled to PLD activation and cAMP accumulation. Moreover, PHE promotes AA release in R-1Fs expressing the alpha-1A AR through PLD activation. Furthermore, cAMP generated by alpha-1A AR stimulation acts as an inhibitory modulator of PLD activity and AA release via protein kinase A.
Adenine↗
Beta adrenergic receptor stimulated prostacyclin synthesis in rabbit coronary endothelial cells is mediated by selective activation of phospholipase D: inhibition by adenosine 3'5'-cyclic monophosphate.
Activation of beta adrenergic receptors in the isolated rabbit heart by catecholamines stimulates prostacyclin (PGI2) synthesis, which is inhibited by adenosine 3'5'-cyclic monophosphate (cAMP). The purpose of this study was to determine if activation of beta adrenergic receptors in cultured coronary endothelial cells (CEC) of rabbit heart with isoproterenol (ISOP) stimulates PGI2 synthesis and if cAMP inhibits the synthesis of this prostanoid and to investigate the underlying mechanism. Incubation of CEC with ISOP increased production of cAMP and PGI2, measured as immunoreactive cAMP and 6-keto-prostaglandin F1alpha, (6-keto-PGF1alpha), respectively. Forskolin, an activator of adenylyl cyclase, increased cAMP accumulation and inhibited ISOP-stimulated 6-keto-PGF1alpha synthesis. 8-(4-chlorophenyl-thio) cAMP also inhibited ISOP-induced 6-keto-PGF1alpha production. However, miconazole, an inhibitor of adenylyl cyclase, reduced cAMP accumulation and enhanced ISOP-stimulated 6-keto-PGF1alpha synthesis in CEC. ISOP-induced 6-keto-PGF1alpha synthesis was attenuated by C2-ceramide, an inhibitor of phospholipase D (PLD) by propranolol, a beta-AR antagonist that also inhibits phosphatidate phosphohydrolase and by the diacylglycerol lipase inhibitor 1,6-bis-(cyclohexyloximinocarbonylamino)-hexane (RHC 80267). Acetylcholine (ACh) induced 6-keto-PGF1alpha synthesis was also inhibited by these agents. Both ISOP and ACh increased PLD activity, which was inhibited by C2-ceramide but not by RHC 80267 or propranolol. ACh but not ISOP increased phospholipase A2 activity in CEC. ISOP- but not ACh-induced increase in PLD activity was attenuated by forskolin and 8-(4-chlorophenyl-thio)-adenosine 3'-5'-cyclic monophosphate and augmented by miconazole. These data suggest that beta adrenergic receptors activation promotes PGI2 synthesis in the CEC by selective activation of PLD and that cAMP decreases PGI2 synthesis by decreasing PLD activity. Moreover, beta adrenergic receptors activated PLD appears to be distinct from that stimulated by ACh.
Animals↗
Signal transduction mechanism(s) involved in prostacyclin production elicited by acetylcholine in coronary endothelial cells of rabbit heart.
The purpose of this study was to elucidate the mechanism by which acetylcholine (ACh) promotes prostacyclin (PGI2) production in cultured coronary endothelial cells (CEC) of the rabbit heart. ACh-induced production of PGI2, measured as immunoreactive 6-keto-PGF1alpha, was enhanced by increasing the extracellular calcium (Ca++) concentration and reduced by Ca++ depletion. The receptor-operated Ca++ channel blocker SK&F96365, but not the voltage-dependent Ca++ channel blockers verapamil or nifedipine, attenuated ACh-induced 6-keto-PGF1alpha production and the associated rise in cytosolic Ca++. Thapsigargin, which depleted Ca++ accumulation from the intracellular Ca++ store, did not prevent the ACh-induced rise in cytosolic Ca++. In the absence of extracellular Ca++, ACh and ATP increased cytosolic Ca++ but did not alter 6-keto-PGF1alpha production. In permeabilized CEC, guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) but not ACh enhanced 6-keto-PGF1alpha synthesis. ACh increased 6-keto-PGF1alpha production in the presence of GTP-gamma-S. These effects of GTP-gamma-S were attenuated by guanosine 5'-O-(2-thiotriphosphate). In the absence of extracellular Ca++, ACh or ATP increased cytosolic Ca++ in cells permeabilized with beta-escin and loaded with GTP-gamma-S; this effect was attenuated by guanosine 5'-O-(2-thiotriphosphate). The effect of ATP but not ACh to mobilize intracellular Ca++ or increase 6-keto-PGF1alpha was inhibited by pertussis toxin. The phospholipase C inhibitor D609, which attenuated ACh- and ATP-induced mobilization of intracellular Ca++, did not alter 6-keto-PGF1alpha production. The NO synthase inhibitor N-monomethyl-arginine also failed to alter ACh-induced 6-keto-PGF1alpha synthesis. These data suggest that, in CEC of the rabbit heart, ACh stimulates prostacyclin production via a pertussis toxin-insensitive G protein and by increasing the influx of extracellular Ca++ through a G protein-independent receptor-operated Ca++ channel.
Acetylcholine↗
Human acute myeloid leukemias may be etiologically associated with new human retroviral infection.
The etiology of human acute myeloid leukemias (AML) remains uncertain. In order to examine the possibility of retroviral etiology in AML, we determined retroviral antigens related to HTLV-I in leukemic cell samples from 32 AML cases and peripheral blood mononuclear cells (PBMNCs) from 20 healthy donors by D-IGSS with high sensitivity and specificity, reverse transcriptase (RT) activity by a simple and sensitive non-radioisotopic RT assay, and retroviral particles by electron microscopy. The HTLV-I-related antigens were detected in 50.0% (16/32) of fresh leukemic cell samples and 87.5% (28/32) of cultured leukemic cell samples. The HTLV-I-related antigen-positive cells in fresh and cultured leukemic samples were 10.2% and 52.8%, respectively. Both frequency and level of HTLV-I-related antigens in cultured samples were much higher than in fresh samples. In contrast, no HTLV-I-related antigens were found in normal hematopoietic cells from 20 healthy donors. Further study results show that RT activity was detected not only in HTLV-I-related antigen-positive samples, but was also well correlated with the level of HTLV-I-related antigens in these samples, and preferred Mn+2 to Mg+2 as a cation. Moreover, typical retroviral particles were localized in most cultured HTLV-I-related antigen-positive samples by immunoelectron microscope. These data suggest that human acute myeloid leukemias may be etiologically associated with new human retroviral infection.
Acute Disease↗
Modulation of beta-adrenergic receptor-stimulated lipolysis in the heart by prostaglandins.
The purpose of the present study was to investigate the contribution of prostaglandins to lipolysis elicited by beta-adrenergic receptor activation in the heart. We have studied the effect of prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), and their precursor arachidonic acid (AA) in the presence and absence of a cyclooxygenase inhibitor, sodium meclofenamate, on glycerol output elicited by stimulation of beta-adrenergic receptors in the isolated rabbit heart with isoproterenol (ISOP). Bolus injections of ISOP (475 pmol) produced a constant increase in glycerol and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) output. Infusion of sodium meclofenamate (16 microM) reduced basal and attenuated ISOP-induced 6-keto-PGF1 alpha output and enhanced glycerol output. During inhibition of endogenous prostaglandin synthesis with meclofenamate, infusion of PGI2 or PGE2 (0.1-1 microM) inhibited ISOP-induced glycerol output. Infusion of AA (0.1-1 microM) increased 6-keto-PGF1 alpha and reduced glycerol output. Infusion of sodium meclofenamate abolished the effect of AA to increase 6-keto-PGF1 alpha and to decrease glycerol output. These data suggest that prostaglandins synthesized in the heart act as an inhibitory modulator of beta-adrenergic receptor-stimulated cardiac lipolysis.
Animals↗
[Effect of green tea polyphenol fraction on 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in the rat].
We studied the anti-tumor effect of green tea polyphenol fraction (Sunphenon, SF: provided by Taiyo Kagaku Inc., Mie, Japan) on DMH-induced colorectal carcinogenesis in male Wistar rats. DMH was subcutaneously administered weekly at 20 mg/kg for 14 weeks. The rats in group I (20 rats) were given tap water for the whole of the study period. The rats in group II (15 rats) were given tap water from weeks 0-14, and 0.1% SF from weeks 15-35. The rats in group III (21 rats) were given 0.1% SF during the whole period. The rats were sacrificed at week 35. The cecal contents were aseptically removed and examined microbiologically to obtain the counts of four bacteria species (including Clostridium perfringens) per 1 g of cecal contents. The incidence of tumors production was significantly decreased (Group I: 100% vs Group II: 57.1%, Group III: 62.5%, p < 0.05), and the frequency of occurrence of C. perfringens (which is thought to yield harmful products which may be carcinogenic) was decreased in the SF-treated groups. These results suggest that SF prevents DMH-induced carcinogenesis in rats, and that its effect may be somehow related to its ability to preserve the composition of the colonic microflora.
1,2-Dimethylhydrazine↗
Modulation by cyclic AMP of beta adrenergic receptor-stimulated prostacyclin synthesis in rabbit ventricular myocytes.
The purpose of the present study was to determine the possible interaction of cyclic AMP (cAMP) and the synthesis of prostacyclin [measured as immunoreactive 6-keto-prostaglandin (PG)F1 alpha] elicited by the beta adrenergic receptor agonist isoproterenol (ISOP), in freshly dissociated rabbit ventricular myocytes. ISOP (10(-13) to 10(-11) M) increased 6-keto-PGF1 alpha synthesis without altering the level of cAMP. Increasing the concentration of ISOP from 10(-10) to 10(-7) M enhanced accumulation of cAMP, which was associated with a decline in 6-keto-PGF1 alpha synthesis. Forskolin (10(-6) M), an activator of adenylyl cyclase, and 3-isobutyl-1-methylxanthine (10(-5) M), an inhibitor of cAMP phosphodiesterase, increased cAMP accumulation and inhibited ISOP-induced 6-keto-PGF1 alpha synthesis. 8-(4-chlorophenylthio) (cpt)-cAMP (10(-7) M) also inhibited ISOP-induced 6-keto-PGF1 alpha production. On the other hand, miconazole (10(-4) M), an inhibitor of adenylyl cyclase, reduced cAMP accumulation and enhanced ISOP-induced 6-keto-PGF1 alpha synthesis in myocytes. Miconazole also attenuated ISOP-, forskolin- and cpt-cAMP-induced increases in protein kinase A activity. The protein kinase A inhibitor H-89 {N-[2-(p-bromocinnamylamino)ethyl] -5-isoquinolinesulfonamide} attenuated the ISOP (10(-7) M)-induced increase in the activity of this enzyme and minimized the decline in 6-keto-PGF1 alpha synthesis produced by 10(-7) M ISOP and the inhibitory effect of cpt-cAMP and forskolin on 6-keto-PGF1 alpha production. 3-Isobutyl-1-methylxanthine, forskolin and cpt-cAMP did not alter the conversion of exogenous arachidonic acid to 6-keto-PGF1 alpha. These data indicate that beta adrenergic receptor activation promotes prostacyclin synthesis in rabbit ventricular myocytes and that cAMP acts as an inhibitory modulator. This action is mediated via activation of protein kinase A, probably by decreasing the activity of the lipase, involved in beta adrenergic receptor-induced arachidonic acid release.
Animals↗
Localization and characterization of the subtypes(s) of muscarinic receptor involved in prostacyclin synthesis in rabbit heart.
The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin(1 alpha) (6-keto-PGF(1 alpha)), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF(1 alpha) synthesis in these cell types. ACh induced 6-keto-PGF(1 alpha) synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 microM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 microM). In coronary endothelial cells, ACh-induced 6-keto-PGF(1 alpha) production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H- pyrido[2,3-b]-benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF(1 alpha) synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardioprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-keto-PGF (1 alpha) production, is mediated by pertussis toxin-sensitive G(alpha i) proteins in these cells.
Acetylcholine↗
Involvement of mitogen-activated protein kinase and translocation of cytosolic phospholipase A2 to the nuclear envelope in acetylcholine-induced prostacyclin synthesis in rabbit coronary endothelial cells.
We previously showed that acetylcholine (ACh) stimulates production of prostacyclin, measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in coronary endothelial cells (CEC) of rabbit heart by increasing influx of extracellular Ca2+ through a receptor-operated Ca2+ channel and by activating a pertussis toxin-insensitive G protein. The purposes of this study were to elucidate the type of phospholipase A2 (PLA2) involved in 6-keto-PGF1 alpha production and the mechanism(s) by which ACh activates PLA2 in cultured CEC. In CEC transiently transfected with cytosolic PLA2 but not secretory PLA2 antisense oligonucleotide, ACh failed to increase 6-keto-PGF1 alpha; this was prevented by cotransfection with cPLA2 sense oligonucleotide. ACh increased production of prostacyclin and increased protein kinase C (PKC) activity. The PKC inhibitor calphostin C attenuated the ACh-induced increase in PKC activity but not 6-keto-PGF1 alpha production. Phorbol-12-myristate-13-acetate and phorbol-12, 13-dibutyrate increased PKC activity but failed to alter 6-keto-PGF1 alpha production. ACh enhanced the activity of cPLA2 and p42 mitogen-activated protein kinase (MAPK) in cell lysate prepared from CEC. ACh also caused phosphorylation of p42 MAPK and cPLA2, which was inhibited by AG126 ([alpha-cyano-(3-hydroxy-4-nitro)cinnamonitrile]), a tyrosine kinase inhibitor known to decrease MAPK activity. In addition, ACh stimulated translocation of cPLA2 from cytosol to nuclear envelope; the translocation of cPLA2 was prevented by removal of extracellular calcium but not by AG126 treatment. Okadaic acid, a protein phosphatase inhibitor, increased cPLA2 activity in cell lysate prepared from CEC but did not alter basal 6-keto-PGF1 alpha production in intact CEC; however, ACh-induced 6-keto-PGF1 alpha was enhanced by okadaic acid. These data suggest that ACh stimulates prostacyclin synthesis by activation of cPLA2 in a PKC-independent mechanism and that both cPLA2 translocation to nuclear envelope and phosphorylation by MAPK are required for ACh-induced 6-keto-PGF1 alpha synthesis in CEC.
6-Ketoprostaglandin F1 alpha↗
Macroscopic Coulomb-blockade effect in a constant-current-driven light-emitting diode.
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Journal Article↗
Extraordinarily high eosinophilia and elevated serum interleukin-5 level observed in a patient infected with Paragonimus westermani.
OBJECTIVE: Although eosinophilia is one of the typical clinical features of some helminth infections, the degree of eosinophilia in helminthiasis is usually 10% to 30% with a total white blood cell count of 10,000 to 20,000/mm3. Here we report a case of extraordinarily high eosinophilia (91%; absolute eosinophil count, 84,000/mm3) caused by Paragonimus westermani infection. To determine the mechanisms of eosinophilia, the levels of several eosinophilopoietic cytokines in the patient's sera were measured during the course of treatment. METHODS: Serum levels of three cytokines, granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 were measured by enzyme-linked immunosorbent assay using commercial kits or our own assay system for IL-5. RESULTS: Although the kinetic changes of IL-5 correlated well with eosinophilia, the serum IL-3 level remained below the detection level throughout the period examined. Although the granulocyte-macrophage colony-stimulating factor level was twofold to threefold higher than the normal level, its kinetics did not parallel the degree of eosinophilia. CONCLUSIONS: These results show that Paragonimus westermani infection can induce an extraordinarily high level of eosinophilia with an associated increase in IL-5 production. Immunoserologic diagnosis for parasitic diseases should be included in the differential diagnosis of eosinophilia.
Animals↗