scholarly journals Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dan Wu ◽  
Qingxun Hu ◽  
Fenfen Ma ◽  
Yi Zhun Zhu
Keyword(s):  
Nitric Oxide ◽  
Hydrogen Sulfide ◽  
Cardiovascular Diseases ◽  
Vascular Tone ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Protein Kinase G ◽  
Cgmp Level ◽  
Vasorelaxant Effect ◽  
Cgmp Pathway

Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H2S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H2S and NO conjugated donor developed by H2S-releasing moiety (S-propyl-L-cysteine (SPRC)) and NO-releasing moiety (furoxan). ZYZ-803 could time- and dose-dependently relax the sustained contraction induced by PE in rat aortic rings, with potencies of 1.5- to 100-fold greater than that of furoxan and SPRC. Inhibition of the generations of H2S and NO with respective inhibitors abolished the vasorelaxant effect of ZYZ-803. ZYZ-803 increased cGMP level and the activity of vasodilator stimulated phosphoprotein (VASP) in aortic rings, and those effects could be suppressed by the inhibitory generation of H2S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of KATPchannel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H2S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases.

scholarly journals Stimulation of Nitric Oxide–cGMP Pathway Excites Striatal Cholinergic Interneurons via Protein Kinase G Activation

2001 ◽  
Vol 21 (4) ◽  
pp. 1393-1400 ◽  
Author(s):  
Diego Centonze ◽  
Antonio Pisani ◽  
Paola Bonsi ◽  
Patrizia Giacomini ◽  
Giorgio Bernardi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Cholinergic Interneurons ◽  
Cgmp Pathway ◽  
Stimulation Of

scholarly journals A Critical Role of the Nitric Oxide/cGMP Pathway in Corticostriatal Long-Term Depression

1999 ◽  
Vol 19 (7) ◽  
pp. 2489-2499 ◽  
Author(s):  
Paolo Calabresi ◽  
Paolo Gubellini ◽  
Diego Centonze ◽  
Giuseppe Sancesario ◽  
Maria Morello ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Critical Role ◽  
Long Term Depression ◽  
Cgmp Pathway

scholarly journals Role of protein kinase G in nitric oxide- and cGMP-induced relaxation of newborn ovine pulmonary veins

1999 ◽  
Vol 87 (3) ◽  
pp. 993-998 ◽  
Author(s):  
Yuansheng Gao ◽  
Srinivas Dhanakoti ◽  
Jean-Francois Tolsa ◽  
J. Usha Raj
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Biochemical Study ◽  
Critical Role ◽  
Pulmonary Veins ◽  
Protein Kinase G ◽  
Fourth Generation ◽  
Cgmp Analog ◽  
A Cell

In a variety of systemic blood vessels, protein kinase G (PKG) plays a critical role in mediating relaxation induced by agents that elevate cGMP, such as nitric oxide. The role of PKG in nitric oxide- and cGMP-induced relaxation is less certain in the pulmonary circulation. In the present study, we examined the effects of inhibitors of PKG on the responses of isolated fourth-generation pulmonary veins of newborn lambs (10 ± 1 days of age) to nitric oxide and cGMP. In vessels preconstricted with endothelin-1, nitric oxide and 8-bromo-cGMP (a cell-membrane-permeable cGMP analog) induced concentration-dependent relaxation. The relaxation was significantly attenuated by β-phenyl-1, N 2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothionate (Rp-8-Br-PET-cGMPS; a PKG inhibitor) and N-[2-(methylamino)ethyl]5-isoquinolinesulfonamide [H-8; an inhibitor of PKG and protein kinase A (PKA)] but was not affected by KT-5720 (a PKA inhibitor). Biochemical study showed that PKG activity in newborn ovine pulmonary veins was inhibited by 8-Br-PET-cGMPS and H-8 but not by KT-5720. PKA activity was not affected by 8-Br-PET-cGMPS but was inhibited by H-8 and KT-5720. These results suggest that PKG is involved in relaxation of pulmonary veins of newborn lambs induced by nitric oxide and cGMP.

scholarly journals Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases

2018 ◽  
Vol 9 ◽  
Author(s):  
Lei Zhang ◽  
Yanan Wang ◽  
Yi Li ◽  
Lingli Li ◽  
Suowen Xu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Cardiovascular Diseases ◽  
Therapeutic Potential

Vasorelaxant Effect of Novel Nitric Oxide-Hydrogen Sulfide Donor Chalcone in Isolated Rat Aorta: Involvement of cGMP Mediated sGC and Potassium Channel Activation

2020 ◽  
Vol 13 (2) ◽  
pp. 126-136
Author(s):  
Amol Sherikar ◽  
Rakesh Dhavale ◽  
Manish Bhatia
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Hydrogen Sulfide ◽  
Potassium Channel ◽  
Rat Aorta ◽  
Tetraethylammonium Chloride ◽  
Vasorelaxant Effect ◽  
Activation Assay ◽  
Isolated Rat

Background and Objective: : Recently, nitric oxide (NO) and hydrogen sulfide (H2S) donating moieties were extensively studied for their role in the vasculature as they are responsible for many cellular and pathophysiological functioning. The objective of the present study is to evaluate novel NO and H2S donating chalcone moieties on isolated rat aorta for vasorelaxation, and to investigate the probable mechanism of action. Methods:: To extend our knowledge of vasorelaxation by NO and H2S donor drugs, here we investigated the vasorelaxing activity of novel NO and H2S donating chalcone moieties on isolated rat aorta. The mechanism of vasorelaxation by these molecules was investigated by performing in vitro cGMP mediated sGC activation assay and using Tetraethylammonium chloride (TEA) as a potassium channel blocker and Methylene blue as NO blocker. Results:: Both NO and H2S donating chalcone moieties were found to be potent vasorelaxant. The compound G4 and G5 produce the highest vasorelaxation with 3.716 and 3.789 M of pEC50, respectively. After the addition of TEA, G4 and G5 showed 2.772 and 2.796 M of pEC50, respectively. The compounds Ca1, Ca2, and D7 produced significant activation and release of cGMP mediated sGC which was 1.677, 1.769 and 1.768 M of pEC50, respectively. Conclusion: : The vasorelaxation by NO-donating chalcones was blocked by Methylene blue but it did not show any effect on H2S donating chalcones. The vasorelaxing potency of NO-donating molecules was observed to be less affected by the addition of TEA but H2S donors showed a decrease in both efficacy and potency. The cGMP release was more in the case of NO-donating molecules. The tested compounds were found potent for relaxing vasculature of rat aorta.

AKT Mediates Platelet Activation by Stimulating Nitric Oxide Synthesis and cGMP Elevation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1652-1652
Author(s):  
Aleksandra Stojanovic ◽  
Jasna A. Marjanovic ◽  
Viktor Brokovych ◽  
Randal A. Skidgel ◽  
Nissim Hay ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Critical Role ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Low Concentrations ◽  
Cgmp Pathway ◽  
Dependent Protein ◽  
Platelet Secretion

Abstract Phosphoinositide 3-kinase (PI3-K) and Akt play important roles in platelet activation. However, the downstream mechanisms for their roles are unclear. We have recently shown that nitric oxide (NO) synthase 3 (NOS3) and cGMP-dependent protein kinase stimulate platelet secretion and aggregation. Here we show that PI3-K-mediated Akt activation plays a critical role in agonist-stimulated platelet NO synthesis and cGMP elevation. Agonist-induced elevation of NO and cGMP was inhibited by Akt inhibitors and reduced in Akt-1 knockout platelets. Akt-1 knockout or Akt inhibitor-treated platelets showed reduced platelet secretion and aggregation in response to low concentrations of agonists, which can be reversed by low concentrations of sodium nitroprusside (SNP) or cGMP analogs. Similarly, PI3-K inhibitors diminished elevation of cGMP and also inhibited platelet secretion and the second-wave platelet aggregation, which was also partially reversed by cGMP analogs and by SNP. These results indicate that the NO-cGMP pathway is an important downstream mechanism mediating PI3-K and Akt signals leading to platelet secretion and aggregation. Conversely, the PI3-K-Akt pathway is a major upstream mechanism responsible for activating the NO-cGMP pathway. Thus, this study delineates a novel platelet activation pathway involving sequential activation of PI3-K, Akt, NOS3, sGC, and cGMP-dependent protein kinase.

scholarly journals Emergence of Hydrogen Sulfide as an Endogenous Gaseous Signaling Molecule in Cardiovascular Disease

2014 ◽  
Vol 114 (4) ◽  
pp. 730-737 ◽  
Author(s):  
David J. Polhemus ◽  
David J. Lefer
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Hydrogen Sulfide ◽  
Therapeutic Potential ◽  
Rapid Development ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Signaling Molecule ◽  
Organ Systems ◽  
Endogenous Enzymes

Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H 2 S) is produced enzymatically in all mammalian species including man and exerts several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H 2 S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H 2 S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H 2 S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H 2 S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H 2 S elicits protective actions, coupled with the rapid development of novel H 2 S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H 2 S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H 2 S, nitric oxide, and carbon monoxide.

Role of nitric oxide and hydrogen sulfide from perivascular adipose tissue in vascular tone of resistant mesenteric arteries from endotoxemic rats

Nitric Oxide ◽  
2012 ◽  
Vol 27 ◽  
pp. S39-S40
Author(s):  
Cheng-Ming Tsao ◽  
Ming-Shin Lee ◽  
Mei-Hui Liao ◽  
Chih-Chin Shih ◽  
Shiu-Jen Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Adipose Tissue ◽  
Hydrogen Sulfide ◽  
Vascular Tone ◽  
Mesenteric Arteries ◽  
Perivascular Adipose Tissue

5-Hydroxytryptamine- and U46619-mediated vasoconstriction in bovine pulmonary conventional and supernumerary arteries: effect of endogenous nitric oxide

1999 ◽  
Vol 98 (1) ◽  
pp. 81-89 ◽  
Author(s):  
D. BUNTON ◽  
A. MACDONALD ◽  
T. BROWN ◽  
A. TRACEY ◽  
J. C. MCGRATH ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Guanylate Cyclase ◽  
Vascular Tone ◽  
No Synthase ◽  
Vasoconstrictor Response ◽  
Cgmp Pathway ◽  
Endogenous Nitric Oxide ◽  
Synthase Inhibitor ◽  
Resting Tone

We compared 5-hydroxytryptamine (5-HT)- and U46619-mediated contractions in bovine pulmonary conventional arteries (CA) and supernumerary arteries (SA). The effects of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (100 μM) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 μM) on the responses of CA and SA to 5-HT and U46619 were also examined. In addition, the effects of the 5-HT2B receptor antagonist SB 200646 (1 nM–1 μM) on the responses to 5-HT in SA and CA were studied. Tissue cGMP levels were measured in the absence and presence of l-NAME, ODQ, 5-HT and U46619. 5-HT was approximately 30 times more potent in SA {-log [EC50 (M)] (pEC50) 6.32±0.13} than in CA (5.05±0.14). U46619 displayed a similar potency in both CA (pEC50 7.80±0.07) and SA (7.75±0.12). l-NAME did not significantly alter the resting tone of CA or SA. In contrast, ODQ produced a transient increase in the tone of both CA and SA. Neither l-NAME nor ODQ altered the responses to 5-HT or U46619 in CA. In addition, neither l-NAME nor ODQ altered the responses to U46619 in SA, but both l-NAME and ODQ increased the magnitude of the response to 5-HT in SA without changing the sensitivity. Inhibition of the 5-HT2B receptor with SB 200646 did not alter the response to 5-HT in SA or CA. Basal levels of cGMP (pmol/mg of protein) were similar in CA (1.16±0.33) and SA (0.8±0.51), and were not significantly changed in the presence of 5-HT or U46619. l-NAME and ODQ reduced the basal levels of cGMP in both SA and CA. The results suggest that endogenous NO selectively attenuates the vasoconstrictor response to 5-HT in SA, but not in CA. These results also suggest that the NO/cGMP pathway may have a role in maintaining low vascular tone, but that other mechanisms are able to compensate for the absence of this pathway.

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