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Activation of mitogen-activated protein kinase pathways by cyclic gmp and cyclic gmp-dependent protein kinase in contractile vascular smooth muscle cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第48期274卷 34301-34309页

作者： Komalavilas, P Shah, PK Jo, HJ Lincoln, TM Univ Alabama Birmingham Div Mol & Cellular Pathol Dept Pathol Birmingham AL 35294 USA

Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic gmp (cgmp) signaling, the cgmp-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cgmp activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cgmp on ERK and JNK activation mere also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cgmp signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cgmp and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.

关键词： 8-溴环腺苷一磷酸/药理学生物碱类/药理学主动脉卡唑类细胞培养的环gmp/类似物和衍生物环gmp/药理学环gmp依赖性蛋白激酶类/拮抗剂和抑制剂环gmp依赖性蛋白激酶类/遗传学环gmp依赖性蛋白激酶类/代谢酶激活/药物作用酶抑制剂/药理学基因表达吲哚类/药理学 JNK丝裂原活化蛋白激酶类 MAP激酶激酶4 MAP激酶激酶激酶类/代谢丝裂原活化蛋白激酶1/代谢丝裂原活化蛋白激酶3 丝裂原激活蛋白激酶激酶类/代谢丝裂原激活蛋白激酶类/代谢肌收缩/药物作用肌收缩/生理学肌平滑血管/细胞学肌平滑血管/药物作用肌平滑血管/酶学血小板源性生长因子/药理学蛋白质丝氨酸苏氨酸激酶吡咯类/药理学大鼠 Sprague-Dawley 重组融合蛋白质类/药物作用重组融合蛋白质类/遗传学重组融合蛋白质类/代谢硫代核苷酸类/药理学时间因素转染肿瘤坏死因子α/药理学 p38丝裂原活化蛋白激酶类动物大鼠

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KT5823 inhibits cgmp-dependent protein kinase activity in vitro but not in intact human platelets and rat mesangial cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第43期275卷 33536-33541页

作者： Burkhardt, M Glazova, M Gambaryan, S Vollkommer, T Butt, E Bader, B Heermeier, K Lincoln, TM Walter, U Palmetshofer, A Med Univ Klin Inst Klin Biochem & Pathobiochem D-97080 Wurzburg Germany Med Univ Klin Div Nephrol D-97080 Wurzburg Germany Russian Acad Sci Sechenov Evolutionary Physiol & Biochem Inst St Petersburg 194223 Russia Univ Alabama Birmingham Div Mol & Cellular Pathol Birmingham AL 35294 USA

Many signal transduction pathways are mediated by the second messengers cgmp and cAMP, cgmp- and cAMP-dependent protein kinases (cGK and PHA), phosphodiesterases, and ion channels. To distinguish among the different cgmp effecters, inhibitors of cGK and PKA have been developed including the K-252 compound KT5823 and the isoquinolinesulfonamide H89, KT5823, an in vitro inhibitor of cGK, has also been used in numerous studies with intact cells to implicate or rule out the involvement of this protein kinase in a given cellular response, However, the efficacy and specificity of KT5823 as cGK inhibitor in intact cells or tissues have never been demonstrated. Here, we analyzed the effects of both KT5823 and H89 on cyclic-nucleotide-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in intact human platelets and rat mesangial cells. These two cell types both express high levels of cGK. KT5823 inhibited purified cGK, However, with both intact human platelets and rat mesangial cells, KT5823 failed to inhibit cGK-mediated serine 157 and serine 239 phosphorylation of VASP induced by nitric oxide, atrial natriuretic peptide, or the membrane-permeant cgmp analog 8-pCPT-cgmp, KT5823 enhanced 8-pCPT-cgmp-stimulated VASP phosphorylation in platelets and did not inhibit forskolin-stimulated VASP phosphorylation in either platelets or mesangial cells, In contrast H89, an inhibitor of both PKA. and cGK, clearly inhibited 8-pCPT-cgmp and forskolin-stimulated VASP phosphorylation in the two cell types. The data indicate that KT5823 inhibits purified cGK but does not affect a cGK-mediated response in the two different cell types expressing cGK I. These observations indicate that data that interpret the effects of KT5823 in intact cells as the major or only criteria supporting the involvement of cGK clearly need to be reconsidered.

关键词：生物碱类/药理学血小板/酶学卡唑类细胞黏附分子/代谢环gmp/类似物和衍生物环gmp/药理学环gmp依赖性蛋白激酶类/拮抗剂和抑制剂酶抑制剂/药理学福司柯林/药理学肾小球膜/酶学吲哚类异喹啉类/药理学微丝蛋白质类一氧化氮/生理学磷蛋白类/代谢磷酰化磺胺类动物牛人类大鼠

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Mechanisms underlying the reduced endothelium-dependent relaxation in human omental resistance artery in pre-eclampsia

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第1期527卷 163-174页

作者： Suzuki, Y Kajikuri, J Suzumori, K Itoh, T Nagoya City Univ Sch Med Dept Pharmacol Nagoya Aichi 4678601 Japan Nagoya City Univ Sch Med Dept Obstet & Gynecol Nagoya Aichi 4678601 Japan

1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre-eclamptic women in the presence of diclofenac (an inhibitor of cyclo-oxygenase). 2. In endothelium-intact strips, the sensitivity to 9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)) was significantly higher in pre-eclampsia, and this was not modified by either N-G-nitro-L-arginine (L-NNA, an inhibitor of NO synthase) or removal of the endothelium. 3. Bradykinin and substance P each produced an endothelium-dependent relaxation of the STA(2)-induced contraction in both groups, although the relaxation was significantly smaller for pre-eclampsia. L-NNA markedly attenuated the endothelium-dependent relaxation in the normotensive pregnant group but not in the pre-eclamptic group. 4. In the presence of L-NNA, the relaxation induced by Sodium nitroprusside (SNP) on the STA(2) contraction was significantly smaller for pre-eclamptic than for normotensive pregnant women. 5. In endothelium-denuded strips, the relaxation induced by 8-para-chlorophenyl thioguanosine-3',5'-cyclic monophosphate (8-pCPT-cgmp) on the STA(2) contraction was significantly less fur pre-eclampsia. 6. In beta-escin-skinned strips from both groups of women, 8-pCPT-cgmp (1-10 mu M) concentration-dependently attenuated the contraction induced by 0.5 mu M Ca2+. However, its relaxing action was significantly weaker in pre-eclampsia. 7. It is suggested that the weaker responsiveness to NO seen in strips fr om pre-eclamptic women may he partly due to a reduced smooth muscle responsiveness to cyclic gmp.

关键词：苯咪唑类/药理学缓激肽/药理学钙/代谢钙通道激动药/药理学环gmp/类似物和衍生物环gmp/生理学环加氧酶抑制药/药理学内皮血管/药物作用内皮血管/生理学肠系膜动脉/药物作用肠系膜动脉/生理学肌收缩/药物作用肌收缩/生理学肌平滑/药物作用肌平滑/生理学一氧化氮/生理学一氧化氮合酶/拮抗剂和抑制剂硝普钠/药理学网膜/血液供给网膜/生理学钾/代谢先兆子痫/病理生理学 P物质/药理学血栓烷A2/类似物和衍生物血栓烷A2/药理学血管舒张/药物作用血管舒张/生理学成年人女(雌)性人类妊娠

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Membrane-permeant, bioactivatable analogues of cgmp as inducers of cell death in IPC-81 leukemia cells

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第6期10卷 571-573页

作者： Schwede, F Brustugun, OT Zorn-Kruppa, M Dioskeland, SO Jastorff, B Univ Bremen Zentrum Umweltforsch & Technol Abt Bioorgan Chem D-28359 Bremen Germany Univ Bergen Dept Anat & Cell Biol Cell Biol Res Grp N-5009 Bergen Norway

We report an improved single-step synthesis to generate the membrane-permeant acetoxymethyl esters (AM-esters) of cgmp and three cgmp-analogues. These bioactivatable compounds were found to induce cell death in rat IPC-81 cells, a model system for acute myelocytic leukemia, in micromolar doses, while the corresponding non-modified cgmp-analogues were inactive. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：抗肿瘤药/化学合成抗肿瘤药/代谢抗肿瘤药/药理学生物转化细胞死亡/药物作用细胞系细胞膜通透性/药物作用环gmp/类似物和衍生物环gmp/化学合成环gmp/药理学白血病实验性/药物疗法白血病髓样急性/药物疗法构效关系肿瘤细胞培养的动物人类大鼠

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Differential role of cyclic gmp-dependent protein kinase II in ion transport in murine small intestine and colon

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GASTROENTEROLOGY 2000年第1期118卷 108-114页

作者： Vaandrager, AB Bot, AGM Ruth, P Pfeifer, A Hofmann, F de Jonge, HR Erasmus Univ Dept Biochem Fac Med Cardiovasc Res Inst COEUR NL-3000 DR Rotterdam Netherlands Tech Univ Munich Inst Pharmakol & Toxikol D-8000 Munich Germany

Background & Aims: The aim of this study was to determine the role of guanosine 3',5'-cyclic monophosphate (cgmp)-dependent protein kinase (cGK) type Ii in intestinal fluid homeostasis under basal conditions and following exposure to cgmp-linked secretagogues, e.g,, Escherichia coli heat-stable enterotoxin (STa) and guanylin. Methods: Fluid and ion transport was determined in different segments of the intestine of wildtype and cGK Il-deficient mice by ligated loop assays in vivo, and by short-circuit current and isotope flux measurements in vitro, Results: Small intestinal fluid absorption in vivo was enhanced in cGK Il-deficient mice under basal conditions and in the presence of STa. Furthermore, STa, guanylin, and 8-pCPT-cgmp stimulation of electrogenic anion secretion and inhibition of Na+ absorption in vitro were markedly reduced in the small intestine from cGK II -/- mice but not in proximal colon, The type III phosphodiesterase inhibitor amrinone mimicked STa action in cGK II -/- mice, and also stimulated ion secretion in humans, Conclusions: This study shows that the cgmp/cGK II pathway regulates fluid homeostasis in the small intestine under basal conditions and mediates STa effects by both increasing anion secretion and inhibiting Na+ absorption. It also demonstrates the presence of a cGK II-independent pathway for STa/cgmp-provoked secretion predominantly in the colon, which possibly involves a cgmp-inhibitable phosphodiesterase and/or activation of the cAMP-dependent protein kinase pathway.

关键词：细菌毒素类/药理学结肠/药物作用结肠/代谢环gmp/类似物和衍生物环gmp/药理学环gmp依赖性蛋白激酶类/代谢肠毒素类/药理学酶激动剂类/药理学大肠杆菌蛋白质类胃肠激素类小肠/药物作用小肠/代谢离子转运/药物作用促尿钠排泄肽类膜片钳术肽类/药理学硫代核苷酸类/药理学动物小鼠

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Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第5期35卷 1338-1346页

作者： Tatsumi, T Matoba, S Kawahara, A Keira, N Shiraishi, J Akashi, K Kobara, M Tanaka, T Katamura, M Nakagawa, C Ohta, B Shirayama, T Takeda, K Asayama, J Fliss, H Nakagawa, M Kyoto Prefectural Univ Med Dept Med 2 Kamigyo Ku Kyoto 6028566 Japan Kyoto Pharmaceut Univ Dept Clin Pharmacol Kyoto 607 Japan Univ Ottawa Dept Cellular & Mol Med Ottawa ON Canada

OBJECTIVES The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1 beta-stimulated cardiac myocytes. BACKGROUND Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility. METHODS Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured using Griess reagent. RESULTS Treatment with IL-1 beta (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with N-G-monomethyl-L-arginine(L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cgmp), a cgmp donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQ reductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1 beta or SNP-treated myocytes. Both IL-1 beta and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (Ic,), and lowered contractility in the myocytes. KT5823, an inhibitor of cgmp-dependent protein kinase, did not block the electrophysiological and contractility effects, CONCLUSIONS These data suggest that IL-1 beta-induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct atta

关键词：腺苷三磷酸/分析腺苷三磷酸/代谢动物新生细胞培养的/生理学环gmp/类似物和衍生物环gmp/药理学疾病模型动物剂量效应关系药物能量代谢/生理学葡萄糖/分析葡萄糖/代谢糖酵解炎症白细胞介素1/生理学乳酸/分析乳酸/代谢线粒体心脏/代谢心肌收缩/生理学心肌/细胞学心肌/代谢一氧化氮/生理学一氧化氮合酶/拮抗剂和抑制剂一氧化氮合酶/生理学硝普钠/药理学 ωN-甲基精氨酸/药理学动物大鼠

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Mutating three residues in the bovine rod cyclic nucleotide-activated channel can switch a nucleotide from inactive to active

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BIOPHYSICAL JOURNAL 2000年第5期78卷 2321-2333页

作者： Scott, SP Cummings, J Joe, JC Tanaka, JC Temple Univ Sch Sci & Technol Dept Biol Philadelphia PA 19122 USA Thomas Jefferson Univ Dept Microbiol & Immunol Philadelphia PA 19107 USA

Cyclic nucleotide-gated (CNG) channels, which were initially studied in retina and olfactory neurons, are activated by cytoplasmic cgmp or cAMP. Detailed comparisons of nucleotide-activated currents using nucleotide analogs and mutagenesis revealed channel-specific residues in the nucleotide-binding domain that regulate the binding and channel-activation properties. Of particular interest are N-1-oxide cAMP, which does not activate bovine rod channels, and Rp-cgmpS, which activates bovine rod, but not catfish, olfactory channels. Previously, we showed that four residues coordinate the purine interactions in the binding domain and that three of these residues vary in the alpha subunits of the bovine rod, catfish, and rat olfactory channels. Here we show that both N1-oxide cAMP and Rp-cgmpS activate rat olfactory channels. A mutant of the bovine rod alpha subunit, substituted with residues from the rat olfactory channel at the three variable positions, was weakly activated by N-1-oxide cAMP, and a catfish olfactory-like bovine rod mutant lost activation by Rp-cgmpS. These experiments underscore the functional importance of purine contacts with three residues in the cyclic nucleotide-binding domain. Molecular models of nucleotide analogs in the binding domains, constructed with AMMP, showed differences in the purine contacts among the channels that might account for activation differences.

关键词：结合部位/遗传学生物物理学鲇鱼类环gmp/类似物和衍生物环gmp/代谢离子通道/化学离子通道/遗传学离子通道/代谢配体模型分子诱变定点核苷酸类环/代谢嗅觉受体神经元/代谢蛋白质结构二级蛋白质结构三级重组蛋白质类/化学重组蛋白质类/遗传学重组蛋白质类/代谢视杆(视网膜)/代谢动物牛人类大鼠

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Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第10期97卷 5480-5485页

作者： De Nadai, C Sestili, P Cantoni, O Lièvremont, JP Sciorati, C Barsacchi, R Moncada, S Meldolesi, J Clementi, E H San Raffaele Sci Inst DIBIT Dept Neurosci I-20132 Milan Italy CNR Ctr Cellular & Mol Pharmacol I-20132 Milan Italy Univ Urbino Inst Pharmacol I-61029 Urbino Italy UCL Wolfson Inst Biomed Res London WC1E 6BT England Univ Calabria Dept Pharmacobiol I-87036 Arcavacata Di Rende Italy

Apoptosis triggered by death receptors proceeds after defined signal-transduction pathways. Whether signaling at the receptor level is regulated by intracellular messengers is still unknown. We have investigated the role of two messengers, ceramide and nitric oxide (NO), on the apoptotic pathway activated in human monocytic U937 cells by tumor necrosis factor-alpha (TNF-alpha) working at its p55 receptor. Two transduction events, the receptor recruitment of the adapter protein, TRADD, and the activation of the initiator caspase, caspase 8, were investigated. When administered alone, neither of the messengers had any effect on these events, in combination with TNF-alpha, however, ceramide potentiated, whereas NO inhibited, TNF-alpha-induced TRADD recruitment and caspase 8 activity. The effect of NO, which was cgmp-dependent, was due to inhibition of the TNF-alpha-induced generation of ceramide. Our results identify a mechanism of regulation of a signal-transduction pathway activated by death receptors.

关键词：抗原 CD/生理学细胞凋亡/药物作用细胞凋亡/生理学半胱氨酸天冬氨酸蛋白酶8 半胱氨酸天冬氨酸蛋白酶9 半胱氨酸天冬氨酸蛋白酶/代谢神经酰胺类/代谢环gmp/类似物和衍生物环gmp/药理学环gmp/生理学酶抑制剂/药理学动力学一氧化氮/生理学一氧化氮供体/药理学恶二唑类/药理学青霉胺/类似物和衍生物青霉胺/药理学蛋白质类/代谢喹恶啉类/药理学受体肿瘤坏死因子/生理学受体肿瘤坏死因子 Ⅰ型 S-亚硝基-N-乙酰基青霉胺第二信使系统信号传导鞘氨醇/类似物和衍生物鞘氨醇/药理学 TNF受体相关因子1 肿瘤坏死因子α/拮抗剂和抑制剂肿瘤坏死因子α/药代动力学肿瘤坏死因子α/药理学 U937细胞人类

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Ethanol stimulates ciliary beating by dual cyclic nucleotide kinase activation in bovine bronchial epithelial cells

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AMERICAN JOURNAL OF PATHOLOGY 2003年第3期163卷 1157-1166页

作者： Wyatt, TA Forgèt, MA Sisson, JH Univ Nebraska Med Ctr Dept Internal Med Pulm & Crit Care Med SectNebraska Med Ctr 985300 Omaha NE 68198 USA Res Serv Med Ctr Dept Vet Affairs Omaha NE USA

Previously, we have shown that ethanol (ROH) stimulates a rapid increase in the ciliary beat frequency (CBF) of bovine bronchial epithelial cells (BBECs) via the activation of PKA. We have also shown that inhibitors of nitric oxide synthase block EtOH-stimulated increases in CBF. We hypothesize that EtOH acutely stimulates CBF via the activation of both PKA and PKG pathways. Using chemiluminescence detection of nitric oxide (NO), we directly measured increases in NO production in BBECs treated with 100 mmol/L of EtOH beginning at 25 minutes. Pretreatment of BBECs with guanylyl cyclase inhibitors, ODQ or LY83583, resulted in the inhibition of EtOH-stimulated CBF. Low concentrations (1 nmol/L) of cyclic nucleotide analogues do not stimulate CBF increases. However, a combination of both I nmol/L of 8Br-cAMP and 8Br-cgmp stimulates a significant increase over baseline CBF. This effect could be blocked by pretreating BBECs with inhibitors of either PKA or PKG. Very high concentrations of either 8Br-cAMP or 8Br-cgmp (greater than or equal to100 mumol/L) were required to cross-activate both PKA and PKG. This suggests that cross-activation of PKA by cgmp is not occurring at the concentrations (1 nmol/L) capable of stimulating CBF. 8-pCPT-cgmpS, an antagonist analogue to cgmp, blocked EtOH-stimulated PKA activity increases. These data support that EtOH-stimulated increases in CBF require the dual activation of both PKA (via cAMP) and PKG (via NO).

关键词：支气管/药物作用支气管/生理学细胞培养的纤毛/药物作用纤毛/生理学环AMP/代谢环AMP依赖性蛋白激酶类/代谢环gmp/类似物和衍生物环gmp/代谢环gmp/药理学环gmp依赖性蛋白激酶类/代谢酶激活酶抑制剂/药理学上皮细胞/药物作用上皮细胞/代谢上皮细胞/生理学乙醇/药理学鸟苷酸环化酶/拮抗剂和抑制剂一氧化氮/代谢恶二唑类/药理学喹恶啉类/药理学硫代核苷酸类/药理学动物牛

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Nitric oxide inhibits L-type Ca²⁺ current in glomus cells of the rabbit carotid body via a cgmp-independent mechanism

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JOURNAL OF NEUROPHYSIOLOGY 1999年第4期81卷 1449-1457页

作者： Summers, BA Overholt, JL Prabhakar, NR Case Western Reserve Univ Sch Med Dept Phys & Biophys Cleveland OH 44106 USA

Previous studies have shown that nitric oxide (NO) inhibits carotid body sensory activity. To begin to understand the cellular mechanisms associated with the actions of NO in the carotid body, we monitored the effects of NO donors on the macroscopic Ca(2+) current in glomus cells isolated from rabbit carotid bodies. Experiments were performed on freshly dissociated glomus cells from adult rabbit carotid bodies using the whole cell configuration of the patch-clamp technique. The NO donors sodium nitroprusside (SNP;600 mu M, n = 7) and spermine nitric oxide (SNO;100 mu M, n = 7) inhibited the Ca(2+) current in glomus cells in a voltage independent manner. These effects of NO donors were rapid in onset and peaked within 1 or 2 min. In contrast, the outward K(+) current was unaffected by SNP (600 mu M, n = 6), indicating that the inhibition by SNP was not a nonspecific membrane effect. 2-(4-carboxyphenyl)-4, 4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO;500 mu M). an NO scavenger, prevented inhibition of the Ca(2+) current by SNP (n = 7), whereas neither superoxide dismutase (SOD;2,000 U/ml, n = 4), a superoxide scavenger, nor sodium hydrosulfite (SHS;1 mM, n = 7), a reducing agent, prevented inhibition of the Ca(2+) current by SNP. However, SNP inhibition of the Ca(2+) current was reversible in the presence of either SOD or SHS. These results suggest that NO itself inhibits Ca(2+) current in a reversible manner and that subsequent formation of peroxynitrites results in irreversible inhibition. SNP inhibition of the Ca(2+) current was not affected by 30 mu M LY 83,583 (n = 7) nor was it mimicked by 600 mu M 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cgmp;n = 6), suggesting that the effects of NO on the Ca(2+) current are mediated, in part, via a cgmp-independent mechanism. N-ethylmaleimide (NEM;2.5 mM, n = 6) prevented the inhibition of the Ca(2+) current by SNP, indicating that SNP is acting via a modification of sulfhydryl groups on Ca(2+) channel

关键词：氨基喹啉类/药理学钙/代谢钙通道/生理学钙通道 L型颈动脉体/化学颈动脉体/细胞学颈动脉体/药物作用细胞培养的氰化物/药理学环gmp/类似物和衍生物环gmp/代谢环gmp/药理学连二亚硫酸盐/药理学电生理学酶抑制剂/药理学乙基马来酰亚胺/药理学离子通道闸门/药物作用离子通道闸门/生理学膜电位/药物作用膜电位/生理学一氧化氮/药理学亚硝酸盐类/代谢硝普钠/药理学钾/代谢钾通道/生理学超氧化物歧化酶/药理学血管舒张药/药理学动物兔

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