Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase

doi:10.1016/0014-2999(87)90493-6

European Journal of Pharmacology

Volume 139, Issue 1, 2 July 1987, Pages 19-30

https://doi.org/10.1016/0014-2999(87)90493-6 Get rights and content

Abstract

Organic nitrates develop their vasodilating potency by stimulating the enzme guanylate cyclase. There are still several theories concerning the molecular mechanism of enzyme activation, the most likely of which sees nitric oxide (NO·) as the true modulator of the soluble guanylate cyclase. We therefore examined the release of nitric oxide from organic nitrates by means of difference-spectrophotometric method and found that our results correlated well with the extent of enzyme activation. The more NO· was liberated from the compounds in question, the higher was the enzyme activation observed. When the examined nitrates were used in a concentration which caused a half-maximal enzyme stimulation, the result was a NO· liberation of striking uniformity. This correlation also applied to SIN-1 for which it has been assumed up to now that the intact molecule itself is able to stimulate the enzyme and not the nitric oxide released from it. We found the reaction between organic nitrates and cysteine to be highly dependent on temperature, while the extent of the observed enhancement increased with the number of nitrate groups per molecule. We also studied the potential effects of certain compounds on non-enzymatic NO· release and found that, in addition to methylene blue, thionine and brilliantcresyl blue, but not ferricyanide were also effective inhibitors. So it seems likely that both an enzymatic and a non-enzymatic mode of inhibition of enzyme activity does exist. Since oxyhemoglobin is an effective scavenger of nitric oxide, its addition can inhibit enzyme activation by nitrovasodilators. Our results stress the important role of the non-enzymatic liberation of NO· from organic nitrates and related compounds as possible, perhaps even as the principal mode of activation of soluble guanylate cyclase by nitrovasditors.

References (36)

P. Craven et al.
Requirement of heme in the activation of purified guanylate cyclase by nitric oxide
Biochim. Biophys. Acta
(1983)
M.P. Doyle et al.
Oxidation of nitrogen oxides by bound dioxygen in hemoproteins
J. Inorg. Biochem.
(1981)
R. Gerzer et al.
Soluble guanylate cyclase purified from bovine lung contains heme and copper
FEBS Lett.
(1981)
L.J. Ignarro et al.
Requiirement of thiols for the activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite
Biochim. Biophys. Acta
(1980)
L.J. Ignarro et al.
Evidence that regulation of hepatic guanylate cyclase activity involves interactions between catalytic site SH-groups and both substrate and activator
Arch. Biochem. Biophys.
(1981)
J.C. Kertesz et al.
Electron spin resonance studies of free radicals in soution. III: pH dependence of thiyl free radical of cysteine
J. Pharm. Sci.
(1974)
H. Kimura et al.
Activation of guanylate cyclase from rat liver and other tissues by sodium azide
J. Biol. Chem.
(1975)
A. Kobayashi et al.
The effects of nitroglycerin on cyclic nucleotides in the coronary artery in vivo
Life Sci.
(1980)
H. Kosaka et al.
Stoichiometry of the reaction of oxyhemoglobin with nitrite
Biochim. Biophys. Acta
(1979)
U. Leuenberger et al.
Determination of nitrate and bromide in foodstuffs by high-performance liquid chromatography
J. Chromatogr.
(1980)

H. Schröder et al.

Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase

J. Mol. Cell. Cardiol.

(1985)

Y. Asahi et al.

Chemical and kinetic study on stabilities of 3-morpholinosydnonimine and its N-ethoxy-carbonyl derivative

Chem. Pharm. Bull.

(1971)

K.L. Axelsson et al.

Nitroglycerin tolerance in vitro: effect of cGMP turnover in vascular smooth muscle

Acta Pharmacol. Toxicol.

(1984)

J.W. Baker et al.

Hydrolytic decomposition of esters of nitric acid. Part I: General experimental techniques. Alkaline hydrolysis and neutral solvolysis of methyl, ethyl, i-propyl, and t-butyl nitrates in aqueous alcohol

J. Chem. Soc.

(1952)

A. Bashir et al.

Pharmacokinetic studies of various preparations of glyceryl trinitrate

Br. J. Clin. Pharmacol.

(1982)

B.M. Bennett et al.

Requirement for reduced, unliganded hemoprotein for the hemoglobin- and myoglobin-mediated biotransformation of glyceryl trinitrate

J. Pharmacol. Exp. Ther.

(1986)

B.M. Bennett et al.

Biotransformation of glyceryl trinitrate to glyceryl dinitrate by human hemoglobin

Can. J. Physiol. Pharmacol.

(1984)

E. Böhme et al.

Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP-formation in smooth muscle and platelets

Adv. Cycl. Nucl. Res.

(1978)

Cited by (859)

Interactive effects of mercuric oxide nanoparticles and future climate CO<inf>2</inf> on maize plant
2021, Journal of Hazardous Materials
So far, the phytotoxic hazards of nano-sized mercuric oxide (HgO-NPs) are not investigated. Herein, the phytotoxicity of fully characterized HgO-NPs (100 mg/kg soil), prepared by coprecipitation method, on maize grown under ambient (aCO₂, 410 ppm) and elevated CO₂ (eCO₂, 620 ppm) was investigated. Regardless of CO₂ concentration, HgO-NPs treatment increased Hg levels in maize organs. HgO-NPs induced severe oxidative stress in aCO₂ grown plants as indicated by reduced growth and photosynthesis and accumulation of reactive oxygen species (ROS), through photorespiration and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activities, and lipid and protein oxidation products. Although HgO-NPs increased molecular (polyphenols, flavonoids, tocopherols) and enzymatic (superoxide dismutase, catalase, peroxidase, ascorbate peroxidase, glutathione peroxidase) antioxidants in shoots of aCO₂ plants, but this failed to fight the eruption of increased ROS. On contrary, eCO₂ treatment mitigated the HgO-NPs impact by promoting photosynthesis and reducing the Hg-induced ROS production. Moreover, eCO₂ promoted ROS detoxification via molecular antioxidants overproduction, enhanced superoxide dismutase, catalase and peroxidases activities, and modulation of reduced ascorbate/oxidized ascorbate and reduced glutathione/oxidized glutathione homeostasis. The combined HgO-NPs + eCO₂ treatment also enhanced the glutathione-S-transferase activity. This study suggests that HgO-NPs cause severe phytotoxic hazards and this effect will be less detrimental under future CO₂ climate.
Historical origins of the discovery of mammalian nitric oxide (nitrogen monoxide) production/physiology/pathophysiology
2020, Biochemical Pharmacology
The award of the 1998 Nobel Prize in Physiology or Medicine to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad “for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system” highlighted the discovery of NO in mammals. This breakthrough also coincided with the discoveries of the role of NO as a cytotoxic effector in the immune system and as an intercellular neurotransmitter in the nervous system. This brief overview describes the chronological development of this trilinear convergence in 1986–1988, including background chemistry and history of human/nitrogen oxide interactions in general.
Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers
2020, Advanced Drug Delivery Reviews
Citation Excerpt :
Subsequently, we focused on nitroglycerin (NG), a drug given for angina pectoris, which has been in use for more than a century. NG generates NO selectively in cardiac infarct tissue and in cancer tissue, which is hypoxic and has a slightly acidic pH (Fig. 6A) [148–151]. Vasodilation and increased blood flow can thereby be obtained in these tissues.
The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors that is related to their particular anatomical and pathophysiological characteristics, e.g. defective vascular architecture; large gaps between endothelial cells in blood vessels; abundant vascular mediators such as bradykinin, nitric oxide, carbon monoxide, and vascular endothelial growth factor; and impaired lymphatic recovery. These features lead to tumor tissues showing considerable extravasation of plasma components and nanomedicines. These data comprise the basic theory underlying the development of macromolecular agents or nanomedicines. The EPR effect is not necessarily valid for all solid tumors, because tumor blood flow and vascular permeability vary greatly. Tumor blood flow is frequently obstructed as tumor size increases, as often seen clinically; early stage, small tumors show a more uniform EPR effect, whereas advanced large tumor show heterogeneity in EPR effect. Accordingly, it would be very important to apply enhancers of EPR effect in clinical setting to make EPR effect more uniform. In this review, we discuss the EPR effect: its history, factors involved, and dynamics and heterogeneity. Strategies to overcome the EPR effect’s heterogeneity may guarantee better therapeutic outcomes of drug delivery to advanced cancers.
NiO-nanoparticles induce reduced phytotoxic hazards in wheat (Triticum aestivum L.) grown under future climate CO<inf>2</inf>
2019, Chemosphere
Due to industrialization and expansion of nanotechnology, ecosystem contamination by nanoparticles is likely. Overall, nanoparticles accumulate in environmental matrices and induce phytotoxicity, however future climate (elevated CO₂ (eCO₂)) may affect the distribution of nanoparticles in ecosystems and alter their impact on plants. In the current study, nickel oxide nanoparticles (NiO-NPs) with an average diameter of 54 nm were synthesized by chemical pericipitation method using Triton X-100 and characterized by scanning electron microscopy (SEM), UV-VIS spectroscopy and Fourier transform infrared spectroscopy (FTIR). We have investigated the impact of NiO-NPs at a concentration of 120 mg kg⁻¹ soil, selected based on the results of a preliminary experiment, on accumulation of Ni ions in wheat (Triticum aestivum L.) and how that could influence plant growth, photosynthesis and redox homeostasis under two CO₂ scenarios, ambient (aCO_2, 400 ppm) and eCO₂ (620 ppm). NiO-NPs alone reduced whole plant growth, inhibited photosynthesis and increased the levels of antioxidants. However, improved defense system was not enough to lessen photorespiration induced H₂O₂ accumulation and oxidative damage (lipid and protein oxidation). Interestingly, eCO₂ significantly mitigated the phytotoxicity of NiO-NPs. Although, eCO₂ did not affect Ni accumulation and translocation in wheat, it promoted photosynthesis and inhibited photorespiration, resulting in reduced ROS production. Moreover, it further improved the antioxidant defense system and maintained ASC/DHA and GSH/GSSG redox balances. Organ specific responses to NiO-NPs and/or eCO₂ were indicated and confirmed by cluster analysis. Overall, we suggest that wheat plants will be more tolerant to NiO-NPs stress under future climate CO₂.
Genetic Biosensors for Imaging Nitric Oxide in Single Cells
2018, Free Radical Biology and Medicine
Over the last decades a broad collection of sophisticated fluorescent protein-based probes was engineered with the aim to specifically monitor nitric oxide (NO), one of the most important signaling molecules in biology. Here we report and discuss the characteristics and fields of applications of currently available genetically encoded fluorescent sensors for the detection of NO and its metabolites in different cell types.
Because of its radical nature and short half-life, real-time imaging of NO on the level of single cells is challenging. Herein we review state-of-the-art genetically encoded fluorescent sensors for NO and its byproducts such as peroxynitrite, nitrite and nitrate. Such probes enable the real-time visualization of NO signals directly or indirectly on the level of single cells and cellular organelles and, hence, extend our understanding of the spatiotemporal dynamics of NO formation, diffusion and degradation. Here, we discuss the significance of NO detection in individual cells and on subcellular level with genetic biosensors. Currently available genetically encoded fluorescent probes for NO and nitrogen species are critically discussed in order to provide insights in the functionality and applicability of these promising tools. As an outlook we provide ideas for novel approaches for the design and application of improved NO probes and fluorescence imaging protocols.
Endothelial modulation of a nitric oxide donor complex-induced relaxation in normotensive and spontaneously hypertensive rats
2018, Life Sciences
Citation Excerpt :
NO binds to the sGC heme domain in vascular smooth muscle cells, to activate sGC and to raise cyclic 3′,5′-guanosine monophosphate (cGMP) concentration. cGMP effects are mediated by cGMP-dependent protein kinase G [34,35], which can activate sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) [36] and potassium channels [37] as well as inhibit inositol tris-phosphate (IP3)-mediated Ca2+-release [38]. All these actions reduce cytosolic calcium concentration in vascular smooth muscle cells, to promote relaxation.
We hypothesized that endothelium modulates relaxation induced by a nitric oxide (NO) donor ruthenium complex (TERPY, [Ru(terpy)(bdq)NO]³⁺) in mesenteric arteries of normotensive and spontaneously hypertensive (SHR) rats in different ways. We analyzed the mechanism involved in TERPY-induced relaxation in the second and third branches of mesenteric arteries and investigated how endothelium contributes to the TERPY vasodilator effect on SHR blood vessels. TERPY induced concentration-dependent relaxation in endothelium-denuded (E⁻) and endothelium-intact (E⁺) mesenteric arteries of normotensive rats and SHR. Pretreatment with ODQ (which inhibits soluble guanylyl cyclase) or TEA (tetraethylammonium, which blocks potassium channels) significantly reduced the TERPY vasodilator effect on E⁻ mesenteric arteries of normotensive rats and SHR. The presence of endothelium shifted the concentration–effect curves for TERPY in E⁺ mesenteric arteries of normotensive rats to the right. Conversely, the presence of endothelium shifted the concentration–effect curves for TERPY in the case of SHR E⁺ mesenteric arteries to the left, which suggested increased potency. L-NNA, a more selective endothelial NO synthase (eNOS) inhibitor, reduced TERPY potency in SHR. The presence of endothelium and notably of NOS contributed to the TERPY vasodilator action in SHR: TERPY promoted eNOS Ser¹¹⁷⁷ phosphorylation with consequent NO production and increased soluble guanylyl cyclase activity, which may have directly activated potassium channels.

View all citing articles on Scopus

View full text

Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase

Abstract

Biochim. Biophys. Acta

J. Inorg. Biochem.

FEBS Lett.

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

J. Pharm. Sci.

J. Biol. Chem.

Life Sci.

Biochim. Biophys. Acta

J. Chromatogr.

J. Mol. Cell. Cardiol.

Chemical and kinetic study on stabilities of 3-morpholinosydnonimine and its N-ethoxy-carbonyl derivative

Chem. Pharm. Bull.

Nitroglycerin tolerance in vitro: effect of cGMP turnover in vascular smooth muscle

Acta Pharmacol. Toxicol.

Hydrolytic decomposition of esters of nitric acid. Part I: General experimental techniques. Alkaline hydrolysis and neutral solvolysis of methyl, ethyl, i-propyl, and t-butyl nitrates in aqueous alcohol

J. Chem. Soc.

Pharmacokinetic studies of various preparations of glyceryl trinitrate

Br. J. Clin. Pharmacol.

Requirement for reduced, unliganded hemoprotein for the hemoglobin- and myoglobin-mediated biotransformation of glyceryl trinitrate

J. Pharmacol. Exp. Ther.

Biotransformation of glyceryl trinitrate to glyceryl dinitrate by human hemoglobin

Can. J. Physiol. Pharmacol.

Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP-formation in smooth muscle and platelets

Adv. Cycl. Nucl. Res.