Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of the M-cholinoceptor agonist carbachol on cyclic GMP (cGMP) content and contractile response in the absence and presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine in guinea-pig isolated ventricular cardiomyocytes. Carbachol (10 mumol/l, 10 min) increased basal cGMP content to approximately 200% and contractile response to 118%. Preincubation of the cardiomyocytes with NG-nitro-L-arginine (0.1 mumol/l, 60 min) did not alter the effects of carbachol on neither cGMP content or contractile response. Moreover, nitric oxide synthase activity was undetectable in crude or ADP-agarose purified cytosolic and particulate fractions of homogenized isolated ventricular cardiomyocytes. Pretreatment with pertussis toxin did not affect the carbachol-mediated increase in cGMP content or contractile response. However, methylene blue abolished the elevation in cGMP content by carbachol, without changing contractile response. It is concluded that the carbachol-mediated increase in cGMP content and contractile response in ventricular cardiomyocytes is neither mediated via a nitric oxidebiosynthesis pathway nor via a pertussis toxin-sensitive GTP-binding protein. Furthermore, the cGMP increase by carbachol is due to an activation of soluble guanylyl cyclase and is dissociated from the contractile response. We therefore assume that carbachol activates two independent effector cascades, one leading to an elevation in cGMP content and the other to an increase in contractile response and that none of the effects are mediated via endogenous nitric oxide formation.
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PMID:Ca(++)-dependent constitutive nitric oxide synthase is not involved in the cyclic GMP-increasing effects of carbachol in ventricular cardiomyocytes. 768 6

We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.
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PMID:Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway. 919 82

Two cDNAs encoding novel isoforms of Xenopus laevis melatonin receptors were cloned using PCR primers specific for the X. laevis-melanophore Mel1c melatonin receptor described in a recent publication. The novel isoforms were highly homologous to the described frog Mel1c cDNA, although the C-terminal tail of both was shorter by 65 amino acid residues. Nucleotide sequences of these novel isoforms, called Mel1c(alpha) and Mel1c(beta), differed from each other by only 35 nucleotides and six amino acid residues. Studies on several animals of various Xenopus species indicate that Mel1c(alpha) and Mel1c(beta) receptors may correspond to allelic variants of the same locus. Studies on cells transfected with both receptor cDNAs showed the expression of high-affinity 2-[125I]iodomelatonin binding sites. Agonist stimulation of Mel1c(alpha) receptor was associated with the inhibition of cAMP accumulation stimulated by forskolin (IC50 approximately 10(-10) M) in HeLa, Ltk-, and human embryonic kidney 293 (HEK 293) cells. Mel1c(beta) receptor modulated cAMP in HeLa and HEK 293 cells but not in Ltk- cells. Both receptors inhibited, in a dose-dependent manner, cGMP accumulation in all three cell lines incubated with a phosphodiesterase inhibitor. This effect was localized upstream of soluble guanylyl cyclase and was blocked by pertussis toxin treatment. However, IC50 values (approximately 10(-10) M for Mel1c(beta) and 10(-9) to 10(-7) M for Mel1c(alpha)) and maximal inhibition levels showed that Mel1c(alpha) receptors are much less efficiently coupled to the cGMP pathway. Coupling differences may be explained by the fact that five of the six amino acid substitutions between Mel1c(alpha) and Mel1c(beta) receptors are located within cytoplasmic regions potentially involved in signal transduction. The existence of coupling differences is in agreement with the observation that expression of both receptors is evolutionally conserved in native tissue. In conclusion, two novel, potentially allelic, isoforms of Xenopus Mel1c melatonin receptors display identical ligand-binding characteristics, but different potencies in modulating cAMP and cGMP levels through G(i)/G(o)-dependent pathways. Furthermore, to our knowledge, this study provides the first data on the modulation of intracellular cGMP levels by cloned melatonin receptors.
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PMID:Novel isoforms of Mel1c melatonin receptors modulating intracellular cyclic guanosine 3',5'-monophosphate levels. 921 55

We have previously reported that the serine protease plasmin triggers chemotaxis in human peripheral monocytes, but not in polymorphonuclear leukocyte. We now show that the structurally related lipoprotein(a) (Lp[a]) as well as recombinant apolipoprotein(a) (apo[a]) trigger chemotactic responses in human monocytes equipotent to that observed with the standard chemoattractant FMLP. The chemotactic effects of Lp(a) and FMLP were additive. Low density lipoprotein (LDL) did not elicit any significant chemotactic response nor did it interfere with that triggered by Lp(a). As assessed by checkerboard analysis, Lp(a)-mediated monocyte locomotion was a true chemotaxis. Both plasminogen as well as catalytically inactivated plasmin inhibited monocyte migration elicited by Lp(a), suggesting binding of Lp(a) to plasminogen binding sites. Lp(a)-mediated signaling proceeds through a pertussis toxin-sensitive guanosine triphosphate (GTP)-binding protein and activation of protein kinase C as implicated by the effects of 1-O-hexadecyl-2-O-methyl-rac-glycerol and chelerythrine. Lp(a) induced generation of guanosine 3',5'-cyclic monophosphate (cGMP), apparently crucial for the Lp(a)-mediated chemotaxis, because an inhibitor of soluble guanylyl cyclase, LY83583, reduced both the Lp(a)-induced cGMP formation as well as the monocyte migration. The latter effect of LY83583 was antagonized by the stable cGMP analog 8-pCPT-cGMP. The data indicate that Lp(a) triggers chemotaxis in human monocytes by way of a cGMP-dependent mechanism. Our findings may have important implications for the atherogenesis associated with elevated levels of Lp(a).
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PMID:Lipoprotein(a) is a potent chemoattractant for human peripheral monocytes. 929 39

The thick ascending limb of Henle's loop (TAL) is involved in the urinary dilution/concentration process by actively reabsorbing NaCl through a complex mechanism. Some years ago, compelling evidence was provided that cAMP stimulates NaCl reabsorption through the activation of adenylyl cyclase by several hormones other than antidiuretic hormone (ADH). Synthesis of cyclic AMP is inhibited by prostaglandin E2 (PGE2) and arachidonic acid per se, via the pertussis toxin-sensitive protein Gi activation. Cyclic GMP cascade down-regulates NaCl reabsorption, through activation of both guanylyl cyclase receptors (by ANF and urodilatin), and soluble guanylyl cyclase (by nitric oxide, NO). In TAL, NO is produced by the cytokine-inducible form of NO synthase, but not by the constitutive one. Agonists known to activate protein kinase C (PKC) in TAL elicit opposite effects on NaCl reabsorption. Five PKC isoforms belonging to the conventional, novel, and atypical enzyme subclasses have been recently defined in TAL and might differently regulate NaCl flux. Increments in intracellular calcium ([Ca2+]i) inhibit NaCl reabsorption via three pathways: (i) a possible direct effect on ion channels, (ii) a PLA2-mediated production of arachidonic acid derivatives (20-HETE), and (iii) inhibition of the ADH-induced cAMP accumulation. This last effect results from activation of phosphodiesterase (common to the agents that increase [Ca2+]i), and inhibition of adenylyl cyclase (only elicited by Ca2+c). Finally, the apical localization of some agonists effects is documented.
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PMID:Transducing pathways involved in the control of NaCl reabsorption in the thick ascending limb of Henle's loop. 955 29

Adenosine is known to play an important role in the regulation of coronary blood flow during metabolic stress. However, there is sparse information on the mechanism of adenosine-induced dilation at the microcirculatory levels. In the present study, we examined the role of endothelial nitric oxide (NO), G proteins, cyclic nucleotides, and potassium channels in coronary arteriolar dilation to adenosine. Pig subepicardial coronary arterioles (50 to 100 microm in diameter) were isolated, cannulated, and pressurized to 60 cm H(2)O without flow for in vitro study. The arterioles developed basal tone and dilated dose dependently to adenosine. Disruption of endothelium, blocking of endothelial ATP-sensitive potassium (K(ATP)) channels by glibenclamide, and inhibition of NO synthase by N(G)-nitro-L-arginine methyl ester and of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one produced identical attenuation of vasodilation to adenosine. Combined administration of these inhibitors did not further attenuate the vasodilatory response. Production of NO from coronary arterioles was significantly increased by adenosine. Pertussis toxin, but not cholera toxin, significantly inhibited vasodilation to adenosine, and this inhibitory effect was only evident in vessels with an intact endothelium. Tetraethylammonium, glibenclamide, and a high concentration of extraluminal KCl abolished vasodilation of denuded vessels to adenosine; however, inhibition of calcium-activated potassium channels by iberiotoxin had no effect on this dilation. Rp-8-Br-cAMPS, a cAMP antagonist, inhibited vasodilation to cAMP analog 8-Br-cAMP but failed to block adenosine-induced dilation. Furthermore, vasodilations to 8-Br-cAMP and sodium nitroprusside were not inhibited by glibenclamide, indicating that cAMP- and cGMP-induced dilations are not mediated by the activation of K(ATP) channels. These results suggest that adenosine activates both endothelial and smooth muscle pathways to exert its vasodilatory function. On one hand, adenosine opens endothelial K(ATP) channels through activation of pertussis toxin-sensitive G proteins. This signaling leads to the production and release of NO, which subsequently activates smooth muscle soluble guanylyl cyclase for vasodilation. On the other hand, adenosine activates smooth muscle K(ATP) channels and leads to vasodilation through hyperpolarization. It appears that the latter vasodilatory process is independent of G proteins and of cAMP/cGMP pathways.
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PMID:cAMP-independent dilation of coronary arterioles to adenosine : role of nitric oxide, G proteins, and K(ATP) channels. 1050 88

Sphingosine 1-phosphate (S1P) can prevent endothelial cell apoptosis. We investigated the molecular mechanisms and signaling pathways by which S1P protects endothelial cells from serum deprivation-induced apoptosis. We show here that human umbilical vein endothelial cells (HUVECs) undergo apoptosis associated with increased DEVDase activity, caspase-3 activation, cytochrome c release, and DNA fragmentation after 24 h of serum deprivation. These apoptotic markers were suppressed by the addition of S1P, the NO donor S-nitroso-N-acetylpenicillamine (100 micrometer), or caspase-3 inhibitor z-VAD-fmk. The protective effects of S1P were reversed by the nitric-oxide synthase (NOS) inhibitor N-monomethyl-l-arginine, but not by the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo[4,3-a]-quanoxaline-1-one, suggesting that NO, but not cGMP, is responsible for S1P protection from apoptosis. Furthermore, S1P increased NO production by enhancing Ca(2+)-sensitive NOS activity without changes in the eNOS protein level. S1P-mediated cell survival and NO production were suppressed significantly by pretreatment with antisense oligonucleotide of EDG-1 and partially by EDG-3 antisense. S1P-mediated NO production was suppressed by the addition of pertussis toxin, an inhibitor of G(i) proteins, the specific inhibitor of phospholipase C (PLC), and the Ca(2+) chelator BAPTA-AM. These findings indicate that S1P protects HUVECs from apoptosis through the activation of eNOS activity mainly through an EDG-1 and -3/G(i)/PLC/Ca(2+) signaling pathway.
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PMID:Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. 1113 47

Previous studies have shown that muscarinic inhibition of cardiac contractility is mediated by either activation of nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP) pathway or stimulation of inhibitory G protein (G(i)). However, it still remains controversial as to whether NO/cGMP pathway or G(i) protein or both mediate(s) the negative inotropic effect of muscarinic agonists in adult ventricular myocytes. In the present study that involves the use of adult rat ventricular myocytes, the muscarinic agonist, carbachol, inhibited beta-adrenergic (isoproterenol) stimulation of contractility (cell shortening) by 82% and increased cGMP levels by 49% within 6 min. Pretreatment of myocytes with soluble guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) or NO synthase inhibitor (N(G)-monomethyl-L-arginine, L-NMMA) for 30 min blocked carbachol-induced increases in cGMP levels. However, neither ODQ nor L-NMMA pretreatment had any effect on carbachol inhibition of isoproterenol-induced contractility. In addition, carbachol did not attenuate increases in myocyte contractility induced by forskolin (a direct activator of adenylyl cyclase) or 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (a cell-permeable cAMP analog which activates cAMP-dependent protein kinase). Pretreatment of myocytes with G(i) protein inhibitor, pertussis toxin (PTX, 1 microg/ml), for 18-20 h abolished carbachol inhibition of isoproterenol-induced contractility. Furthermore, in ventricular myocytes isolated 3 days after in vivo treatment of rats with PTX (3 microg/100 g, i.p.), there was a complete loss of the negative inotropic effect of carbachol. These data indicate that pertussis toxin-sensitive G protein but not NO/cGMP pathway is required for muscarinic inhibition of beta-adrenoceptor-mediated increases in contractility in adult rat ventricular myocytes.
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PMID:Pertussis toxin-sensitive G protein but not NO/cGMP pathway mediates the negative inotropic effect of carbachol in adult rat cardiomyocytes. 1464 56

Mammals express nine membranous adenylyl cyclase isoforms (ACs 1-9), a structurally related soluble guanylyl cyclase (sGC) and a soluble AC (sAC). Moreover, Bacillus anthracis and Bacillus pertussis produce the AC toxins, edema factor (EF), and adenylyl cyclase toxin (ACT), respectively. 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-[gamma-thio]triphosphate is a potent competitive inhibitor of AC in S49 lymphoma cell membranes. These data prompted us to study systematically the effects of 24 nucleotides on AC in S49 and Sf9 insect cell membranes, ACs 1, 2, 5, and 6, expressed in Sf9 membranes and purified catalytic subunits of membranous ACs (C1 of AC5 and C2 of AC2), sAC, sGC, EF, and ACT in the presence of MnCl(2). N-Methylanthraniloyl (MANT)-GTP inhibited C1.C2 with a K(i) of 4.2 nm. Phe-889 and Ile-940 of C2 mediate hydrophobic interactions with the MANT group. MANT-inosine 5'-[gamma-thio]triphosphate potently inhibited C1.C2 and ACs 1, 5, and 6 but exhibited only low affinity for sGC, EF, ACT, and G-proteins. Inosine 5'-[gamma-thio]triphosphate and uridine 5'-[gamma-thio]triphosphate were mixed G-protein activators and AC inhibitors. AC5 was up to 15-fold more sensitive to inhibitors than AC2. EF and ACT exhibited unique inhibitor profiles. At sAC, 2',5'-dideoxyadenosine 3'-triphosphate was the most potent compound (IC(50), 690 nm). Several MANT-adenine and MANT-guanine nucleotides inhibited sGC with K(i) values in the 200-400 nm range. UTP and ATP exhibited similar affinities for sGC as GTP and were mixed sGC substrates and inhibitors. The exchange of MnCl(2) against MgCl(2) reduced inhibitor potencies at ACs and sGC 1.5-250-fold, depending on the nucleotide and cyclase studied. The omission of the NTP-regenerating system from cyclase reactions strongly reduced the potencies of MANT-ADP, indicative for phosphorylation to MANT-ATP by pyruvate kinase. Collectively, AC isoforms and sGC are differentially inhibited by purine and pyrimidine nucleotides.
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PMID:Differential inhibition of adenylyl cyclase isoforms and soluble guanylyl cyclase by purine and pyrimidine nucleotides. 1498 Oct 84

In gastrointestinal smooth muscle, cGMP levels in response to relaxant agonists are regulated by activation of phosphodiesterase 5 and inhibition of soluble guanylyl cyclase (sGC) in a feedback mechanism via cGMP-dependent protein kinase. The aim of the present study was to determine whether contractile agonists modulate cGMP levels by cross-regulating sGC activity. In gastric muscle cells, acetylcholine (ACh) stimulated Src activity and induced sGC phosphorylation. Concurrent stimulation of cells with ACh attenuated sGC activity and cGMP formation in response to the nitric oxide (NO) donor, S-nitrosoglutathione (GSNO). The effect of ACh on Src activity, sGC phosphorylation, and on GSNO-stimulated sGC activity and cGMP formation were blocked by the m2 receptor antagonist (methoctramine), pertussis toxin, and by inhibitors of phosphatidylinositol 3 kinase, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or Src kinase, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, in dispersed muscle cells and in cells expressing Galpha(i) minigene or Gbetagamma-scavenging peptide, whereas the m3 receptor antagonist, N-(2-chloroethyl)-4-piperidinyl diphenylacetate, or expression of the Galpha(q) minigene had no effect. ACh also attenuated sGC activity and cGMP formation in response to the NO-independent activator, YC-1 [3-(5'-hydroxymethyl-2'furyl)-1-benzylindazole]. The pattern implied that phosphorylation of sGC by c-Src kinase inhibits NO-sensitive sGC activity, and the inhibition was not due to a decrease in the binding of NO but probably due to decrease in catalytic activity. We conclude that cGMP levels are cross-regulated by contractile agonists via a mechanism that involves c-Src-dependent phosphorylation of sGC, leading to inhibition of sGC activity and cGMP formation. The finding highlights a novel mechanism for attenuation of the NO/sGC/cGMP signal by G(i)-coupled contractile agonists, in addition to their inhibitory effect on adenylyl cyclase and cAMP formation.
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PMID:Inhibitory phosphorylation of soluble guanylyl cyclase by muscarinic m2 receptors via Gbetagamma-dependent activation of c-Src kinase. 1818 Mar 73


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