scholarly journals A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation

2004 ◽  
Vol 286 (3) ◽  
pp. H1043-H1056 ◽  
Author(s):  
Nikolaos M. Tsoukias ◽  
Mahendra Kavdia ◽  
Aleksander S. Popel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Cgmp Formation

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency-rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of Ca2+ oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for Ca2+ oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo.

Development of a Red-Light-Controllable Nitric Oxide Releaser to Control Smooth Muscle Relaxation in Vivo

2020 ◽  
Vol 15 (11) ◽  
pp. 2958-2965
Author(s):  
Naoya Ieda ◽  
Yuji Hotta ◽  
Ayaka Yamauchi ◽  
Atsushi Nishikawa ◽  
Takahiro Sasamori ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Red Light ◽  
Smooth Muscle Relaxation

scholarly journals Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation

Reproduction ◽  
2021 ◽  
Vol 161 (1) ◽  
pp. 31-41
Author(s):  
Deepak S Hiremath ◽  
Fernanda B M Priviero ◽  
R Clinton Webb ◽  
CheMyong Ko ◽  
Prema Narayan
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Erectile Dysfunction ◽  
Sodium Nitroprusside ◽  
Signaling Pathway ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Activating Mutations

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction

2001 ◽  
Vol 280 (1) ◽  
pp. G32-G42 ◽  
Author(s):  
Ya-Ping Fan ◽  
Sushanta Chakder ◽  
Feng Gao ◽  
Satish Rattan
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Muscarinic Agonist ◽  
Basal Tone ◽  
Before And After ◽  
Oxide Synthase ◽  
Nanc Relaxation

We examined the effect of endotoxin lipopolysaccharide (LPS) on the basal tone and on the effects of different stimuli and agonists and transcriptional and translational expression of nitric oxide (NO) synthase (NOS) isozymes in the lower esophageal sphincter (LES), pyloric sphincter (PS), and internal anal sphincter (IAS). NO release was also examined before and after LPS. LPS caused a dose-dependent fall in the basal tone and augmentation of the relaxation caused by nonadrenergic, noncholinergic (NANC) nerve stimulation in the LES and IAS. In the PS, LPS had no significant effect on the basal tone and caused an attenuation of the NANC relaxation and an augmentation of the contractile response of muscarinic agonist. Interestingly, the smooth muscle relaxation by atrial natriuretic factor was suppressed in the LES and IAS but not in the PS. These changes in the sphincteric function following LPS may be associated with increase in the inducible NOS (iNOS) expression since they were blocked by iNOS inhibitorl-canavanine. Augmentation of NANC relaxation in the LES and IAS smooth muscle by LPS may be due to the increased activity of neuronal NOS and NO production.

Nitric oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs

1993 ◽  
Vol 264 (2) ◽  
pp. H419-H422 ◽  
Author(s):  
F. Trigo-Rocha ◽  
W. J. Aronson ◽  
M. Hohenfellner ◽  
L. J. Ignarro ◽  
J. Rajfer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Specific Inhibitor ◽  
Phosphodiesterase Inhibitor ◽  
Smooth Muscle Relaxation ◽  
Pelvic Nerve ◽  
Intracavernous Injection ◽  
Penile Tumescence

We sought to determine whether the L-arginine-nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) pathway, known to mediate neurostimulation-induced smooth muscle relaxation in penile tissue of rabbits and humans in vitro, is operative also in vivo. Adult male dogs (n = 9) were subjected to direct electrical stimulation of the pelvic nerves to induce penile tumescence. Intracavernous injection of the nitric oxide-releasing substance S-nitroso-N-acetylpenicillamine resulted in similar tumescence. Intracavernous injection of a specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginine, blocked pelvic nerve-stimulated tumescence, and this was partially reversed by intracavernous injection of the nitric oxide precursor L-arginine. Furthermore, neurostimulated tumescence was inhibited by methylene blue, an inhibitor of cytosolic guanylate cyclase and enhanced by M&B 22948, a cGMP phosphodiesterase inhibitor. These in vivo findings support the hypothesis that cavernous smooth muscle relaxation and penile tumescence are mediated by nitric oxide and cGMP.

Endothelial calcium-activated potassium channels as therapeutic targets to enhance availability of nitric oxide

2012 ◽  
Vol 90 (6) ◽  
pp. 739-752 ◽  
Author(s):  
Paul M. Kerr ◽  
Raymond Tam ◽  
Deepak Narang ◽  
Kyle Potts ◽  
Dane McMillan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Inflammatory Responses ◽  
Muscle Relaxation ◽  
Critical Role ◽  
Current Data ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Arterial Diameter ◽  
Local Cell

The vascular endothelium plays a critical role in vascular health by controlling arterial diameter, regulating local cell growth, and protecting blood vessels from the deleterious consequences of platelet aggregation and activation of inflammatory responses. Circulating chemical mediators and physical forces act directly on the endothelium to release diffusible relaxing factors, such as nitric oxide (NO), and to elicit hyperpolarization of the endothelial cell membrane potential, which can spread to the surrounding smooth muscle cells via gap junctions. Endothelial hyperpolarization, mediated by activation of calcium-activated potassium (KCa) channels, has generally been regarded as a distinct pathway for smooth muscle relaxation. However, recent evidence supports a role for endothelial KCa channels in production of endothelium-derived NO, and indicates that pharmacological activation of these channels can enhance NO-mediated responses. In this review we summarize the current data on the functional role of endothelial KCa channels in regulating NO-mediated changes in arterial diameter and NO production, and explore the tempting possibility that these channels may represent a novel avenue for therapeutic intervention in conditions associated with reduced NO availability such as hypertension, hypercholesterolemia, smoking, and diabetes mellitus.

scholarly journals Nitric Oxide: From Gastric Motility to Gastric Dysmotility

2021 ◽  
Vol 22 (18) ◽  
pp. 9990
Author(s):  
Eglantina Idrizaj ◽  
Chiara Traini ◽  
Maria Giuliana Vannucchi ◽  
Maria Caterina Baccari
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Gastric Motility ◽  
Muscle Relaxation ◽  
Physiological Role ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Main Role ◽  
Motor Responses

It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.

Ca2+-independent PLA2 controls endothelial store-operated Ca2+ entry and vascular tone in intact aorta

2008 ◽  
Vol 295 (6) ◽  
pp. H2466-H2474 ◽  
Author(s):  
François-Xavier Boittin ◽  
Françoise Gribi ◽  
Karima Serir ◽  
Jean-Louis Bény
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Physiological Mechanism ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Arterial Tone ◽  
Endothelium Dependent Relaxation ◽  
Stimulation Of

During an agonist stimulation of endothelial cells, the sustained Ca2+ entry occurring through store-operated channels has been shown to significantly contribute to smooth muscle relaxation through the release of relaxing factors such as nitric oxide (NO). However, the mechanisms linking Ca2+ stores depletion to the opening of such channels are still elusive. We have used Ca2+ and tension measurements in intact aortic strips to investigate the role of the Ca2+-independent isoform of phospholipase A2 (iPLA2) in endothelial store-operated Ca2+ entry and endothelium-dependent relaxation of smooth muscle. We provide evidence that iPLA2 is involved in the activation of endothelial store-operated Ca2+ entry when Ca2+ stores are artificially depleted. We also show that the sustained store-operated Ca2+ entry occurring during physiological stimulation of endothelial cells with the circulating hormone ATP is due to iPLA2 activation and significantly contributes to the amplitude and duration of ATP-induced endothelium-dependent relaxation. Consistently, both iPLA2 metabolites arachidonic acid and lysophosphatidylcholine were found to stimulate Ca2+ entry in native endothelial cells. However, only the latter triggered endothelium-dependent relaxation through NO release, suggesting that lysophosphatidylcholine produced by iPLA2 upon Ca2+ stores depletion may act as an intracellular messenger that stimulates store-operated Ca2+ entry and subsequent NO production in endothelial cells. Finally, we found that ACh-induced endothelium relaxation also depends on iPLA2 activation, suggesting that the iPLA2-dependent control of endothelial store-operated Ca2+ entry is a key physiological mechanism regulating arterial tone.

scholarly journals Acetate intolerance is mediated by enhanced synthesis of nitric oxide by endothelial cells.

1997 ◽  
Vol 8 (9) ◽  
pp. 1431-1436 ◽  
Author(s):  
A Amore ◽  
P Cirina ◽  
S Mitola ◽  
L Peruzzi ◽  
R Bonaudo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Powerful Stimulus ◽  
Necrosis Factor

The clinical picture of acetate intolerance strictly mimics the nitric oxide (NO) effect, including smooth muscle relaxation and extreme vasodilation. Because acetate induces production of cAMP, which is a powerful stimulus of NO synthase (NOS), we evaluated the effect of different dialysate solutions with and without acetate on NOS activity in endothelial cells (EC). NOS activity of EC, evaluated as H3-citrulline produced from H3-arginine, was modulated by the dialysate composition (e.g., 38 mmol/L acetate produced an increase of 3.2 +/- 0.39-fold compared with basal values (P < 0.0005), and the small amount of acetate (4 mmol/L) in 35 mmol/L bicarbonate solution increased the NOS activity by 2 +/- 0.49-fold (P < 0.05). Conversely, the acetate-free solution produced no effect on NOS activity. The mRNA encoding for inducible NOS was highly expressed in EC incubated with acetate buffer and also with acetate in bicarbonate dialysis buffer. The EC proliferative index was depressed by acetate (P < 0.0005), and tumor necrosis factor synthesis was increased (P < 0.0005) compared with acetate-free buffer. This study suggests that dialytic "acetate intolerance" can be induced by the activation, through cAMP and tumor necrosis factor release, of NOS. The small amount of acetate in bicarbonate dialysate, although capable of inducing in vitro NOS activation, is likely to be rapidly metabolized, whereas the large amounts of this anion in acetate fluids overwhelm metabolism by the liver. Acetate-free dialysate is the only solution that provides an acceptable level of biocompatibility both in vivo and in vitro.

Computational Modeling of Nitric Oxide Bioavailability in Hemolytic Anemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1209-1209
Author(s):  
Anne Jeffers ◽  
Mark Gladwin ◽  
Daniel Kim-Shapiro
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Blood Cell ◽  
Computational Modeling ◽  
Red Blood Cell ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Rbc Membrane ◽  
No Bioavailability

Abstract Intravascular hemoglobin (Hb) scavenges nitric oxide (NO), which decreases the availability of endothelial-derived NO, thereby reducing smooth muscle relaxation. Under normal conditions, there are various mechanisms that limit consumption of NO by Hb in vivo includinga physical barrier to NO diffusion across the red blood cell (RBC) membrane,an unstirred layer creating a concentration gradient in NO outside the RBC, andand a cell-free zone between the endothelium where NO is made and the location of the RBCs. However, in hemolytic conditions, these mechanisms can be compromised, leading to reduced levels of NO reaching the smooth muscle cells to cause vasodilation. Although it is generally accepted that cell-free Hb scavenges NO more effectively than Hb encapsulated in the red blood cell (RBC), some do not believe that the low concentrations of cell-free Hb that are present in hemolytic conditions, such as sickle cell disease, can impact NO bioavailability in the presence of the large amounts of RBC encapsulated Hb (about 10 mM in heme) present in vivo. We have performed computational modeling looking at the effects of cell-free Hb on NO bioavailability within blood vessels. We have found that concentrations of cell-free Hb as low as one micromolar significantly reduces the availability of NO. Thus, 0.01% hemolysis has a significant affect on steady state NO levels. Extravasation of cell-free Hb into the interstitial space of as low as one micromolar further reduces the bioavailability of NO. At low hematocrit values, cell-free Hb scavenging of NO was found to be more efficient than at high hematocrit values. We have also found that the effect of RBC membrane permeability diminishes at cell-free Hb concentrations of only four micromolar and above. These theoretical results support experimental evidence indicating that cell-free Hb contributes to the pathology of hemolytic diseases. Supported by NIH grant RG0489.

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