scholarly journals Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway

Reproduction ◽  
2011 ◽  
Vol 141 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Erica Miraglia ◽  
Federico De Angelis ◽  
Elena Gazzano ◽  
Hossain Hassanpour ◽  
Angela Bertagna ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinases ◽  
Sperm Motility ◽  
Soluble Guanylate Cyclase ◽  
Human Sperm ◽  
Computer Assisted ◽  
No Donor ◽  
Sperm Analysis ◽  
Cgmp Analog ◽  
Dependent Protein

Nitric oxide (NO), a modulator of several physiological processes, is involved in different human sperm functions. We have investigated whether NO may stimulate the motility of human spermatozoa via activation of the soluble guanylate cyclase (sGC)/cGMP pathway. Sperm samples obtained by masturbation from 70 normozoospermic patients were processed by the swim-up technique. The kinetic parameters of the motile sperm-rich fractions were assessed by computer-assisted sperm analysis. After a 30–90 min incubation, the NO donor S-nitrosoglutathione (GSNO) exerted a significant enhancing effect on progressive motility (77, 78, and 78% vs 66, 65, and 62% of the control at the corresponding time), straight linear velocity (44, 49, and 48 μm/s vs 34, 35, and 35.5 μm/s), curvilinear velocity (81, 83, and 84 μm/s vs 68 μm/s), and average path velocity (52, 57, and 54 μm/s vs 40, 42, and 42 μm/s) at 5 μM but not at lower concentrations, and in parallel increased the synthesis of cGMP. A similar effect was obtained with the NO donor spermine NONOate after 30 and 60 min. The GSNO-induced effects on sperm motility were abolished by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (a specific sGC inhibitor) and mimicked by 8-bromo-cGMP (8-Br-cGMP; a cell-permeating cGMP analog); the treatment with Rp-8-Br-cGMPS (an inhibitor of cGMP-dependent protein kinases) prevented both the GSNO- and the 8-Br-cGMP-induced responses. On the contrary, we did not observe any effect of the cGMP/PRKG1 (PKG) pathway modulators on the onset of hyperactivated sperm motility. Our results suggest that NO stimulates human sperm motility via the activation of sGC, the subsequent synthesis of cGMP, and the activation of cGMP-dependent protein kinases.

Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

2004 ◽  
Vol 286 (5) ◽  
pp. L984-L991 ◽  
Author(s):  
Lisa K. Kelly ◽  
Stephen Wedgwood ◽  
Robin H. Steinhorn ◽  
Stephen M. Black
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Primary Cultures ◽  
No Donor ◽  
Endothelin 1 ◽  
Cgmp Analog ◽  
Pulmonary Arterial ◽  
Long Acting ◽  
Arterial Endothelial Cells

The use of exogenous nitric oxide (NO) has been shown to alter the regulation of other endothelially derived mediators of vascular tone, such as endothelin-1 (ET-1). However, the interaction between NO and ET-1 appears to be complex and remains incompletely understood. One of the major actions of NO is the activation of soluble guanylate cyclase (sGC) with the subsequent generation of cGMP. Therefore, we undertook this study to test the hypothesis that NO regulates ET-1 production via the activation of the sGC/cGMP pathway. The results obtained indicated that the exposure of primary cultures of 4-wk-old ovine pulmonary arterial endothelial cells (4-wk PAECs) to the long-acting NO donor DETA NONOate induced both a dose- and time-dependent decrease in secreted ET-1. This decrease in ET-1 secretion occurred in the absence of changes in endothelin-converting enzyme-1 or sGC expression but in conjunction with a decrease in prepro-ET-1 mRNA. The changes in ET-1 release were inversely proportional to the cellular cGMP content. Furthermore, the NO-independent activator of sGC, YC-1, or treatment with a cGMP analog also produced significant decreases in ET-1 secretion. Conversely, pretreatment with the sGC inhibitor ODQ blocked the NO-induced decrease in ET-1. Therefore, we conclude that exposure of 4-wk PAECs to exogenous NO decreases secreted ET-1 resulting from the activation of sGC and increased cGMP generation.

scholarly journals A non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

2018 ◽  
Author(s):  
Vu Thao-Vi Dao ◽  
Mahmoud H. Elbatreek ◽  
Martin Deile ◽  
Pavel I. Nedvetsky ◽  
Andreas Güldner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cyclic Gmp ◽  
Soluble Guanylate Cyclase ◽  
Feedback Inhibition ◽  
No Donor ◽  
Cgmp Signaling ◽  
Dependent Protein ◽  
Direct Feedback

AbstractNitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted for example in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase or exogenous NO from NO donor compounds decreased sGC protein and activity. This was not mediated by cGMP as the NO-independent sGC stimulator or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent, N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC whilst leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP-independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.

Nitric oxide inhibits human and canine pulmonary vascular tone via a postjunctional, nonelectromechanical, cGMP-dependent pathway

1999 ◽  
Vol 77 (5) ◽  
pp. 320-329 ◽  
Author(s):  
Luke J Janssen ◽  
Kai Mardi ◽  
Stuart Netherton ◽  
Pierre-A. Betti
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Electrical Field Stimulation ◽  
Adrenergic Nerve ◽  
Synthesis Inhibitor ◽  
No Donor ◽  
Phasic Activity ◽  
Dependent Protein ◽  
Adrenergic Nerve Endings ◽  
Dependent Pathway

We examined nitric oxide mediated regulation of pulmonary arterial and venous smooth muscle (PASM and PVSM, respectively): whether this inhibition is mediated via prejunctional receptors on adrenergic nerve endings; whether NO is neuronally derived; the relationship between degree of inhibition and vessel size; and identification of the signalling mechanisms involved. Canine pulmonary vascular tissues were generally quiescent, while human PASM exhibited spontaneous phasic activity. The nitric oxide (NO) synthesis inhibitor Nω-nitro-L-arginine (L-NNA; 10-4M) increased tone and enhanced phasic activity. Electrical field stimulation (EFS) evoked contractions were markedly enhanced by L-NNA in an endothelium-dependent fashion, and antagonized by the NO donor S-nitroso-N-acetyl-penicillamine (SNAP; 10-7to 10-5M). 8-Bromo-cGMP mimicked the effects of SNAP on basal tone and EFS contractions, while an inhibitor of soluble guanylate cyclase mimicked those of L-NNA. While mechanical responses to exogenously added norepinephrine (10-9-10-4M) were also enhanced by L-NNA and suppressed by SNAP, EFS-evoked excitatory junction potentials were unaffected by SNAP. We conclude that, in human and canine PASM and PVSM, there is a tonic generation of NO originating within the endothelium that does not mediate a prejunctional effect, but which acts postjunctionally to activate a cGMP-dependent pathway within the smooth muscle.Key words: adrenergic neurotransmission, norepinephrine, regiospecificity, cGMP-dependent protein kinase.

Constitutive and permissive roles of nitric oxide activity in embryonic ciliary cells

2003 ◽  
Vol 285 (2) ◽  
pp. R348-R355 ◽  
Author(s):  
Shandra A. Doran ◽  
Cam Ha Tran ◽  
Cagla Eskicioglu ◽  
Tev Stachniak ◽  
Kee-Chan Ahn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
No Production ◽  
Moderate Increase ◽  
No Donor ◽  
Cgmp Analog ◽  
Ly 83583 ◽  
Oxide Synthase

Embryos of Helisoma trivolvis exhibit cilia-driven rotation within the egg capsule during development. In this study we examined whether nitric oxide (NO) is a physiological regulator of ciliary beating in cultured ciliary cells. The NO donor S-nitroso- N-acetylpenicillamine (SNAP; 1–1,000 μM) produced a dose-dependent increase in ciliary beat frequency (CBF). In contrast, the nitric oxide synthase (NOS) inhibitor 7-nitroindazole (10 and 100 μM) inhibited the basal CBF and blocked the stimulatory effects of serotonin (100 μM). NO production in response to serotonin was investigated with 4,5-diaminofluorescein diacetate imaging. Although SNAP (100 μM) produced a rise in NO levels in all cells, only 22% of cells responded to serotonin with a moderate increase. The cGMP analog 8-bromo-cGMP (8-Br-cGMP; 0.2 and 2 mM) increased CBF, and the soluble guanylate cyclase inhibitor LY-83583 (10 μM) blocked the cilioexcitatory effects of SNAP and serotonin. These data suggest that NO has a constitutive cilioexcitatory effect in Helisoma embryos and that the stimulatory effects of serotonin and NO work through a cGMP pathway. It appears that in Helisoma cilia, NO activity is necessary, but not sufficient, to fully mediate the cilioexcitatory action of serotonin.

Localization of the cGMP-dependent protein kinases in relation to nitric oxide synthase in the brain

1999 ◽  
Vol 17 (1) ◽  
pp. 45-55 ◽  
Author(s):  
A.E.-D El-Husseini ◽  
J Williams ◽  
P.B Reiner ◽  
S Pelech ◽  
S.R Vincent
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Protein Kinases ◽  
Dependent Protein ◽  
Oxide Synthase ◽  
The Brain

Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway

2007 ◽  
Vol 292 (2) ◽  
pp. H893-H903 ◽  
Author(s):  
Galina N. Antonova ◽  
Connie M. Snead ◽  
Alexander S. Antonov ◽  
Christiana Dimitropoulou ◽  
Richard C. Venema ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Injury ◽  
Soluble Guanylate Cyclase ◽  
Heat Shock Protein 90 ◽  
Protective Effects ◽  
No Donor ◽  
Spermine Nonoate

Large (pathological) amounts of nitric oxide (NO) induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells with low concentrations of NO (preconditioning) would prevent injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAECs) by exposing them to either 4 mM sodium nitroprusside (SNP) or 0.5 mM N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) for 8 h, was abolished by 24-h pretreatment with either 100 μM SNP, 10 μM spermine NONOate, or 100 μM 8-bromo-cGMP (8-Br-cGMP). Repair of BAECs following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-h exposure to 4 mM SNP, and this delay was significantly attenuated by 24-h pretreatment with 100 μM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and heat shock protein 90 (HSP90). The protective effect of NO preconditioning, but not the injurious effect of 4 mM SNP, was abolished by either a sGC activity inhibitor 1H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one (ODQ) or a HSP90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the HSP90/sGC pathway. HSP90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.

A Substance Isolated from Cornus officinalis Enhances the Motility of Human Sperm

1997 ◽  
Vol 25 (03n04) ◽  
pp. 301-306 ◽  
Author(s):  
Hellen Jeng ◽  
Chao Mei Wu ◽  
Shuen-Jiing Su ◽  
Wen-Chang Chang
Keyword(s):  
Sperm Motility ◽  
Crude Extract ◽  
High Performance ◽  
Chinese Herb ◽  
Human Sperm ◽  
Final Concentration ◽  
Dried Fruits ◽  
Sperm Analysis ◽  
Cornus Officinalis ◽  
Phosphate Buffered Saline

The effects of a Chinese herb, Cornus officinalis, on the motility of human sperm was studied. An aqueous extract was prepared from the dried fruits of the herb and used in this study. The crude extract at a final concentration of 0.5 μg/μl in phosphate buffered saline (pH 7.4) increased sperm motility from 25.8 ± 7.7% to 42.8 ± 10.3% (i.e. 68% increase, n = 7), as determined by the computer-aided-sperm-analysis (CASA) method. The crude extract was fractionated by high-performance liquid chromatography (HPLC) into four fractions: Cl , C2, C3 and C4. Their effects on sperm motility were further studied by CASA. Only the C4 fraction showed substantial stimulatory effects on sperm motility. At a concentration of 5 ng/μl, C4 increased the sperm motility from 15.7 ± 3.8% to 34.5 ± 6.4% (i.e. 120% increase, n = 6) by CASA and from 14.9 ± 4.3 to 28.5 ± 8.1 (i.e. 91% increase, n = 8) by transmembrane migration ratio (TMMR) method. This result suggests that C4 is the active component in Cornus officinalis that enhances sperm motility.

Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle

2007 ◽  
Vol 293 (4) ◽  
pp. E1062-E1068 ◽  
Author(s):  
Vitor A. Lira ◽  
Quinlyn A. Soltow ◽  
Jodi H. D. Long ◽  
Jenna L. Betters ◽  
Jeff E. Sellman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Glucose Transporter ◽  
No Donor ◽  
Ampk Signaling ◽  
L6 Myotubes ◽  
Glut4 Expression ◽  
Compound C ◽  
Cgmp Analog

Nitric oxide (NO) and 5′-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4) and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO donor S-nitroso- N-penicillamine (SNAP, 1 and 10 μM) significantly increased GLUT4 mRNA (∼3-fold; P < 0.05) in L6 myotubes, and cotreatment with the AMPK inhibitor compound C ablated this effect. The cGMP analog 8-bromo-cGMP (8-Br-cGMP, 2 mM) increased GLUT4 mRNA by ∼50% ( P < 0.05). GLUT4 protein expression was elevated 40% by 2 days treatment with 8-Br-cGMP, whereas 6 days treatment with 10 μM SNAP increased GLUT4 expression by 65%. Cotreatment of cultures with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one prevented the SNAP-induced increase in GLUT4 protein. SNAP (10 μM) also induced significant phosphorylation of α-AMPK and acetyl-CoA carboxylase and translocation of phosphorylated α-AMPK to the nucleus. Furthermore, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 16 h presented an approximately ninefold increase in GLUT4 mRNA, whereas cotreatment with the non-isoform-specific NOS inhibitor NG-nitro-l-arginine methyl ester, prevented ∼70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12 h after AICAR injection, and this induction was reduced by ∼50% in animals cotreated with the neuronal and inducible nitric oxide synthases selective inhibitor 1-(2-trifluoromethyl-phenyl)-imidazole. We conclude that, in skeletal muscle, NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.

scholarly journals Endogenous flow-induced nitric oxide reduces superoxide-stimulated Na/H exchange activity via PKG in thick ascending limbs

2015 ◽  
Vol 308 (5) ◽  
pp. F444-F449 ◽  
Author(s):  
Nancy J. Hong ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Inhibitory Effect ◽  
Dependent Protein Kinase ◽  
Two Factors ◽  
Endogenous Nitric Oxide ◽  
Dependent Protein ◽  
Acid Load ◽  
Luminal Flow ◽  
Ly 83583

Luminal flow stimulates endogenous nitric oxide (NO) and superoxide (O2−) production by renal thick ascending limbs (TALs). The delicate balance between these two factors regulates Na transport in TALs; NO enhances natriuresis, whereas O2− augments Na absorption. Endogenous, flow-stimulated O2− enhances Na/H exchange (NHE). Flow-stimulated NO reduces flow-induced O2−, a process mediated by cGMP-dependent protein kinase (PKG). However, whether flow-stimulated, endogenously-produced NO diminishes O2−-stimulated NHE activity and the signaling pathway involved are unknown. We hypothesized that flow-induced NO reduces the stimulation of NHE activity caused by flow-induced O2− via PKG in TALs. Intracellular pH recovery after an acid load was measured as an indicator of NHE activity in isolated, perfused rat TALs. l-Arginine, the NO synthase substrate, decreased NHE activity by 34 ± 5% ( n = 5; P < 0.04). The O2− scavenger tempol decreased NHE activity by 46 ± 8% ( n = 6; P < 0.004) in the absence of NO. In the presence of l-arginine, the inhibitory effect of tempol on NHE activity was reduced to −19 ± 6% ( n = 6; P < 0.03). The soluble guanylate cyclase inhibitor LY-83583 blocked the effect of l-arginine thus restoring tempol's effect on NHE activity to −42 ± 4% ( n = 6; P < 0.0005). The PKG inhibitor KT-5823 also inhibited l-arginine's effect on tempol-reduced NHE activity (−43 ± 5%; n = 5; P < 0.03). We conclude that flow-induced NO reduces the stimulatory effect of endogenous, flow-induced O2− on NHE activity in TALs via an increase in cGMP and PKG activation.

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