Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Endothelium-dependent relaxation of mesenteric resistance arteries of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats was studied. Acetylcholine-induced relaxation of SHR vessels precontracted with 10 microM norepinephrine was endothelium dependent and attenuated compared with WKY vessels. The impaired response of SHR vessels was normalized by inhibition of cyclooxygenase with indomethacin. Blockade of nitric oxide synthetase with NG-nitro L-arginine methyl ester (L-NAME) or inhibition of guanylate cyclase with methylene blue attenuated acetylcholine-induced relaxation of norepinephrine-contracted SHR vessels but had no effect on WKY vessels. When vessels were precontracted with 30 nM arginine vasopressin, acetylcholine induced similar degrees of relaxation in both strains. A similar response was detected when lysine vasopressin was used to induce tone. Indomethacin had no effect on relaxation responses of SHR and WKY vessels precontracted with either form of vasopressin. L-NAME and methylene blue partially inhibited acetylcholine-induced relaxation of vasopressin-contracted vessels from both strains. Acetylcholine added at baseline did not induce contraction of vessels from either strain. It is concluded that endothelium-dependent relaxation of SHR resistance arteries is not impaired under all circumstances. Acetylcholine-induced relaxation may be suppressed in SHR resistance arteries when norepinephrine is used to induce contraction as a result of catecholamine-induced production of an endothelium-derived contracting factor. Vasopressin, on the other hand, does not elicit production of this contracting factor and may enhance the vasorelaxant action of acetylcholine in resistance arteries of both strains via actions on endothelial or vascular smooth muscle cells.
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PMID:Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. 841 84

Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone-stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone-stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone-stimulated water permeability was 317 +/- 47 microm/s (P < .001). Addition of spermine NONOate, a nitric oxide donor, to the bath decreased water permeability to 74 +/- 38 microm/s (P < .002). In the presence of LY 83583, an inhibitor of soluble guanylate cyclase, spermine NONOate did not change water permeability. Addition of spermine NONOate increased cGMP production (P < .01). In the presence of the cGMP-dependent protein kinase inhibitor, spermine NONOate did not change water permeability. Since antidiuretic hormone increases water permeability by increasing cAMP, we hypothesized that nitric oxide inhibits water permeability by decreasing cAMP. In tubules pretreated with antidiuretic hormone, intracellular cAMP was 18.9 +/- 3.9 fmol/mm. In tubules treated with antidiuretic hormone and spermine NONOate, cAMP was 9.3 +/- 1.7 fmol/mm (P < .03). We also examined the effect of spermine NONOate on dibutyryl-cAMP-stimulated water permeability. In the presence of dibutyryl-cAMP, water permeability was 388 +/- 30 microm/s. Addition of spermine NONOate had no significant effect on water permeability. Time controls and inhibitors by themselves did not change antidiuretic hormone-stimulated water permeability. We concluded that nitric oxide decreases antidiuretic hormone-stimulated water permeability by increasing cGMP via soluble guanylate cyclase, activating cGMP-dependent protein kinase and decreasing cAMP.
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PMID:Mechanism of the nitric oxide-induced blockade of collecting duct water permeability. 861 24

Activating direct olfactory (glutamatergic) inputs to supraoptic nucleus (SON) neurons increases interneuronal coupling in slices from lactating but from not virgin or male rats. Studied here were influences on coupling of another monosynaptic input to SON, the histaminergic tuberomammillary nucleus (TM) projection, activation of which selectively excites phasically firing (putative vasopressin) cells. Effects of TM stimulation and its possible downstream consequences on Lucifer yellow (LY) dye coupling among putative vasopressin cells were determined in male rat SONs. In unstimulated slices, 12 LY injections (1 cell/SON) yielded eight single and four pairs of coupled neurons. In slices in which TM was stimulated for 10 min at 10 Hz, 13 injections yielded 4 single and 28 coupled cells, with groups of 2 to 4 cells coupled to the injected neuron, a threefold increase in the number of coupled cells per injection (p < 0.02). Bathing slices in medium containing 10 microM pyrilamine (H1 antagonist) blocked this stimulation-induced coupling increase, suggesting mediation by activation of guanylate cyclase-cGMP to which H1 receptors often are linked . Bathing slices in medium containing 0.5-1 mM 8-bromo-cGMP yielded results similar to those of TM stimulation, a 2.5-fold increase over control in the number of coupled cells per injection. Effects of TM stimulation on coupling also were blocked by bathing slices in a guanylate cyclase inhibitor (10 microM LY83583). In contrast to cGMP, 1 mM 8-bromo-cAMP significantly reduced coupling. We conclude that synaptically released histamine increases coupling via cGMP-dependent mechanisms.
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PMID:Synaptically released histamine increases dye coupling among vasopressinergic neurons of the supraoptic nucleus: mediation by H1 receptors and cyclic nucleotides. 861 78

Atrial natriuretic peptide (ANP) and its receptors are present in hypothalamic nuclei containing the magnocellular neurosecretory cells (MNCs), which release vasopressin and oxytocin. In the rat, intracerebroventricular injections of ANP inhibit the release of both hormones in response to hypertonicity. Although these findings suggest a role for endogenous ANP in the central control of fluid balance, cellular mechanisms underlying the modulatory actions of ANP are unknown. We therefore examined the effects of ANP on the osmoresponsiveness of MNCs impaled in rat hypothalamic explants. Applications of ANP (75-150 nM) over the supraoptic nucleus did not affect depolarizing responses to local hypertonicity, but they reversibly abolished the synaptic excitation of MNCs after hypertonic stimulation of the organum vasculosum laminae terminalis (OVLT). These effects were associated with decreased spontaneous EPSP (sEPSP) amplitude rather than with changes in sEPSP frequency. Accordingly, application of ANP reduced the amplitude of glutamatergic EPSPs evoked by electrical stimulation of the OVLT (IC50 approximately 3 nM). The inhibitory effects of ANP on EPSP amplitude were mimicked by application of 3'-5'-dibutyryl cGMP, consistent with the guanylate cyclase activity of natriuretic peptide receptors. Although depolarizing responses of MNCs to ionotropic glutamate receptor agonists were unaffected by ANP, the peptide reversibly enhanced paired-pulse facilitation of electrically evoked EPSPs. These results indicate that centrally released ANP may inhibit osmotically evoked neurohypophysial hormone release through presynaptic inhibition of glutamate release from osmoreceptor afferents derived from the OVLT.
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PMID:Atrial natriuretic peptide modulates synaptic transmission from osmoreceptor afferents to the supraoptic nucleus. 892 8

1. The present study was performed to characterize the tachyphylaxis of rat aortae to vasopressin. Isometric tension generated by rat thoracic aorta sliced in 4 mm rings, was recorded. 2. Tension generated by intact rings increased with cumulative additions of vasopressin up to 10 nM (1.51 +/- 0.15 g). After this concentration, most rings lost their tension and relaxed to 1.09 +/- 0.17 g (P < 0.001) despite further addition of vasopressin. This tachyphylaxis was not observed in endothelium-denuded rings (from 2.87 +/- 0.12 g to 2.68 +/- 0.17 g). 3. Repeated administrations of supramaximal concentration (100 nM) of vasopressin confirmed an enhanced desensitization in intact rings, compared to endothelium-denuded rings. No desensitization to phenylephrine was observed in intact or in endothelium-denuded rings. 4. Dose-response curves to a V1 receptor agonist, [Phe2, Ile3, Orn8]-vasopressin, and to a V2 receptor agonist, [deamino-Cys1,D-Arg8]-vasopressin, were performed in intact preparations. An increase in tension, followed by a desensitization was observed with the V1 receptor agonist. In contrast, the V2 receptor agonist did not induce any response. 5. Pretreatment of intact aortic rings with the cyclo-oxygenase inhibitor, diclofenac (1 microM), did not prevent the desensitization to vasopressin. In contrast, NO synthase inhibition with NG-nitro-L-arginine (30 microM) resulted in an attenuated desensitization to vasopressin in intact rings (from 2.46 +/- 0.17 to 2.25 +/- 0.22 g, NS). 6. To confirm the involvement of NO, endothelium-denuded rings were pretreated with sodium nitroprusside (SNP). At a concentration of 10 nM, SNP induced a desensitization to vasopressin comparable with that observed in intact rings. 7. Pretreatment of endothelium-denuded rings with 8-bromo-cyclic GMP (100 microM) reduced maximum contraction to vasopressin without producing any desensitization. In contrast, guanylate cyclase inhibition with either LY 83,583 (10 microM) or methylene blue (10 microM) blocked completely the desensitization of intact rings to vasopressin. 8. The results suggest that the endothelium-dependent tachyphylaxis to vasopressin is due to rapid desensitization and is mediated by NO. However, it is unclear whether this effect of NO involves cyclic GMP.
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PMID:Endothelium-dependent and NO-mediated desensitization to vasopressin in rat aorta. 892 38

Recent work has demonstrated that the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO). There is growing evidence that these gaseous molecules function as novel neural messengers in the brain. This article reviews the pertinent literature concerning the putative role of NO and CO as critical neurotransmitters and biological mediators of the neuroendocrine axis. Abundant evidence is presented which suggests that NO has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus. NO potently stimulates GnRH secretion and also appears to mediate the action of one of the major transmitters controlling GnRH secretion, glutamate. Evidence is presented which suggests that NO stimulates GnRH release due to its ability to modulate the heme-containing enzyme, guanylate cyclase, which leads to enhanced production of the second messenger molecule, cGMP. A physiological role for NO in the preovulatory LH surge was also evidenced by findings that inhibitors and antisense oligonucleotides to nitric oxide synthase (NOS) attenuate the steroid-induced and preovulatory LH surge. CO may also play a role in stimulating GnRH secretion as heme molecules stimulate GnRH release in vitro, an effect which requires heme oxygenase activity and is blocked by the gaseous scavenger molecule, hemoglobin. Evidence is also reviewed which suggests that NO acts to restrain the hypothalamic-pituitary-adrenal (HPA) axis, as it inhibits HPA stimulation by various stimulants such as interleukin-1 beta, vasopressin, and inflammation. This effect fits a proinflammatory role of NO as it leads to suppression of the release of the anti-inflammatory corticosteroids from the adrenal. Although not as intensely studied as NO, CO has been shown to suppress stimulated CRH release and may also function to restrain the HPA axis. Evidence implicating NO in the control of prolactin and growth hormone secretion is also reviewed and discussed, as is the possible role of NO acting directly at the anterior pituitary. Taken as a whole, the current data suggest that the diffusible gases, NO and CO, act as novel transmitters in the neuroendocrine axis and mediate a variety of important neuroendocrine functions.
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PMID:Gaseous transmitters and neuroendocrine regulation. 920

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

The binding of atrial natriuretic peptide and C-type natriuretic peptide (CNP) to the guanylyl cyclase-linked natriuretic peptide receptors A and B (NPR-A and -B), respectively, stimulates increases in intracellular cGMP concentrations. The vasoactive peptides vasopressin, angiotensin II, and endothelin inhibit natriuretic peptide-dependent cGMP elevations by activating protein kinase C (PKC). Recently, we identified six in vivo phosphorylation sites for NPR-A and five sites for NPR-B and demonstrated that the phosphorylation of these sites is required for ligand-dependent receptor activation. Here, we show that phorbol 12-myristate 13-acetate, a direct activator of PKC, causes the dephosphorylation and desensitization of NPR-B. In contrast to the CNP-dependent desensitization process, which results in coordinate dephosphorylation of all five sites in the receptor, phorbol 12-myristate 13-acetate treatment causes the dephosphorylation of only one site, which we have identified as Ser(523). The conversion of this residue to alanine or glutamate did not reduce the amount of mature receptor protein as indicated by detergent-dependent guanylyl cyclase activities or Western blot analysis but completely blocked the ability of PKC to induce the dephosphorylation and desensitization of NPR-B. Thus, in contrast to previous reports suggesting that PKC directly phosphorylates and inhibits guanylyl cyclase-linked natriuretic peptide receptors, we show that PKC-dependent dephosphorylation of NPR-B at Ser(523) provides a possible molecular explanation for how pressor hormones inhibit CNP signaling.
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PMID:Activation of protein kinase C stimulates the dephosphorylation of natriuretic peptide receptor-B at a single serine residue: a possible mechanism of heterologous desensitization. 1091 2

The roles of cGMP, prostaglandins, the entry of extracellular Ca2+ through slow channels, endothelium and V1 receptors in the negative inotropic, chronotropic and coronary vasoconstrictor responses to arginine vasopressin (AVP) have been investigated in isolated perfused rat hearts. The bolus injection of 5 x 10(-5) M AVP produced a significant decrease in contractile force, heart rate and coronary flow. AVP also significantly decreased contractile force, heart rate and coronary flow in hearts pretreated with an inhibitor of soluble guanylate cyclase methylene blue (10(-6) M), an effective drug for removing endothelium saponin (500 micrograms/ml), an inhibitor of cyclooxygenase indomethacin (10(-5) M) or a calcium channel antagonist verapamil (5 x 10(-7) M). The potent V1 receptor antagonist [Deamino-Pen1, Val4, D-Arg8]-vasopressin (9 x 10(-5) M) did not alter effects of AVP but the very potent V1 receptor antagonist [beta-Mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin (8 x 10(-5) M) abolished these effects. Our results suggest that AVP produces negative inotropic, chronotropic and coronary vasoconstrictor effects in isolated perfused rat hearts. cGMP, prostaglandin release and Ca2+ entry does not involve in the effects of AVP. These effects are endothelium independent and mediated by V1 receptors. The use of V1 receptor antagonist [beta-mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin may be beneficial for preventing the negative inotropy, chronotropy and coronary vasoconstriction induced by AVP.
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PMID:The effects of vasopressin in isolated rat hearts. 1121 71

Natriuretic peptides bind their cognate cell surface guanylyl cyclase receptors and elevate intracellular cGMP concentrations. In vascular smooth muscle cells, this results in the activation of the type I cGMP-dependent protein kinase and vasorelaxation. In contrast, pressor hormones like arginine-vasopressin, angiotensin II, and endothelin bind serpentine receptors that interact with G(q) and activate phospholipase Cbeta. The products of this enzyme, diacylglycerol and inositol trisphosphate, activate the conventional and novel forms of protein kinase C (PKC) and elevate intracellular calcium concentrations, respectively. The latter response results in vasoconstriction, which opposes the actions of natriuretic peptides. Previous reports have shown that pressor hormones inhibit natriuretic peptide receptors NPR-A or NPR-B in a variety of different cell types. Although the mechanism for this inhibition remains unknown, it has been universally accepted that PKC is an obligatory component of this pathway primarily because pharmacologic activators of PKC mimic the inhibitory effects of these hormones. Here, we show that in A10 vascular smooth muscle cells, neither chronic PKC down-regulation nor specific PKC inhibitors block the AVP-dependent desensitization of NPR-B even though both processes block PKC-dependent desensitization. In contrast, the cell-permeable calcium chelator, BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester), abrogates the AVP-dependent desensitization of NPR-B, and ionomycin, a calcium ionophore, mimics the AVP effect. These data show that the inositol trisphosphate/calcium arm of the phospholipase C pathway mediates the desensitization of a natriuretic peptide receptor in A10 cells. In addition, we report that CNP attenuates AVP-dependent elevations in intracellular calcium concentrations. Together, these data reveal a dominant role for intracellular calcium in the reciprocal regulation of these two important vasoactive signaling systems.
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PMID:Vasopressin-dependent inhibition of the C-type natriuretic peptide receptor, NPR-B/GC-B, requires elevated intracellular calcium concentrations. 1219 32


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