Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of methylene blue, an inhibitor of soluble guanylate cyclase, on responses to ventilatory and precapillary hypoxia was investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. Because methylene blue increased vascular tone, responses to hypoxia were compared when lobar arterial pressure was raised to similar levels with U 46619 and with methylene blue. When lobar arterial pressure was raised with U 46619, ventilation with 7.5% O2 increased lobar arterial pressure significantly. Infusion of methylene blue in concentrations that raised lobar arterial pressure to a value similar to that attained with U 46619 prevented the pressor response to hypoxia, and a significant depressor response was unmasked. The depressor response to hypoxia in the methylene blue-treated animal was not altered by meclofenamate but was blocked by propranolol. A reduction in lobar arterial perfusate PO2 induces an increase in pulmonary vascular resistance in the cat, and this response was prevented by methylene blue. During methylene blue infusion, the vasodilator response to acetylcholine was reduced, whereas the response to isoproterenol was not altered. Although the response to hypoxia was prevented, the pressor response to prostaglandin F2 alpha was not changed. The response to ventilatory hypoxia was enhanced by propranolol or ICI 118551, suggesting that the response is modulated by circulating catecholamines that are probably of adrenal origin. The effects of methylene blue on vascular tone and responses to hypoxia and acetylcholine were reversible, and responses returned to control value after the infusion was terminated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methylene blue prevents hypoxic pulmonary vasoconstriction in cats. 167 38

The vascular relaxant effect of salbutamol and its dependence on the endothelium were studied in the isolated dog coronary artery, precontracted with prostaglandin F2 alpha. Salbutamol induced a concentration-dependent relaxation which was partially inhibited by removal of endothelial cells. Atenolol 10(-6) mol/l, a beta 1-selective antagonist, inhibited the relaxant effect of salbutamol both in the presence and in the absence of endothelium. Conversely, ICI 118,551 10(-6) mol/l, a beta 2-selective antagonist, antagonized the response to salbutamol only in intact vessels. Methylene blue amplified markedly the relaxation to salbutamol but only in denuded rings. Therefore, the vasodilating effect of salbutamol on large coronary arteries seems to result from the stimulation of both, beta 1-receptors on smooth muscle cells and beta 2-receptors on endothelial cells, demonstrating the existence of the two types of adrenoceptors in the wall of large dog coronary arteries. In addition, the effect obtained with methylene blue in this study shed some doubts on its specificity as a guanylate cyclase inhibitor.
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PMID:Study of the vasodilating activity of salbutamol on dog coronary arteries. Unexpected effects of methylene blue. 167 90

The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of inflammatory hyperalgesia induced by carrageenin. The rat paw pressure test was applied before and 3 h after the intraplantar (i.pl.) injection of carrageenin. The venom administered per os before and 1 or 2 h after carrageenin blocked hyperalgesia. When carrageenin was injected in both hind paws and naloxone into one hind paw, antinociception was abolished only in the paw injected with naloxone. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) and nor-binaltorphimine, antagonists of micro- and kappa-opioid receptors, respectively, did not alter the effect of the venom. N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI 174,864), an antagonist of delta-opioid receptors, antagonised this effect. Prolonged administration of the venom did not induce tolerance to this antinociceptive effect. N(G)-methyl-L-arginine (L-NMMA) and methylene blue, inhibitors of nitric oxide synthase and soluble guanylate cyclase, respectively, injected i.pl., antagonised antinociception. These data indicate that both delta-opioid receptors and nitric oxide participate in the mediation of the peripheral antinociceptive effect of C. durissus terrificus venom.
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PMID:delta-opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom. 1072 Jun 35

Estrogen induces both rapid and delayed effects on the cardiovascular system. The early effects take place within minutes (e.g., changes in vasomotor tone) and are mediated through rapid intracellular signaling pathways; whereas the delayed effects (e.g., remodeling or lipid alterations) require hours to days to occur and require transcriptional effects with subsequent modulation of protein expression. To study the acute effects of 17beta-estradiol (E2) treatment on vascular function, we have investigated the rapid (on the order of minutes) effects of E2 treatment on intracellular signaling in human endothelial cells (EC). Our previous data have shown that E2 induces rapid release of NO from and activation of guanylate cyclase in human EC. In this study, we demonstrate that E2 also activates mitogen-activated protein kinase (extracellular signal-related kinase) signaling within minutes in EC. We hypothesized that this effect might be mediated by estrogen receptors (ER) localized to the cell surface. Our data show that membrane-impermeant forms of E2 also activate EC mitogen-activated protein kinase as well as stimulate cGMP production and NO release. The ER antagonist ICI 182,780 blocks this effect. Using confocal microscopy and flow cytometric analysis, we demonstrate that EC contain surface binding sites for E2, detectable by cell-impermeant ligand binding and equally with an anti-ERalpha antibody. Immunoreactive bands of 66 and 45 kDa are detectable with an anti-ERalpha mAb in human EC, and their individual presence correlates functionally with E2-stimulated genomic and rapid nongenomic responses, respectively. Membrane ERs may provide key molecular switches in these novel, rapid signaling pathways induced by E2 in EC.
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PMID:Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. 1082 45

In atrial myocytes, an initial exposure to isoproterenol (ISO) acts via cAMP to mediate a subsequent acetylcholine (ACh)-induced activation of ATP-sensitive K(+) current (I(K,ATP)). In addition, beta-adrenergic receptor (beta-AR) stimulation activates nitric oxide (NO) release. The present study determined whether the conditioning effect of beta-AR stimulation acts via beta(1)- and/or beta(2)-ARs and whether it is mediated via NO signaling. 0.1 microM ISO plus ICI 118,551 (ISO-beta(1)-AR stimulation) or ISO plus atenolol (ISO-beta(2)-AR stimulation) both increased L-type Ca(2+) current (I(Ca,L)) markedly, but only ISO-beta(2)-AR stimulation mediated ACh-induced activation of I(K,ATP). 1 microM zinterol (beta(2)-AR agonist) also increased I(Ca,L) and mediated ACh-activated I(K,ATP). Inhibition of NO synthase (10 microM L-NIO), guanylate cyclase (10 microM ODQ), or cAMP-PKA (50 microM Rp-cAMPs) attenuated zinterol-induced stimulation of I(Ca,L) and abolished ACh-activated I(K,ATP). Spermine-NO (100 microM; an NO donor) mimicked beta(2)-AR stimulation, and its effects were abolished by Rp-cAMPs. Intracellular dialysis of 20 microM protein kinase inhibitory peptide (PKI) abolished zinterol-induced stimulation of I(Ca,L). Measurements of intracellular NO ([NO](i)) using the fluorescent indicator DAF-2 showed that ISO-beta(2)-AR stimulation or zinterol increased [NO](i). L-NIO (10 microM) blocked ISO- and zinterol-induced increases in [NO](i). ISO-beta(1)-AR stimulation failed to increase [NO](i). Inhibition of G(i)-protein by pertussis toxin significantly inhibited zinterol-mediated increases in [NO](i). Wortmannin (0.2 microM) or LY294002 (10 microM), inhibitors of phosphatidylinositol 3'-kinase (PI-3K), abolished the effects of zinterol to both mediate ACh-activated I(K,ATP) and stimulate [NO](i). We conclude that both beta(1)- and beta(2)-ARs stimulate cAMP. beta(2)-ARs act via two signaling pathways to stimulate cAMP, one of which is mediated via G(i)-protein and PI-3K coupled to NO-cGMP signaling. Only beta(2)-ARs acting exclusively via NO signaling mediate ACh-induced activation of I(K,ATP). NO signaling also contributes to beta(2)-AR stimulation of I(Ca,L). The differential effects of beta(1)- and beta(2)-ARs can be explained by the coupling of these two beta-ARs to different effector signaling pathways.
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PMID:Beta 2-adrenergic receptor signaling acts via NO release to mediate ACh-induced activation of ATP-sensitive K+ current in cat atrial myocytes. 1177 39

The present study determined the effects of acetylcholine (ACh) on the L-type Ca(2+) current (I(Ca,L)) stimulated by beta(1)- or beta(2)-adrenergic receptor (AR) agonists in cat atrial myocytes. When isoproterenol (ISO; 0.1 microM) plus the beta(2)-AR antagonist ICI 118,551 (ISO-beta(1)-AR stimulation) or 0.1 microM fenoterol, a beta(2)-AR agonist (FEN-beta(2)-AR stimulation) increased I(Ca,L), ACh (1 microM) inhibited I(Ca,L) by -60 +/- 4 and -63 +/- 6 %, respectively. When ISO plus the beta(1)-AR antagonist atenolol (ISO-beta(2)-AR stimulation) or 1 microM zinterol (ZIN-beta(2)-AR stimulation) increased I(Ca,L), ACh-induced inhibition of I(Ca,L) was significantly smaller, at -21 +/- 3 and -24 +/- 3 %, respectively. L-N(5)-(1-iminoethyl)ornithine (L-NIO, 10 microM), an inhibitor of nitric oxide (NO) synthase, enhanced ACh-induced inhibition of I(Ca,L) when stimulated by ZIN-beta(2)-ARs, but not when stimulated by ISO-beta(1)-ARs or FEN-beta(2)-ARs. Haemoglobin (50 microM), a NO scavenger, also enhanced ACh-induced inhibition when I(Ca,L) was stimulated by ZIN-beta(2)-ARs, but not when stimulated by FEN-beta(2)-ARs. ACh-induced inhibition of I(Ca,L) stimulated by ZIN-beta(2)-ARs was not affected by 10 microM 1H-[1,2,4] oxadiazolo[4,3-a] quinoxaline-1-one (ODQ) a guanylate cyclase inhibitor, but was significantly enhanced by 500 microM reduced glutathione or 100 microM dithiothreitol, agents that act as sinks for S-nitrosylation. ACh-induced inhibition was smaller when I(Ca,L) was stimulated by spermine/NO, a NO donor, than by milrinone, a phosphodiesterase type III inhibitor. ISO (ISO-beta(1)/beta(2)-AR stimulation) increased I(Ca,L) and even though ISO releases NO, ACh prominently inhibited I(Ca,L). This inhibitory effect of ACh was enhanced by L-NIO. Stimulation of ZIN-beta(2)-ARs increased intracellular NO, whereas ISO-beta(1)-ARs or FEN-beta(2)-ARs failed to increase intracellular NO. These results indicate that in atrial myocytes, NO released by selective beta(2)-AR stimulation prevents ACh-induced inhibition of I(Ca,L) stimulated by beta(2)-ARs. NO acts via a cGMP-independent, S-nitrosylation mechanism. Although FEN acts via beta(2)-ARs, it fails to stimulate G(i)-/NO signalling and preferentially stimulates G(s)-/adenylate cyclase signalling, similar to beta(1)-ARs. These findings indicate that NO signalling modulates muscarinic receptor inhibition of atrial function stimulated by beta(2)-ARs.
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PMID:Nitric oxide signalling by selective beta(2)-adrenoceptor stimulation prevents ACh-induced inhibition of beta(2)-stimulated Ca(2+) current in cat atrial myocytes. 1215 73

Our experiments were designed to determine the acute effects of 17beta-estradiol on femoral veins from intact and ovariectomized female pigs. Rings of femoral veins with or without endothelium were suspended in organ chambers for measurement of isometric force. Concentration-response curves to 17beta-estradiol (10(-9) to 10(-5) M) were obtained in veins contracted with prostaglandin F(2alpha) in the absence and presence of inhibitors of either estrogen receptors (ICI-182780; 10(-5) M), nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 10(-4) M], soluble guanylate cyclase (1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10(-5) M), or potassium channels (tetraethylammonium; 10(-2) M). Estrogen receptors were identified with the use of Western blotting and immunostaining in veins of both groups. 17beta-Estradiol caused acute endothelium-dependent relaxations in both groups. Relaxations to 17beta-estradiol were inhibited by l-NMMA and 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but not ICI-182780. Tetraethylammonium inhibited relaxations only in veins with endothelium from intact females. Results indicate that 17beta-estradiol causes acute endothelium-dependent relaxations in femoral veins. The relative contribution of nitric oxide and K(+) channels as mechanisms involved in relaxations to 17beta-estradiol in femoral veins is modulated by ovarian status.
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PMID:Acute effects of 17beta -estradiol on femoral veins from adult gonadally intact and ovariectomized female pigs. 1238 82

Clinical studies suggest that estrogen may improve cognition in Alzheimer's patients. Basic experiments demonstrate that 17beta-estradiol protects against neurodegeneration in both cell and animal models. In the present study, a human SH-SY5Y cell model was used to investigate molecular mechanisms underlying the receptor-mediated neuroprotection of physiological concentrations of 17beta-estradiol. 17beta-estradiol (<10 nM) concomitantly increased neuronal nitric oxide synthase (NOS1) expression and cell viability. 17beta-estradiol-induced neuroprotection was blocked by the receptor antagonist ICI 182,780, also prevented by inhibitors of NOS1 (7-nitroindazole), guanylyl cyclase (LY 83,583), and cGMP-dependent protein kinase (PKG) (Rp-8-pCPT-cGMPs). In addition to the expression of NOS1 and MnSOD, 17beta-estradiol increased the expression of the redox protein thioredoxin (Trx), which was blocked by the inhibition of either cGMP formation or PKG activity. The expression of heme oxygenase 2 and brain-derived neurotrophic factor was not altered. Estrogen receptor-enhanced cell viability against oxidative stress may be linked to Trx expression because the Trx reductase inhibitor, 5,5'-dithio-bis(2-nitrobenzoic acid) significantly reduced the cytoprotective effect of 17beta-estradiol. Furthermore, Trx (1 microM) inhibited lipid peroxidation, proapoptotic caspase-3, and cell death during oxidative stress caused by serum deprivation. We conclude that cGMP-dependent expression of Trx--the redox protein with potent antioxidative and antiapoptotic properties--may play a pivotal role in estrogen-induced neuroprotection.
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PMID:17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMP-dependent thioredoxin expression for neuroprotection. 1262 28

1. In phenylephrine (PHE) (1 micro M)-precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H(2)O(2), 10-100 micro M) caused only contraction, while high concentration of H(2)O(2) (0.3-1 mM) caused a biphasic response: a transient contraction followed by a relaxation response. 2. Endothelium removal did not affect the biphasic response. 7,7-Dimethyl-(5Z,8Z)-eicosadienoic acid, diclofenac, furegrelate, or SQ 29548 greatly inhibited the contraction but did not affect the relaxation. 17-Octadecynoic acid, eicosatriynoic acid, ICI 198615, SQ 22536, or ODQ did not inhibit the biphasic response. 3. KCl at 40 mM inhibited the relaxation response to H(2)O(2) by 98+/-24%. 4-Aminopyridine (4-AP) inhibited while tetraethylammonium chloride (TEA), charybdotoxin, or glibenclamide attenuated the relaxation response. A combination of 4-AP, TEA and glibenclamide mimicked the effects of 40 mM KCl. Iberiotoxin, apamin, or barium chloride did not inhibit the relaxation response. 4. H(2)O(2) at 1 mM hyperpolarized membrane potential and reversibly augmented K(+) current in smooth muscle cells of mesenteric artery. These effects of H(2)O(2) were attenuated significantly by 4-AP. 5. In summary, in PHE-precontracted rat mesenteric artery: (1) the response to H(2)O(2) shifted qualitatively from contraction to a biphasic response as H(2)O(2) increased to 0.3 mM or higher; (2) the relaxation response is caused by the activation of K(+) channels, with voltage-dependent K(+) channels playing a primary role; and the contraction is likely to be mediated by thromboxane A(2); (3) the K(+) channel activation by H(2)O(2) is independent of phospholipase A(2), cyclooxygenase, lipoxygenase, cytochrome P450 monooxygenase, adenylate or guanylate cyclase.
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PMID:Mechanisms of hydrogen-peroxide-induced biphasic response in rat mesenteric artery. 1268 64

In this study we determine different signaling pathways involved in beta(3) adrenoceptor (beta(3)-AR) dependent frequency stimulation in isolated rodent atria. Promiscuous coupling between different G-proteins and beta(3)-AR could explain the multiple functional effects of beta(3)-AR stimulation. We examine the mechanisms and functional consequences of dual adenylate cyclase and guanylate cyclase pathways coupling to beta(3)-AR in isolated rodent atria. The beta(3)-AR selective agonists ZD 7114 and ICI 215001 stimulated in a dose-dependent manner the contraction frequency that significantly correlated with cyclic AMP (cAMP) accumulation. Inhibition of adenylate cyclase shifted the chronotropic effect to the right. On the other hand, the ZD 7114 activity on frequency was enhanced by the inhibition of nitric oxide synthase (NOS) and soluble guanylate cyclase. This countervailing negative chronotropic nitric oxide-cyclic GMP (NO-cGMP) significantly correlated with the increase on NOS activity and cGMP accumulation. Current analysis showed a negative cross talk between cAMP chronotropic and NO-cGMP effects by inhibition of phospholipase C (PLC), calcium/calmodulin (CaM), protein kinase C (PKC), NOS isoforms and Gi-protein on the effects of beta(3)-AR stimulation. RT-PCR detected both eNOS and nNOS in isolated rat atria. NOS isoforms performed independently. Only nNOS participated in limiting the effect of beta(3)-AR stimulation. In eNOS-KO (eNOS-/-) mice the chronotropic effect of beta(3)-AR agonists did not differ from wild type (WT) mice atria, but it was increased by the inhibition of nNOS activity. Our results suggest that the increase in frequency by beta(3)-AR activation on isolated rodent atria is associated to a parallel increases in cAMP. The nNOS-cGMP pathway negatively modulates beta(3)-AR activation. Multiple signal transduction pathways between G-protein and beta(3)-AR may protect myocardium from catecholamine-induced cardiotoxic effects.
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PMID:Role of nitric oxide/cyclic GMP and cyclic AMP in beta3 adrenoceptor-chronotropic response. 1651 Jan 53


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