Bench to bedside review: therapeutic modulation of nitric oxide in sepsis—an update

AbstractNitric oxide is a signalling molecule with an extensive range of functions in both health and disease. Discovered in the 1980s through work that earned the Nobel prize, nitric oxide is an essential factor in regulating cardiovascular, immune, neurological and haematological function in normal homeostasis and in response to infection. Early work implicated exaggerated nitric oxide synthesis as a potentially important driver of septic shock; however, attempts to modulate production through global inhibition of nitric oxide synthase were associated with increased mortality. Subsequent work has shown that regulation of nitric oxide production is determined by numerous factors including substrate and co-factor availability and expression of endogenous regulators. In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. This bench to bedside review summarises our current understanding of the ways in which nitric oxide production is regulated on a tissue and cellular level before discussing progress in translating these observations into novel therapeutic strategies for patients with sepsis.

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Adenosine Regulates Renal Nitric Oxide Production in Hypothyroid Rats

Journal of the American Society of Nephrology ◽

10.1681/asn.v1081681 ◽

1999 ◽

Vol 10 (8) ◽

pp. 1681-1688

Author(s):

MARTHA FRANCO ◽

EDILIA TAPIA ◽

FLAVIO MARTÍNEZ ◽

MA. EUGENIA DAVILA ◽

JUANA INÉS GRIMALDO ◽

...

Keyword(s):

Nitric Oxide ◽

Renal Function ◽

Urinary Excretion ◽

Kidney Function ◽

Normal Values ◽

Inhibitory Effect ◽

No Production ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Oxide Production

Abstract. In the hypothyroid kidney, exogenous adenosine (ADO) produces vasodilation and restores renal function to near-normal values. This study evaluates whether this response is mediated by nitric oxide synthesis stimulated by adenosine. GFR and urinary excretion of NO2-/NO3- (UNO2-/NO3-) were measured in normal (NL) and hypothyroid (HTX) rats under basal conditions and during infusion of: intra-aortic ADO, intravenously, 1,3-dipropyl-8p-sulfophenylxanthine (DPSPX), 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX), Nω-nitro-L-arginine methylester (L-NAME) + ADO, L-NAME + PSPX, L-NAME + DPCPX, and intrarenal (IR) ADO or DPCPX + IR ADO. Intra-aortic ADO induced a fall in GFR and increased UNO2-/NO3- slightly in NL rats; in HTX rats, both GFR and UNO2-/NO3- increased significantly. DPSPX and DPCPX increased UNO2-/NO3- excretion in NL animals with minor changes in GFR; the blockers increased both GFR and UNO2-/NO3- in HTX rats. L-NAME completely blocked the increase in NO2-/NO3- induced by ADO, DPSPX, and DPCPX. The intrarenal infusion of ADO at 1, 10, and 35 nmol/kg per min progressively decreased GFR with a slight increase in UNO2-/NO3- in NL rats; in the HTX, GFR increased with the highest dose and UNO2-/NO3- progressively increased. DPCPX prevented the fall in GFR induced by intrarenal ADO in NL rats, with no further changes in UNO2-/NO3-; in HTX rats, intrarenal ADO under A1 blockade further increased GFR and UNO2-/NO3-. Arterial and venous ADO concentrations were lower in the HTX rats. In the HTX kidney, NO production was stimulated by ADO, most likely through activation of A2 or A3 receptors, whereas A1 receptors had an inhibitory effect. Thus, ADO receptors are involved in the regulation of kidney function in pathophysiologic conditions.

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Thiopental inhibits nitric oxide production in rat aorta

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-103 ◽

1999 ◽

Vol 77 (12) ◽

pp. 958-966 ◽

Cited By ~ 11

Author(s):

Carlos Castillo ◽

Juan Asbun ◽

Bruno Escalante ◽

Carlos M Villalón ◽

Pedro López ◽

...

Keyword(s):

Nitric Oxide ◽

Inhibitory Effect ◽

Rat Aorta ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Oxide Production ◽

Nitrite Production ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Endothelium Dependent Relaxation

We studied whether thiopental affects endothelial nitric oxide dependent vasodilator responses and nitrite production (an indicator of nitric oxide production) elicited by acetylcholine, histamine, and A23187 in rat aorta (artery in which nitric oxide is the main endothelial relaxant factor). In addition, we evaluated the barbiturate effect on nitric oxide synthase (NOS) activity in both rat aorta and kidney homogenates. Thiopental (10-100 µg/mL) reversibly inhibited the endothelium-dependent relaxation elicited by acetylcholine, histamine, and A23187. On the contrary, this anesthetic did not modify the endothelium-independent but cGMP-dependent relaxation elicited by sodium nitroprusside (1 nM - 1 µM) and nitroglycerin (1 nM - 1 µM), thus excluding an effect of thiopental on guanylate cyclase of vascular smooth muscle. Thiopental (100 µg/mL) inhibited both basal (87.8 ± 14.3%) and acetylcholine- or A23187-stimulated (78.6 ± 3.9 and 39.7 ± 5.6%, respectively) production of nitrites in aortic rings. In addition the barbiturate inhibited (100 µg/mL) the NOS (45 ± 4 and 42.8 ± 9%) in aortic and kidney homogenates, respectively (measured as 14C-labeled citrulline production). In conclusion, thiopental inhibition of endothelium-dependent relaxation and nitrite production in aortic rings strongly suggests an inhibitory effect on NOS. Thiopental inhibition of the NOS provides further support to this contention.Key words: thiopental, rat aorta, endothelium-dependent relaxation, nitric oxide synthesis.

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Dietary L-citrulline supplementation modulates nitric oxide synthesis and anti-oxidant status of laying hens during summer season

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-020-00507-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Victoria A. Uyanga ◽

Hongchao Jiao ◽

Jingpeng Zhao ◽

Xiaojuan Wang ◽

Hai Lin

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Laying Hens ◽

Shape Index ◽

Summer Season ◽

Production Performance ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Oxide Production ◽

Anti Oxidant

Abstract Background L-citrulline (L-Cit), a non-protein amino acid, has been implicated in several physiological functions including anti-inflammatory, anti-oxidative, and hypothermic roles, however, there is a paucity of information with regards to its potential in poultry production. Methods This study was designed to investigate the effects of dietary L-Cit supplementation on the production performance, nitric oxide production, and antioxidant status of laying hens during summer period. Hy-Line Brown laying hens (n = 288, 34 weeks old) were allotted to four treatment, 6 replicates of 12 chickens each. Dietary treatments of control (basal diets), 0.25%, 0.50% and 1.00% L-Cit supplementation were fed to chickens for eight (8) weeks. Production performance, free amino acid profiles, nitric oxide production, and antioxidant properties were measured. Blood samples were collected at the 4th and 8th weeks of the experiment. Results Air temperature monitoring indicated an average daily minimum and maximum temperatures of 25.02 °C and 31.01 °C respectively. Dietary supplementation with L-Cit did not influence (P > 0.05) the production performance, and rectal temperature of laying hens. Egg shape index was increased (P < 0.05) with increasing levels of L-Cit. Serum-free content of arginine, citrulline, ornithine, tryptophan, histidine, GABA, and cystathionine were elevated, but taurine declined with L-Cit diets. Plasma nitric oxide (NOx) concentration was highest at 1% L-Cit. Likewise, nitric oxide synthase (NOS) activity for total NOS (tNOS) and inducible NOS (iNOS) were upregulated with increasing L-Cit levels, although, tNOS was not affected at the 4th week. Anti-oxidant enzymes including catalase and superoxide dismutase (SOD) were increased with L-Cit supplementation, however, SOD activity was unchanged at 4th week, while total anti-oxidant capacity increased at the 8th week. L-Cit supplementation attenuated the extent of lipid peroxidation, and also inhibited glutathione peroxidase activity. Conclusion Dietary L-Cit supplementation modulated systemic arginine metabolism, nitric oxide synthesis, antioxidant defense system, and increased the egg shape index of laying hens during the summer season. 1% L-Cit supplementation proved most effective in potentiating these effects and may be adopted for feed formulation strategies.

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Dietary L-Citrulline supplementation modulates nitric oxide synthesis and anti-oxidant status of laying hens during summer season

10.21203/rs.3.rs-22779/v1 ◽

2020 ◽

Author(s):

VICTORIA ANTHONY UYANGA ◽

Hongchao Jiao ◽

Jingpeng Zhao ◽

Xiaojuan Wang ◽

Hai Lin

Keyword(s):

Nitric Oxide ◽

Laying Hens ◽

Egg Quality ◽

Summer Season ◽

Production Performance ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Oxide Production ◽

Anti Oxidant ◽

Oxidant Status

Abstract Background L-Citrulline (L-Cit), a non-protein amino acid, has been implicated in several physiological functions including anti-inflammatory, anti-oxidative, and hypothermic roles, however, there is paucity of information with regards to its potential in poultry production. This study was designed to investigate the effects of dietary L-Cit supplementation on the production performance, nitric oxide production and anti-oxidant status of laying hens during summer periods. Hy-line laying hens (n = 288, 34 weeks old) were allotted to four treatment with 6 replicates of 12 chickens each. Dietary treatments of control (basal diets), 0.25%, 0.50% and 1.00% L-Cit supplementation were fed to chickens for eight (8) weeks. Production performance, egg quality characteristics, nitric oxide production and antioxidant properties were measured. Blood samples were collected at 4th and 8th weeks of experiment. Results Air temperature monitoring indicated average minimum and maximum recordings of 25.02 0C and 31.01 0C respectively. Dietary supplementation with L-Cit did not significantly (P > 0.05) influence the production performance, plasma biochemistry and rectal temperatures of laying hens. Egg shape index was increased with L-Cit diet, similarly, albumen heights and Haugh units also tended (P < 0.10) to improve with higher L-Cit supplementation. Plasma nitric oxide (NOx) concentration was observed to increase with highest contents at 1% L-Cit supplementation. Likewise, nitric oxide synthase (NOS) enzyme activity for both total NOS (tNOS) and inducible NOS (iNOS) were upregulated with increasing L-Cit levels, although, tNOS was not affected at week 4. Anti-oxidant enzymes including catalase and superoxide dismutase (SOD) were increased with L-Cit supplementation, however, SOD activity was unchanged at week 4. Total anti-oxidant capacity increased with L-Cit groups at week 8. L-Cit supplementation attenuated the extent of lipid peroxidation measured by malondialdehyde levels, and also inhibited glutathione peroxidase activity. Conclusion Dietary L-Cit supplementation enhanced nitric oxide synthesis, promoted antioxidant defense systems, and tended to improve internal egg quality traits of laying hens during summer season. 1% L-Cit supplementation proved most effective in enhancing both nitric oxide production and anti-oxidant defenses.

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Dietary L-citrulline supplementation modulates nitric oxide synthesis and anti-oxidant status of laying hens during summer season

10.21203/rs.3.rs-22779/v2 ◽

2020 ◽

Author(s):

VICTORIA ANTHONY UYANGA ◽

Hongchao Jiao ◽

Jingpeng Zhao ◽

Xiaojuan Wang ◽

Hai Lin

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Laying Hens ◽

Shape Index ◽

Summer Season ◽

Production Performance ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Oxide Production ◽

Anti Oxidant

Abstract Background: L-citrulline (L-Cit), a non-protein amino acid, has been implicated in several physiological functions including anti-inflammatory, anti-oxidative, and hypothermic roles, however, there is a paucity of information with regards to its potential in poultry production. This study was designed to investigate the effects of dietary L-Cit supplementation on the production performance, nitric oxide production, and antioxidant status of laying hens during summer period. Hy-Line Brown laying hens (n=288, 34 weeks old) were allotted to four treatment, 6 replicates of 12 chickens each. Dietary treatments of control (basal diets), 0.25%, 0.50 % and 1.00 % L-Cit supplementation were fed to chickens for eight (8) weeks. Production performance, free amino acid profiles, nitric oxide production, and antioxidant properties were measured. Blood samples were collected at the 4th and 8th weeks of the experiment. Results: Air temperature monitoring indicated an average daily minimum and maximum temperatures of 25.02 oC and 31.01 oC respectively. Dietary supplementation with L-Cit did not influence (P > 0.05) the production performance, and rectal temperature of laying hens. Egg shape index was increased (P < 0.05) with increasing levels of L-Cit. Serum-free content of arginine, citrulline, ornithine, tryptophan, histidine, GABA, and cystathionine were elevated, but taurine declined with L-Cit diets. Plasma nitric oxide (NOx) concentration was highest at 1% L-Cit. Likewise, nitric oxide synthase (NOS) activity for total NOS (tNOS) and inducible NOS (iNOS) were upregulated with increasing L-Cit levels, although, tNOS was not affected at the 4th week. Anti-oxidant enzymes including catalase and superoxide dismutase (SOD) were increased with L-Cit supplementation, however, SOD activity was unchanged at 4th week, while total anti-oxidant capacity increased at the 8th week. L-Cit supplementation attenuated the extent of lipid peroxidation, and also inhibited glutathione peroxidase activity. Conclusion: Dietary L-Cit supplementation modulated systemic arginine metabolism, nitric oxide synthesis, antioxidant defense system, and increased the egg shape index of laying hens during the summer season. 1% L-Cit supplementation proved most effective in potentiating these effects and may be adopted for feed formulation strategies.

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Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.5.2078 ◽

1996 ◽

Vol 81 (5) ◽

pp. 2078-2087 ◽

Cited By ~ 42

Author(s):

Candice D. Fike ◽

Mark R. Kaplowitz

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Chronic Hypoxia ◽

Nitric Oxide Production ◽

Nitric Oxide Synthesis ◽

Synthesis Inhibitor ◽

Vascular Responses ◽

Oxide Production ◽

Newborn Pigs ◽

Isolated Lungs

Fike, Candice D., and Mark R. Kaplowitz. Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs. J. Appl. Physiol. 81(5): 2078–2087, 1996.—Almost all of the studies evaluating the effect of chronic hypoxia on lung nitric oxide production have been performed in adult animals. Because results of studies in adult lungs should not be extrapolated to represent the newborn lung, we performed studies to determine whether decreased nitric oxide production might be involved in the pathogenesis of chronic hypoxia-induced pulmonary hypertension in newborns. We kept newborn pigs in chambers filled with room air (control) or 11–12% O2 for either 3–5 (short) or 10–12 (long) days. Using isolated lungs, we measured pulmonary vascular responses to agents that either stimulate or inhibit the synthesis of nitric oxide. To define the vascular sites of altered production of nitric oxide, we applied the micropuncture technique and measured small venular pressures before and after treatment with a nitric oxide synthesis inhibitor. Pulmonary vascular responses to acetylcholine were blunted in chronically hypoxic piglets of both the short and long groups. The nitric oxide synthesis inhibitor had a different effect in the lungs of control piglets than in those of chronically hypoxic piglets of the long but not of the short group. For the long group, the nitric oxide synthesis inhibitors caused constriction of both arteries and veins in lungs of control but not of chronically hypoxic piglets. These findings support the idea that decreased pulmonary vascular nitric oxide production occurs with chronic hypoxia in newborn pigs and might therefore contribute to the pathogenesis of pulmonary hypertension in newborns.

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