The Utilization of a Nitric Oxide Generating Serum for Improving Vascularity in Wound Healing

Introduction: Poor vascularity in injured or operated tissue predisposes the patient to poor healing. Many disease states such as diabetes mellitus, atherosclerosis, and Raynaud’s Disease exhibit delayed or compromised healing. Post-radiated tissue is another example of poor healing potential. Any surgical wound, local, regional, or free flap reconstruction, can see delayed healing or lack of healing with poor blood supply. Nitric oxide (NO) is an endothelial cell, endogenously produced, free radical gas. It is a potent vasodilator and inhibitor of platelet aggregation. A NO producing serum has recently been developed (Pneuma Nitric Oxide, Austin Texas). This is the first study to examine the potential efficacy of a NO generating serum in the wound healing population. Objective: The objective of this study is to examine the potential efficacy of a Nitric oxide generating serum in the wound healing patient population Method: Twenty-five patients were studied in two centers between December 2018 and June 2020. Prior to utilizing NO serum, a double-blind, placebo controlled (glycerin) safety study was performed on 10 patients. There were no allergic or irritation reactions to NO serum in this population. NO serum was applied to non-healing diabetic ulcers, vascular compromised non-healing wounds, surgical incisions, split thickness grafts, full thickness grafts, regional and free flaps. Patients were followed weekly and photographed regularly to monitor healing until total healing was reached. Results: Without exception, the study population showed a more rapid and improved quality of healing in the wounds that were treated with Nitric oxide generating serum as compared to control sites. Rapid reepithelialization, wound contraction, less bruising and edema were commonly seen. Neo-vascularization was more rapid in surgical flap cases. Burn wounds healed dramatically. Conclusion: This study shows the benefits of a Nitric oxide- generating serum in the wound healing patient population. The vasodilatory and capillary recruitment capabilities of Nitric oxide are hypothesized as key factors leading to this improved healing. NO is also paramount in the differentiation and proliferation of fibroblasts, keratinocytes, monocytes, and macrophages. Topically, NO has also been shown in the literature to have strong anti-bacterial, anti-fungal, and anti-viral roles. NO serum is a valuable addition to the armamentarium of wound healing protocols.

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Nitric Oxide Therapy for Diabetic Wound Healing

Advanced Healthcare Materials ◽

10.1002/adhm.201801210 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1801210 ◽

Cited By ~ 26

Author(s):

Maggie J. Malone‐Povolny ◽

Sara E. Maloney ◽

Mark H. Schoenfisch

Keyword(s):

Nitric Oxide ◽

Wound Healing ◽

Diabetic Wound ◽

Diabetic Wound Healing ◽

Nitric Oxide Therapy

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Effects of L-citrulline supplementation on nitric oxide and antioxidant markers after high-intensity interval exercise in young men: a randomized controlled trial

British Journal Of Nutrition ◽

10.1017/s0007114521002178 ◽

2021 ◽

pp. 1-23

Author(s):

Kosar Valaei ◽

Javad Mehrabani ◽

Alexei Wong

Keyword(s):

Nitric Oxide ◽

High Intensity ◽

Controlled Trial ◽

Young Men ◽

No Production ◽

Double Blind ◽

Interval Exercise ◽

Damage Indices ◽

High Intensity Interval ◽

Antioxidant Markers

Abstract L-citrulline (L-Cit) is a nonessential amino acid that stimulates nitric oxide (NO) production and improves exercise performance by reducing muscle damage indices; however, the direct benefits of L-Cit on antioxidant markers are unclear. The aim of this study was to examine antioxidant responses to high-intensity interval exercise following acute L-Cit supplementation. Nine young men (21 ± 1 years) participated in a double-blind crossover study in which they received 12 g of L-Cit and placebo (PL) an hour prior to high-intensity interval exercise on two occasions, separated by a seven-day washout period. Blood samples were obtained before (PRE), immediately after (IP), 10 (10P), and 30 min after exercise (30P) from the cubital vein using standard procedures. Serum concentrations of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and NO metabolites (NOx) were measured. The exercise protocol significantly elevated SOD (p = 0.01) and GPx (p = 0.048) from PRE to 10P in the L-Cit group with greater changes than the PL group. CAT concentrations increased IP (p = 0.014) and remained elevated at 10P (p = 0.03) and 30P (p = 0.015) in both the L-Cit and PL conditions. NOx concentrations increased IP (p = 0.05) in the L-Cit group with greater changes than PL group in PRE to IP, PRE to 10P, and PRE to 30P (p < 0.05). Our data indicate that L-Cit supplementation (single 12 g dose pre-exercise) induces improvements in antioxidant markers following a session of high-intensity interval exercise in young men.

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Nitric oxide release in rat skeletal muscle capillary

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.5.h1696 ◽

1996 ◽

Vol 270 (5) ◽

pp. H1696-H1703 ◽

Cited By ~ 3

Author(s):

D. Mitchell ◽

K. Tyml

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Leukocyte Adhesion ◽

Microvascular Blood Flow ◽

Capillary Length ◽

Nitric Oxide Release ◽

Longus Muscle ◽

Potent Vasodilator ◽

Capillary Bed ◽

Synthase Inhibitor

Nitric oxide (NO) has been shown to be a potent vasodilator released from endothelial cells (EC) in large blood vessels, but NO release has not been examined in the capillary bed. Because the capillary bed represents the largest source of EC, it may be the largest source of vascular NO. In the present study, we used intravital microscopy to examine the effect of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on the microvasculature of the rat extensor digitorum longus muscle. L-NAME (30 mM) applied locally to a capillary (300 micron(s) from the feeding arteriole) reduced red blood cell (RBC) velocity [VRBC; control VRBC = 238 +/- 58 (SE) micron/s; delta VRBC = -76 +/- 8%] and RBC flux (4.4 +/- 0.7 to 2.8 +/- 0.7 RBC/s) significantly in the capillary, but did not change feeding arteriole diameter (Dcon = 6.3 +/- 0.7 micron, delta D = 5 +/- 7%) or draining venule diameter (Dcon = 10.1 +/- 0.6 micron, delta D = 4 +/- 2%). Because of the VRBC change, the flux reduction was equivalent to an increased local hemoconcentration from 1.8 to 5 RBCs per 100 micron capillary length. L-NAME also caused an increase in the number of adhering leukocytes in the venule from 0.29 to 1.43 cells/100 micron. L-NAME (30 mM) applied either to arterioles or to venules did not change capillary VRBC. Bradykinin (BK) locally applied to the capillary caused significant increases in VRBC (delta VRBC = 111 +/- 23%) and in arteriolar diameter (delta D = 40 +/- 5%). This BK response was blocked by capillary pretreatment with 30 mM L-NAME (delta VRBC = -4 +/- 27%; delta D = 5 +/- 9% after BK). We concluded that NO may be released from capillary EC both basally and in response to the vasodilator BK. We hypothesize that 1) low basal levels of NO affect capillary blood flow by modulating local hemoconcentration and leukocyte adhesion, and 2) higher levels of NO (stimulated by BK) may cause a remote vasodilation to increase microvascular blood flow.

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Transdermal Nitroglycerine in the Management of Pain Associated with Primary Dysmenorrhoea: A Multinational Pilot Study

Journal of International Medical Research ◽

10.1177/030006059702500106 ◽

1997 ◽

Vol 25 (1) ◽

pp. 41-44 ◽

Cited By ~ 16

Author(s):

O Ré ◽

Keyword(s):

Nitric Oxide ◽

Pain Relief ◽

Muscle Relaxation ◽

Nitric Oxide Donor ◽

Controlled Study ◽

Smooth Muscle Relaxation ◽

Uterine Contractility ◽

Double Blind ◽

Patch Application ◽

Endogenous Nitric Oxide

Endogenous nitric oxide mediates smooth-muscle relaxation with subsequent vasodilatation in the vascular, pulmonary, gastrointestinal and genitourinary tissues. Transdermal nitroglycerine (a nitric oxide donor) has been found effective in inhibiting uterine contractility during premature labour. Sixty-five women with histories of moderate-to-severe pain associated with menses were treated with nitroglycerine patches that delivered 0.2 or 0.1 mg/h. Patches were applied as necessary during the first 3 days of the menstrual cycle for up to three consecutive cycles. Pain intensity was assessed at baseline and at 30 min and at 1, 2 and 4 h after patch application. Most patients obtained pain relief with the first dose of the first day. Pain relief was satisfactory to excellent in 90% of the patients. Headache was reported by 20% of the patients, most often in patients using two consecutive patches. A randomized, double-blind, placebo-controlled study is underway in an attempt to confirm the above findings.

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Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study

The Lancet ◽

10.1016/s0140-6736(00)02869-5 ◽

2000 ◽

Vol 356 (9240) ◽

pp. 1464-1469 ◽

Cited By ~ 150

Author(s):

Owen I Miller ◽

Swee Fong Tang ◽

Anthony Keech ◽

Nicholas B Pigott ◽

Elaine Beller ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Congenital Heart ◽

Heart Surgery ◽

Congenital Heart Surgery ◽

Inhaled Nitric Oxide ◽

Blind Study ◽

Double Blind Study ◽

Double Blind

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Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)36601-3 ◽

1992 ◽

Vol 267 (30) ◽

pp. 21277-21280 ◽

Cited By ~ 4

Author(s):

D.E. Heck ◽

D.L. Laskin ◽

C.R. Gardner ◽

J.D. Laskin

Keyword(s):

Nitric Oxide ◽

Hydrogen Peroxide ◽

Wound Healing ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Potential Role ◽

Hydrogen Peroxide Production ◽

Epidermal Growth

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Cellular Localization of Inducible Nitric Oxide Synthase in Experimental Endotoxic Shock in the Rat

Clinical Science ◽

10.1042/cs0870179 ◽

1994 ◽

Vol 87 (2) ◽

pp. 179-186 ◽

Cited By ~ 67

Author(s):

H. Terence Cook ◽

Alison J. Bune ◽

Albertine S. Jansen ◽

G. Michael Taylor ◽

Rashpal K. Loi ◽

...

Keyword(s):

Nitric Oxide ◽

In Situ Hybridization ◽

Cellular Localization ◽

Endotoxic Shock ◽

No Synthase ◽

Similar Distribution ◽

Mouse Macrophage ◽

Inducible No Synthase ◽

Monocytes And Macrophages

1. Endotoxin induces a shock-like syndrome with increased nitric oxide synthesis. To clarify the cellular source of NO in endotoxic shock we used immunohistochemistry and in situ hybridization to localize inducible NO synthase in rats given lipopolysaccharide or Corynebacterium parvum and lipopolysaccharide. Immunohistochemistry was carried out with an antibody raised against a synthetic peptide of mouse macrophage NO synthase. In situ hybridization was performed with 35S-labelled oligonucleotide probes corresponding to cDNA sequences common to mouse macrophage inducible NO synthase and rat vascular smooth inducible NO synthase. Monocytes and macrophages were identified by immunohistochemistry with the mouse monoclonal antibody ED1. 2. After lipopolysaccharide alone, the major site of NO synthase induction was monocytes and macrophages in multiple organs, principally liver and spleen. Bronchial, bile duct, intestinal and bladder epithelium and some hepatocytes also expressed inducible NO synthase. Expression peaked at 5 h and had returned to normal by 12 h except in spleen. 3. After priming with C. parvum, lipopolysaccharide led to a similar distribution of inducible NO synthase as lipopolysaccharide alone, but in addition there was more prominent hepatocyte staining, staining in macrophage granulomas in the liver and inducible NO synthase was present in some endothelial cells in the aorta. 4. These findings provide a direct demonstration of the cellular localization of inducible NO synthase after lipopolysaccharide.

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