Lyla
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- Mar 25, 2016
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I found following email response while reading about rosacea I would like to share. I only cut/pasted Dr Peat's response.
Cause for rosacea?
In major newspapers across the country they are saying scientists have found the cause of rosacea. For instance the Los Angeles Times, US News and World Report, the Washington Post, UCSD News and Medical News Today. The abstract is already published on PubMed.
Here is the Abstract
Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki, Anna Di Nardo, Antonella Bardan, Masamoto Murakami, Takaaki Ohtake, Alvin Coda1, Robert A Dorschner1, Chrystelle Bonnart, Pascal Descargues, Alain Hovnanian, Vera B Morhenn & Richard L Gallo
Nature Medicine, 5 August 2007 | doi:10.1038/nm1616; http://www.nature.com [type in rosacea in the search box]
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia1, 2, 3. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides4. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
1. Division of Dermatology, University of California, San Diego, and VA San Diego Health Care System, 3350 2. La Jolla Village Drive, San Diego, California 92161, USA.
3. Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan.
4. Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigacka Hidashi, Asahikawa 078-8510, Japan.
5. INSERM, U563, Toulouse F-31000, France.
UniversitÈ Paul-Sabatier, Toulouse F-31000, France.
6. CHU Toulouse, Department of Genetics, Place du Dr. Baylac, Toulouse F-31000, France.
David A Jones, MD 0[/paste:font]
Dr. Gallo has done some very interesting work in innate immunity, and this is no exception. Definitely warrants some follow-up and confirmatory studies. However, it's important not to confuse "associated finding" with "cause". There is no end to literature linking the latest inflammatory mediator with a clinical disease. They rarely hold up to the test of time as being truly significant.
-David Jones
Posted August 8, 2007
The following are replies by email to this topic:
___________________________________________
From: Raymond Peat, Ph.D
Subject: Re: RRDi MAC Members Question
Date: August 8, 2007 1:52:33 PM HST
To: [email protected]
Things that cause inflammation, such as bacterial endotoxin, stimulate the defensive formation of proteases and cathelicidin, so it doesn't seem productive to say that "too much" of those defensive proteins is the cause of rosacea. Isn't it a little like saying that pus is the cause of boils?
Nutritional deficiencies lead to excessive exposure to endotoxin and nitric oxide, and the associated factors that cause vascular leakiness, vasodilation, angiogenesis, stimulation of fibroblast growth and collagen production. Medical people who are willing to talk about the antiinflammatory action of antibiotics seem to be unaware of the antiinflammatory effects of many simple essential nutrients, such as niacinamide, riboflavin, and glycine, or of the natural antiinflammatory hormones that are consistently deficient in the inflammatory-"autoimmune" diseases.
Acta Anaesthesiol Scand. 2003 Feb;47(2):213-20.
Effects of human cathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro.
Ciornei CD, Egesten A, Bodelsson M.
Department of Anaesthesiology and Intensive Care, Lund University, Lund, Sweden.
BACKGROUND: Lipopolysaccharides (LPS), released by Gram-negative bacteria, cause
vascular expression of inducible nitric oxide synthase (iNOS) leading to nitric
oxide (NO) production and septic shock. Human cathelicidin antimicrobial peptide
(LL-37) can bind and neutralize LPS. We wanted to study whether LL-37 affects LPS
or interleukin-1beta (IL-1beta)-induced production, release and function of NO in
intact rat aorta rings and cultured rat aorta smooth muscle cells. METHODS:
Isolated segments of thoracic aorta and cultured cells were incubated in the
presence of LPS, LL-37, LPS + IL-37, IL-1beta, IL-1beta + IL-37 or in medium
alone. Smooth muscle contraction in response to phenylephrine and accumulation of
the sdegradation products of NO, nitrate and nitrite, were measured on aorta
segments. Levels of iNOS were assessed by Western blot and cytotoxic effects were
detected by measurement of DNA fragmentation in cultured cells. Number of viable
cells were determined after Trypan blue treatment. RESULTS: Both LPS and IL-1beta
reduced contractility in response to phenylephrine and increased NO production as
well as iNOS expression. LL-37 inhibited the LPS depression of vascular
contractility induced only by LPS. LL-37 reduced both the LPS- and
IL-1beta-induced NO production and iNOS expression. LL-37 at high concentrations
induced DNA fragmentation and decreased the number of living cells. CONCLUSION:
IL-37 reduces NO production induced by LPS and IL-1beta. The reduction does not
seem to result only from neutralization of LPS but also from a cytotoxic effect,
possibly via induction of apoptosis. Copyright Acta Anaesthesiologica
Scandinavica 47 (2003)
Infect Immun. 1995 Apr;63(4):1291-7.
Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein.
Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, Wright SC.
Palo Alto Institute of Molecular Medicine, Mountain View, California 94043.
CAP18 (18-kDa cationic antimicrobial protein) is a protein originally identified
and purified from rabbit leukocytes on the basis of its capacity to bind and
inhibit various activities of lipopolysaccharide (LPS). Here we report the
cloning of human CAP18 and characterize the anti-LPS activity of the C-terminal
fragment. Oligonucleotide probes designed from the rabbit CAP18 cDNA were used to
identify human CAP18 from a bone marrow cDNA library. The cDNA encodes a protein
composed of a 30-amino-acid signal peptide, a 103-amino-acid N-terminal domain of
unknown function, and a C-terminal domain of 37 amino acids homologous to the
LPS-binding antimicrobial domain of rabbit CAP18, designated CAP18(104-140). A
human CAP18-specific antiserum was generated by using CAP18 expressed as a fusion
protein with the maltose-binding protein. Western blots (immunoblots) with this
antiserum showed specific expression of human CAP18 in granulocytes. Synthetic
human CAP18(104-140) and a more active truncated fragment, CAP18(104-135), were
shown to (i) bind to erythrocytes coated with diverse strains of LPS, (ii)
inhibit LPS-induced release of nitric oxide from macrophages, (iii) inhibit
LPS-induced generation of tissue factor, and (iv) protect mice from LPS
lethality. CAP18(104-140) may have therapeutic utility for conditions associated
with elevated concentrations of LPS.
Life Sci. 2005 Nov 26;78(2):134-9. Epub 2005 Aug 19.
Inhibitory mechanisms of highly purified vitamin B2 on the productions of proinflammatory cytokine and NO in endotoxin-induced shock in mice.
Kodama K, Suzuki M, Toyosawa T, Araki S.
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki
300-2635, Japan. [email protected]
Inhibitory effects of highly purified vitamin B2 (riboflavin-5'-sodium phosphate,
>97%) on the interleukin (IL)-6, macrophage inflammatory protein (MIP)-2 and
nitric oxide (NO) in LPS-induced shock mice were evaluated. Vitamin B2 at 20
mg/kg (protective effect on mice mortality induced by LPS), intravenously
administered 6 h after LPS injection, significantly decreased the plasma elevated
levels of IL-6 and MIP-2 at 9 and 12 h. In addition, vitamin B2 lowered the
tissue concentration and the mRNA expression of IL-6 in lung and those of MIP-2
in liver at 9 h. Vitamin B2 also reduced concentration of MIP-2 concentration in
lung, and inhibited mRNA expression in kidney, respectively. Vitamin B2 decreased
the plasma elevated NO levels in accordance with a reduction in expression of
inducible NO synthase (iNOS) both at 21 and 24 h. Accordingly, the reduction in
elevated plasma cytokine levels and NO based on the inhibitory effect on local
cytokine mRNA expression and iNOS would be responsible for the anti-septic effect
of vitamin B2.
Eur J Pharmacol. 2004 May 25;492(2-3):273-80.
Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice.
Toyosawa T, Suzuki M, Kodama K, Araki S.
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki
300-2635, Japan.
We investigated the effect of an i.v. infusion of highly purified vitamin B(2)
(riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock
and bacterial infection in mice. Six hours after lipopolysaccharide injection or
1 h after bacterial infection, vitamin B(2) or human activated protein C (APC)
was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80
mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC
was also effective at low doses, but was deleterious at higher doses. Moreover,
vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia
coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h
was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of
proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These
results suggest that i.v. infusion of vitamin B(2) represents a promising
strategy for the treatment of sepsis and septic shock.
Eur J Pharmacol. 2004 May 10;492(1):35-40.
Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat.
Granados-Soto V, Ter·n-Rosales F, Rocha-Gonz·lez HI, Reyes-GarcÌa G,
Medina-Santill·n R, RodrÌguez-Silverio J, Flores-Murrieta FJ.
Departamento de FarmacobiologÌa, Centro de InvestigaciÛn y de Estudios Avanzados
del Instituto PolitÈcnico Nacional, Calzada Tenorios 235, Colonia Granjas Coapa,
14330 MÈxico, DF, Mexico. [email protected]
Vitamin B2 (riboflavin) has been proposed as a prophylactic therapy of migraine.
However, so far there are no preclinical studies about the analgesic properties
of this vitamin. The current study was designed to investigate the possible
antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in
formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation
models, respectively. Oral riboflavin produced a dose-related antinociceptive
(6.25-50 mg/kg), antihyperalgesic (25-150 mg/kg) and anti-inflammatory (50-150
mg/kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin
(150-600 mg/kg), reduced tactile allodynia in neuropathic rats.
Riboflavin-induced antinociception in the formalin test was reversed by
pretreatment with NG-L-nitro-arginine methyl ester and glibenclamide, but not by
NG-D-nitro-arginine methyl ester or naloxone. Our results indicate that
riboflavin is able to produce antinociception and anti-inflammatory, but not
antiallodynic, effect in the rat. The effect of riboflavin could be due to the
activation of K+ channels or nitric oxide release, but not activation of opioid
mechanisms.
J Biol Chem. 2000 Oct 13;275(41):31581-7.
Nitric-oxide dioxygenase activity and function of flavohemoglobins. sensitivity to nitric oxide and carbon monoxide inhibition.
Gardner PR, Gardner AM, Martin LA, Dou Y, Li T, Olson JS, Zhu H, Riggs AF.
Division of Critical Care Medicine, Children's Hospital Medical Center,
Cincinnati, Ohio 45229, USA.
Cause for rosacea?
In major newspapers across the country they are saying scientists have found the cause of rosacea. For instance the Los Angeles Times, US News and World Report, the Washington Post, UCSD News and Medical News Today. The abstract is already published on PubMed.
Here is the Abstract
Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki, Anna Di Nardo, Antonella Bardan, Masamoto Murakami, Takaaki Ohtake, Alvin Coda1, Robert A Dorschner1, Chrystelle Bonnart, Pascal Descargues, Alain Hovnanian, Vera B Morhenn & Richard L Gallo
Nature Medicine, 5 August 2007 | doi:10.1038/nm1616; http://www.nature.com [type in rosacea in the search box]
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia1, 2, 3. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides4. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
1. Division of Dermatology, University of California, San Diego, and VA San Diego Health Care System, 3350 2. La Jolla Village Drive, San Diego, California 92161, USA.
3. Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan.
4. Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigacka Hidashi, Asahikawa 078-8510, Japan.
5. INSERM, U563, Toulouse F-31000, France.
UniversitÈ Paul-Sabatier, Toulouse F-31000, France.
6. CHU Toulouse, Department of Genetics, Place du Dr. Baylac, Toulouse F-31000, France.
David A Jones, MD 0[/paste:font]
Dr. Gallo has done some very interesting work in innate immunity, and this is no exception. Definitely warrants some follow-up and confirmatory studies. However, it's important not to confuse "associated finding" with "cause". There is no end to literature linking the latest inflammatory mediator with a clinical disease. They rarely hold up to the test of time as being truly significant.
-David Jones
Posted August 8, 2007
The following are replies by email to this topic:
___________________________________________
From: Raymond Peat, Ph.D
Subject: Re: RRDi MAC Members Question
Date: August 8, 2007 1:52:33 PM HST
To: [email protected]
Things that cause inflammation, such as bacterial endotoxin, stimulate the defensive formation of proteases and cathelicidin, so it doesn't seem productive to say that "too much" of those defensive proteins is the cause of rosacea. Isn't it a little like saying that pus is the cause of boils?
Nutritional deficiencies lead to excessive exposure to endotoxin and nitric oxide, and the associated factors that cause vascular leakiness, vasodilation, angiogenesis, stimulation of fibroblast growth and collagen production. Medical people who are willing to talk about the antiinflammatory action of antibiotics seem to be unaware of the antiinflammatory effects of many simple essential nutrients, such as niacinamide, riboflavin, and glycine, or of the natural antiinflammatory hormones that are consistently deficient in the inflammatory-"autoimmune" diseases.
Acta Anaesthesiol Scand. 2003 Feb;47(2):213-20.
Effects of human cathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro.
Ciornei CD, Egesten A, Bodelsson M.
Department of Anaesthesiology and Intensive Care, Lund University, Lund, Sweden.
BACKGROUND: Lipopolysaccharides (LPS), released by Gram-negative bacteria, cause
vascular expression of inducible nitric oxide synthase (iNOS) leading to nitric
oxide (NO) production and septic shock. Human cathelicidin antimicrobial peptide
(LL-37) can bind and neutralize LPS. We wanted to study whether LL-37 affects LPS
or interleukin-1beta (IL-1beta)-induced production, release and function of NO in
intact rat aorta rings and cultured rat aorta smooth muscle cells. METHODS:
Isolated segments of thoracic aorta and cultured cells were incubated in the
presence of LPS, LL-37, LPS + IL-37, IL-1beta, IL-1beta + IL-37 or in medium
alone. Smooth muscle contraction in response to phenylephrine and accumulation of
the sdegradation products of NO, nitrate and nitrite, were measured on aorta
segments. Levels of iNOS were assessed by Western blot and cytotoxic effects were
detected by measurement of DNA fragmentation in cultured cells. Number of viable
cells were determined after Trypan blue treatment. RESULTS: Both LPS and IL-1beta
reduced contractility in response to phenylephrine and increased NO production as
well as iNOS expression. LL-37 inhibited the LPS depression of vascular
contractility induced only by LPS. LL-37 reduced both the LPS- and
IL-1beta-induced NO production and iNOS expression. LL-37 at high concentrations
induced DNA fragmentation and decreased the number of living cells. CONCLUSION:
IL-37 reduces NO production induced by LPS and IL-1beta. The reduction does not
seem to result only from neutralization of LPS but also from a cytotoxic effect,
possibly via induction of apoptosis. Copyright Acta Anaesthesiologica
Scandinavica 47 (2003)
Infect Immun. 1995 Apr;63(4):1291-7.
Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein.
Larrick JW, Hirata M, Balint RF, Lee J, Zhong J, Wright SC.
Palo Alto Institute of Molecular Medicine, Mountain View, California 94043.
CAP18 (18-kDa cationic antimicrobial protein) is a protein originally identified
and purified from rabbit leukocytes on the basis of its capacity to bind and
inhibit various activities of lipopolysaccharide (LPS). Here we report the
cloning of human CAP18 and characterize the anti-LPS activity of the C-terminal
fragment. Oligonucleotide probes designed from the rabbit CAP18 cDNA were used to
identify human CAP18 from a bone marrow cDNA library. The cDNA encodes a protein
composed of a 30-amino-acid signal peptide, a 103-amino-acid N-terminal domain of
unknown function, and a C-terminal domain of 37 amino acids homologous to the
LPS-binding antimicrobial domain of rabbit CAP18, designated CAP18(104-140). A
human CAP18-specific antiserum was generated by using CAP18 expressed as a fusion
protein with the maltose-binding protein. Western blots (immunoblots) with this
antiserum showed specific expression of human CAP18 in granulocytes. Synthetic
human CAP18(104-140) and a more active truncated fragment, CAP18(104-135), were
shown to (i) bind to erythrocytes coated with diverse strains of LPS, (ii)
inhibit LPS-induced release of nitric oxide from macrophages, (iii) inhibit
LPS-induced generation of tissue factor, and (iv) protect mice from LPS
lethality. CAP18(104-140) may have therapeutic utility for conditions associated
with elevated concentrations of LPS.
Life Sci. 2005 Nov 26;78(2):134-9. Epub 2005 Aug 19.
Inhibitory mechanisms of highly purified vitamin B2 on the productions of proinflammatory cytokine and NO in endotoxin-induced shock in mice.
Kodama K, Suzuki M, Toyosawa T, Araki S.
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki
300-2635, Japan. [email protected]
Inhibitory effects of highly purified vitamin B2 (riboflavin-5'-sodium phosphate,
>97%) on the interleukin (IL)-6, macrophage inflammatory protein (MIP)-2 and
nitric oxide (NO) in LPS-induced shock mice were evaluated. Vitamin B2 at 20
mg/kg (protective effect on mice mortality induced by LPS), intravenously
administered 6 h after LPS injection, significantly decreased the plasma elevated
levels of IL-6 and MIP-2 at 9 and 12 h. In addition, vitamin B2 lowered the
tissue concentration and the mRNA expression of IL-6 in lung and those of MIP-2
in liver at 9 h. Vitamin B2 also reduced concentration of MIP-2 concentration in
lung, and inhibited mRNA expression in kidney, respectively. Vitamin B2 decreased
the plasma elevated NO levels in accordance with a reduction in expression of
inducible NO synthase (iNOS) both at 21 and 24 h. Accordingly, the reduction in
elevated plasma cytokine levels and NO based on the inhibitory effect on local
cytokine mRNA expression and iNOS would be responsible for the anti-septic effect
of vitamin B2.
Eur J Pharmacol. 2004 May 25;492(2-3):273-80.
Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice.
Toyosawa T, Suzuki M, Kodama K, Araki S.
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki
300-2635, Japan.
We investigated the effect of an i.v. infusion of highly purified vitamin B(2)
(riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock
and bacterial infection in mice. Six hours after lipopolysaccharide injection or
1 h after bacterial infection, vitamin B(2) or human activated protein C (APC)
was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80
mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC
was also effective at low doses, but was deleterious at higher doses. Moreover,
vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia
coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h
was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of
proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These
results suggest that i.v. infusion of vitamin B(2) represents a promising
strategy for the treatment of sepsis and septic shock.
Eur J Pharmacol. 2004 May 10;492(1):35-40.
Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat.
Granados-Soto V, Ter·n-Rosales F, Rocha-Gonz·lez HI, Reyes-GarcÌa G,
Medina-Santill·n R, RodrÌguez-Silverio J, Flores-Murrieta FJ.
Departamento de FarmacobiologÌa, Centro de InvestigaciÛn y de Estudios Avanzados
del Instituto PolitÈcnico Nacional, Calzada Tenorios 235, Colonia Granjas Coapa,
14330 MÈxico, DF, Mexico. [email protected]
Vitamin B2 (riboflavin) has been proposed as a prophylactic therapy of migraine.
However, so far there are no preclinical studies about the analgesic properties
of this vitamin. The current study was designed to investigate the possible
antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in
formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation
models, respectively. Oral riboflavin produced a dose-related antinociceptive
(6.25-50 mg/kg), antihyperalgesic (25-150 mg/kg) and anti-inflammatory (50-150
mg/kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin
(150-600 mg/kg), reduced tactile allodynia in neuropathic rats.
Riboflavin-induced antinociception in the formalin test was reversed by
pretreatment with NG-L-nitro-arginine methyl ester and glibenclamide, but not by
NG-D-nitro-arginine methyl ester or naloxone. Our results indicate that
riboflavin is able to produce antinociception and anti-inflammatory, but not
antiallodynic, effect in the rat. The effect of riboflavin could be due to the
activation of K+ channels or nitric oxide release, but not activation of opioid
mechanisms.
J Biol Chem. 2000 Oct 13;275(41):31581-7.
Nitric-oxide dioxygenase activity and function of flavohemoglobins. sensitivity to nitric oxide and carbon monoxide inhibition.
Gardner PR, Gardner AM, Martin LA, Dou Y, Li T, Olson JS, Zhu H, Riggs AF.
Division of Critical Care Medicine, Children's Hospital Medical Center,
Cincinnati, Ohio 45229, USA.
