scholarly journals Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation

2009 ◽  
Vol 297 (4) ◽  
pp. H1494-H1503 ◽  
Author(s):  
Zeling Cao ◽  
Jeffrey B. Bell ◽  
Joy G. Mohanty ◽  
Enika Nagababu ◽  
Joseph M. Rifkind
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Cells ◽  
Purinergic Receptors ◽  
Atp Release ◽  
Atp Synthesis ◽  
No Synthase ◽  
Endothelial No Synthase ◽  
Rbc Membrane

A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by Nω-nitro-l-arginine methyl ester (l-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation.

Effects of the RBC membrane and increased perfusate viscosity on hypoxic pulmonary vasoconstriction

2000 ◽  
Vol 88 (5) ◽  
pp. 1520-1528 ◽  
Author(s):  
Steven Deem ◽  
John T. Berg ◽  
Mark E. Kerr ◽  
Erik R. Swenson
Keyword(s):  
Nitric Oxide ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Respir Crit ◽  
Inhibitory Effect ◽  
No Synthase ◽  
Small Reduction ◽  
Rbc Membrane ◽  
Pulmonary Vasoconstriction

Red blood cells (RBCs) augment hypoxic pulmonary vasoconstriction (HPV) in part by scavenging of nitric oxide (NO) by Hb (Deem S, Swenson ER, Alberts MK, Hedges RG, and Bishop MJ, Am J Respir Crit Care Med 157: 1181–1186, 1998). We studied the contribution of the RBC compartmentalization of Hb to augmentation of HPV and scavenging of NO in isolated perfused rabbit lungs. Lungs were initially perfused with buffer; HPV was provoked by a 5-min challenge with hypoxic gas (inspired O2 fraction 0.05). Expired NO was measured continuously. Addition of free Hb to the perfusate (0.25 mg/ml) resulted in augmentation of HPV and a fall in expired NO that were similar in magnitude to those associated with a hematocrit of 30% (intracellular Hb of 100 mg/ml). Addition of dextran resulted in a blunting of HPV after free Hb but no change in expired NO. Blunting of HPV by dextran was not prevented by NO synthase inhibition with N ω-nitro-l-arginine and/or cyclooxygenase inhibition. RBC ghosts had a mild inhibitory effect on HPV but caused a small reduction in expired NO. In conclusion, the RBC membrane provides a barrier to NO scavenging and augmentation of HPV by Hb. Increased perfusate viscosity inhibits HPV by an undetermined mechanism.

Direct and reversible inhibition of endothelial nitric oxide synthase by nitric oxide

1995 ◽  
Vol 268 (6) ◽  
pp. H2216-H2223 ◽  
Author(s):  
L. V. Ravichandran ◽  
R. A. Johns ◽  
A. Rengasamy
Keyword(s):  
Nitric Oxide ◽  
Enzyme Activity ◽  
Feedback Mechanism ◽  
No Synthase ◽  
Maximal Velocity ◽  
Dependent Manner ◽  
Reversible Inhibition ◽  
Endothelial No Synthase ◽  
Endothelial Nitric Oxide

The objective of this study was to investigate the regulation of endothelial nitric oxide (NO) synthase by NO. Partially purified endothelial NO synthase was exposed to authentic NO (10-200 microM) and to the nitrovasodilators sodium nitroprusside (SNP; 10-1,000 microM) and S-nitroso-N-acetylpenicillamine (SNAP; 100-1,000 microM), and enzyme activity was assayed by measuring the conversion of L-[3H]arginine to L-[3H]citrulline in the presence of added cofactors. NO, SNP, and SNAP inhibited NO synthase activity in a dose-dependent manner, NO being the most potent inhibitor. The Michaelis constant for L-arginine was not altered (4.87 microM) by NO (50 microM), whereas the maximal velocity of the enzyme decreased from 784 to 633 pmol.mg-1.min-1. Oxyhemoglobin (10 microM) partially prevented the inhibition of NO synthase by NO (50 microM). The data also suggest that NO inhibits endothelial NO synthase activity by directly interacting with the NO synthase and not by an indirect mechanism such as limitation of cofactor or oxygen availability. Dialysis of NO synthase treated with NO (50 microM) partially restored the enzyme activity. This study demonstrates a direct and reversible inhibition of NO synthase by NO, suggesting a feedback mechanism in vivo.

scholarly journals Cedrelopsis grevei induced hypotension and improved endothelial vasodilatation through an increase of Cu/Zn SOD protein expression

2004 ◽  
Vol 286 (2) ◽  
pp. H775-H781 ◽  
Author(s):  
Hantamalala Ralay Ranaivo ◽  
Olivier Rakotoarison ◽  
Angela Tesse ◽  
Christa Schott ◽  
Adolphe Randriantsoa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Oral Administration ◽  
Ex Vivo ◽  
No Synthase ◽  
Mesenteric Arteries ◽  
Endothelial No Synthase ◽  
Enhanced Expression ◽  
Male Wistar Rats ◽  
Endothelium Dependent Relaxation

This study was designed to investigate the cardiovascular consequences of oral administration of Cedrelopsis grevei (CG) in normotensive rats. Experiments were designed to investigate hemodynamic parameters in vivo as well as the consequences of CG treatment on the vasoconstriction response to norepinephrine and the vasorelaxant response to ACh ex vivo in isolated aortas and small mesenteric arteries (SMA). Treatment of male Wistar rats with 80 mg/kg CG for 4 wk induced a progressive decrease in systolic blood pressure. In the aorta, CG did not significantly alter the response to norepinephrine despite the participation of extraendothelial nitric oxide (NO)-induced hyporeactivity. In the SMA, contraction to norepinephrine was not modified by CG treatment even though it enhanced the participation of endothelial NO. Endothelium-dependent relaxation to ACh was increased in both the aorta and SMA from CG-treated rats. In the aorta from CG-treated rats, the mechanism involved superoxide dismutase (SOD)- and catalase-sensitive free radical production. The latter was associated with enhanced expression of Cu/Zn SOD and endothelial NO synthase. These results suggest that oral administration of CG produces a decrease in blood pressure in normotensive rats. This hemodynamic effect was associated with enhanced endothelium-dependent relaxation and an induction of Cu/Zn SOD and endothelial NO synthase expressions in the vessel wall. They also show subtle mechanisms that compensate for the increased participation of NO to maintain unchanged agonist-induced contractility. These data provide a pharmacological basis for the empirical use of CG against cardiovascular diseases.

In vivo lipopolysaccharide pretreatment inhibits cGMP release from the isolated-perfused rat lung

1995 ◽  
Vol 269 (5) ◽  
pp. L618-L624 ◽  
Author(s):  
M. M. Kurrek ◽  
W. M. Zapol ◽  
A. Holzmann ◽  
G. Filippov ◽  
M. Winkler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Signal Transduction ◽  
Superoxide Dismutase ◽  
Soluble Guanylate Cyclase ◽  
No Synthase ◽  
Rat Lung ◽  
Signal Transduction System ◽  
Endothelial No Synthase ◽  
Cgmp Signal

Administration of bacterial lipopolysaccharide (LPS) to rats stimulates synthesis of nitric oxide (NO), a free radical molecule that activates soluble guanylate cyclase, thereby increasing intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration and inducing systemic vasodilatation. To investigate the effect of endotoxemia on the pulmonary NO/cGMP signal transduction system, we measured the release of cGMP by isolated-perfused lungs of rats that received an intraperitoneal injection of LPS (1 mg/kg) or saline 2 days earlier. Over 90 min, 1.4 +/- 0.78 and 0.079 +/- 0.016 nmol cGMP accumulated in pulmonary perfusates of saline- and LPS-treated rats, respectively (P < 0.05). Despite addition to the perfusate of Zaprinast, superoxide dismutase, or A23187, markedly less cGMP was released from the lungs of rats exposed to LPS than from the lungs of control rats. In contrast, after ventilation with 100 parts per million NO gas, cGMP accumulating in the perfusate of the lungs of both groups of rats was markedly increased, and the quantity of cGMP released from the lungs of LPS-treated rats was similar to that released by control rat lungs (2.8 +/- 0.57 vs. 3.3 +/- 0.88 nmol, P = NS). With the use of immunoblot techniques, equal concentrations of constitutive endothelial NO synthase were detected in the lungs of rats treated with saline or LPS. These results demonstrate that the NO/cGMP signal transduction system is abnormal in the lungs of rats exposed to LPS, at least in part, at the level of endothelial NO synthase activation.

Effects of Neuroactive Amino Acids Derivatives on Cardiac and Cerebral Mitochondria and Endothelial functions in Animals Exposed to Stress

2017 ◽  
Vol 2 (2) ◽  
pp. 34
Author(s):  
TA Popova ◽  
II Prokofiev ◽  
IS Mokrousov ◽  
Valentina Perfilova ◽  
AV Borisov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Platelet Aggregation ◽  
Atp Synthesis ◽  
Elevated Concentration ◽  
Blood Pressure Monitor ◽  
Pressure Monitor ◽  
Griess Reagent ◽  
Arterial Blood ◽  
Endothelial Functions

Introduction: To study the effects of glufimet, a new derivative of glutamic acid, and phenibut, a derivative of γ-aminobutyric acid (GABA), on cardiac and cerebral mitochondria and endothelial functions in animals following exposure to stress and inducible nitric oxide synthase (iNOS) inhibition. Methods: Rats suspended by their dorsal cervical skin fold for 24 hours served as the immobilization and pain stress model. Arterial blood pressure was determined using a non-invasive blood pressure monitor. Mitochondrial fraction of heart and brain homogenates were isolated by differential centrifugation and analysed for mitochondrial respiration intensity, lipid peroxidation (LPO) and antioxidant enzyme activity using polarographic method. The concentrations of nitric oxide (NO) terminal metabolites were measured using Griess reagent. Hemostasis indices were evaluated. Platelet aggregation was estimated using modified version of the Born method described by Gabbasov et al., 1989. Results: The present study demonstrated that stress leads to an elevated concentration of NO terminal metabolites and LPO products, decreased activity of antioxidant enzymes, reduced mitochondrial respiratory function, and endothelial dysfunction. Inhibition of iNOS by aminoguanidine had a protective effect. Phenibut and glufimet inhibited a rise in stress-induced nitric oxide production. This resulted in enhanced coupling of substrate peroxidation and ATP synthesis. The reduced LPO processes caused by glufimet and phenibut normalized the endothelial function which was proved by the absence of average daily blood pressure (BP) elevation episodes and a significant increase in platelet aggregation level. Conclusion: Glufimet and phenibut restrict the harmful effects of stress on the heart and brain possibly by modulating iNOS activity.

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

1994 ◽  
Vol 267 (1) ◽  
pp. R84-R88 ◽  
Author(s):  
M. Huang ◽  
M. L. Leblanc ◽  
R. L. Hester
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Output ◽  
No Synthase ◽  
Before And After ◽  
Regional Hemodynamics ◽  
Autonomic Blockade ◽  
Infusion Of Norepinephrine ◽  
Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

scholarly journals Nitric Oxide as an Endogenous Mutagen for Sendai Virus without Antiviral Activity

2004 ◽  
Vol 78 (16) ◽  
pp. 8709-8719 ◽  
Author(s):  
Jun Yoshitake ◽  
Takaaki Akaike ◽  
Teruo Akuta ◽  
Fumio Tamura ◽  
Tsutomu Ogura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Viral Replication ◽  
Mutation Frequency ◽  
Sendai Virus ◽  
No Synthase ◽  
Mutagenic Potential ◽  
Gfp Gene ◽  
Sw480 Cells

ABSTRACT Nitric oxide (NO) may affect the genomes of various pathogens, and this mutagenesis is of particular interest for viral pathogenesis and evolution. Here, we investigated the effect of NO on viral replication and mutation. Exogenous or endogenous NO had no apparent antiviral effect on influenza A virus and Sendai virus. The mutagenic potential of NO was analyzed with Sendai virus fused to a green fluorescent protein (GFP) gene (GFP-SeV). GFP-SeV was cultured in SW480 cells transfected with a vector expressing inducible NO synthase (iNOS). The mutation frequency of GFP-SeV was examined by measuring loss of GFP fluorescence of the viral plaques. GFP-SeV mutation frequency in iNOS-SW480 cells was much higher than that in parent SW480 cells and was reduced to the level of mutation frequency in the parent cells by treatment with an NO synthase (NOS) inhibitor. Immunocytochemistry showed generation of more 8-nitroguanosine in iNOS-SW480 cells than in SW480 cells without iNOS transfection. Authentic 8-nitroguanosine added exogenously to GFP-SeV-infected CV-1 cells increased the viral mutation frequency. Profiles of the GFP gene mutations induced by 8-nitroguanosine appeared to resemble those of mutations occurring in mouse lungs in vivo. A base substitution that was characteristic of both mutants (those induced by 8-nitroguanosine and those occurring in vivo) was a C-to-U transition. NO-dependent oxidative stress in iNOS-SW480 cells was also evident. Together, the results indicate unambiguously that NO has mutagenic potential for RNA viruses such as Sendai virus without affecting viral replication, possibly via 8-nitroguanosine formation and cellular oxidative stress.

Abstract P388: Extra-cardiac BCAA Catabolism Lowers Blood Pressure And Protects From Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Danielle Murashige ◽  
Cholsoon Jang ◽  
Michael Neinast ◽  
Michael Levin ◽  
Jae Woo Jung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Blood Pressure ◽  
Mendelian Randomization ◽  
Multiple Models ◽  
Direct Effects ◽  
Heavy Isotope ◽  
Branched Chain Amino Acid ◽  
Branched Chain

Pharmacologic activation of branched chain amino acid (BCAA) catabolism is protective in numerous models of heart failure (HF). How this protection occurs has remained unclear, although a causative block in cardiac BCAA oxidation has been proposed. We use here in vivo heavy isotope infusion studies to show that cardiac preference for BCAA oxidation increases, rather than decreases, in multiple models of HF. We use various genetic models to show that cardiac-specific activation of BCAA oxidation does not protect from HF, even though systemic activation of BCAA oxidation does. Lowering plasma and cardiac BCAAs by genetic means is also not sufficient to confer protection comparable to that conferred by pharmacologic activation of BCAA oxidation, suggesting alternative mechanisms of protection. Surprisingly, telemetry and invasive hemodynamic studies showed that pharmacological activation of BCAA catabolism lowers blood pressure, a well-established cardioprotective mechanism. The effects on blood pressure occurred independently of nitric oxide (NO), and reflected a vascular resistance to adrenergic constriction. Finally, mendelian randomization studies revealed that elevations in plasma BCAAs portend higher blood pressure in large human cohorts. Together, these data indicate that activation of BCAA oxidation lowers blood pressure and protects from heart failure independently of any direct effects on the heart itself.

scholarly journals Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2403-2415 ◽  
Author(s):  
Elena Grossini ◽  
Giulia Raina ◽  
Serena Farruggio ◽  
Lara Camillo ◽  
Claudio Molinari ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Coronary Artery ◽  
Coronary Blood Flow ◽  
No Synthase ◽  
Cardiac Perfusion ◽  
No Release ◽  
Acyl Ghrelin

Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P &lt; .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.

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