drnase
5th July 2005, 04:36 AM
We have been waiting too long for nitric oxide inhibitors. A pharmaceutical company is finally in phase Ic to treat rosacea with an oral pill that blocks iNOS (inducible Nitric Oxide Synathase)!!!! It is still a ways off, but it has already shown great efficacy in two pre-clinical studies. If you dont know anything about nitric oxide, I took this from my book:
Two of the most exciting flushing therapies include: (1) Blocking the production of nitric oxide (a potent dilator released from facial blood vessels and nearby cells), and (2) Blocking the action of dilator nerves supplying facial blood vessels.
NITRIC OXIDE INHIBITORS
Nitric oxide is a powerful dilator substance that is produced by enzymes located in and around skin blood vessels (nitric oxide synthase enzymes). Clinical studies demonstrate that nitric oxide is intimately involved in many inflammatory skin disorders including rosacea, psoriasis, atopic dermatitis, irritant dermatitis, and allergic dermatitis. (1-9)
In the facial skin, nitric oxide is produced from:
• The inner wall of blood vessels
• Epidermal and dermal cells
• Dilator nerves around blood vessels
After nitric oxide is produced from these cells it diffuses to nearby blood vessels and binds to receptors on vascular smooth muscle cells causing potent dilation and substantial increases in blood flow. Topical medications that block nitric oxide production hold the potential to reduce rosacea redness and inhibit many forms of facial flushing.
Nitric Oxide’s Role in Facial Flushing and
Rosacea Progression
There is considerable speculation that nitric oxide plays an important role in facial flushing and rosacea progression. (1-3) Below are a few medical descriptions on this important topic:
• In a superb medical article in the Archives of Dermatology (1996), Drs. Qureshi and colleagues, from Massachusetts General Hospital, USA, speculate that nitric oxide may be involved in the pathogenesis of facial redness, facial flushing, and rosacea. (1) They state, “Whatever the cause for erythema in the skin, whether excessive sun exposure or an inflammatory process, the final mediator may be nitric oxide. Inhibitors of nitric oxide production may thus provide a valuable mode of therapy to relieve symptoms of flushing and erythema in the skin.” These medical experts also pose the ultimate question, “Could the erythema that is so difficult to treat in patients with rosacea be reversed with nitric oxide synthase inhibitors?”
• In the medical article, “Nitric Oxide and its Implications in Skin Homeostasis and Disease: A Review”, Drs. Bruch-Gerharz and colleagues discuss the therapeutic actions of topical nitric oxide inhibitors. (3) They suggest that rosacea may be one of the most important targets for nitric oxide inhibitor therapy. They further state that topical nitric oxide inhibitors, “May be available in the near future.”
• In a recent clinical study in the Journal of Investigative Dermatology (1997), titled, “Influence of NO-Synthase Antagonists in Rosacea Patients”, Dr. Sauermann and colleagues detailed their findings on the effect of topical nitric oxide inhibitor therapy on rosacea patients. (2) They found that treatment with a topical nitric oxide inhibitor (1% L-NAME cream, 2 times daily for 3 weeks), resulted in significant improvement of vascular symptoms in all rosacea patients. These findings are very exciting, indicating the great potential for topical nitric oxide inhibitors in the treatment of rosacea.
Nitric oxide’s Role in Inflammatory
Skin Disorders
Numerous clinical studies demonstrate that nitric oxide also plays an important role in other inflammatory skin disorders. These studies indicate that nitric oxide is one of the key mediators of skin flushing and inflammation. (3-7, 10, 11)
• In a recent medical article in the Journal of Investigative Dermatology (1999), Drs. Ormerod and colleagues demonstrated that nitric oxide can cause significant flushing and inflammation in human skin. (4) They indicate that their results are consistent with other studies demonstrating that increased nitric oxide production is involved in psoriasis, atopic dermatitis, irritant dermatitis, allergic dermatitis, lupus erythematous, sunburn-induced flushing, nerve-mediated flushing, and skin swelling. They conclude that topical nitric oxide inhibitors may be of therapeutic use in many forms of skin inflammation.
• In a recent controlled clinical study in the International Journal of Dermatology (1995), titled, “Clinical Application of Nitric Oxide Synthase Inhibitor for Atopic Dermatitis”, Dr. Morita and colleagues detailed their preliminary findings on the effect of a topical nitric oxide inhibitor in 15 patients with an inflammatory skin disorder. (7) They found that treatment with a topical nitric oxide inhibitor (1% NLA cream, 2 times daily for 4 weeks), resulted in significant improvement in skin redness in 66% of the cases, and reduced uncomfortable skin sensations in 80% of the patients. No side effects were noted in any patients.
• In a superb clinical study on patients with atopic and allergic dermatitis, Dr. Rowe and colleagues demonstrated that nitric oxide synthase was abnormally high in areas of inflamed skin. (5) The greatest areas of nitric oxide synthase expression were in the walls of blood vessels and immediately outside the vessels. These investigators concluded that increased nitric oxide production could be central to skin flushing and inflammation in these disorders.
• In a controlled clinical study on patients with psoriasis, nitric oxide production was abnormally high in all areas of skin redness; in fact, it was up to 10 times higher than that found in normal human skin. (6)
• In a recent clinical study, medical researchers irritated the skin of humans with a soap detergent (sodium lauryl sulphate), and then measured nitric oxide synthase expression. (12) Skin biopsies taken from the subjects showed dramatic increases in nitric oxide synthase expression in all areas of skin irritation. These medical researchers indicated that increased nitric oxide production under these conditions was responsible for the irritant reaction. They concluded that topical nitric oxide inhibitors might block skin flushing associated with irritant and contact dermatitis.
Nitric Oxide’s Role in Skin Flushing
Nitric oxide is intimately involved in many forms of skin flushing because it is produced in great concentrations from the inner wall of skin blood vessels. Nitric oxide is produced continuously to ensure adequate blood flow to the skin, and can be generated in response to a wide variety of stimuli such as chronic skin inflammation, blood vessel damage, increased blood flow conditions, external warming of the skin, environmental insults, internal body overheating, exercise, skin irritation, sunlight, nerve activation, hormones, stress, and in response to dozens of normally produced substances within the body. These findings strongly suggest that even though rosacea sufferers may have different underlying triggers for facial redness, flushing, and rosacea progression, nitric oxide may be one of the key final mediators in causing the vascular response. Below are some important findings on this subject:
1. Nitric oxide is continuously produced from the inner wall of blood vessels in the skin: During resting conditions, the inside of the blood vessel wall continuously produces low levels of this potent dilator to ensure adequate blood flow. (13) Two superb studies have recently demonstrated the importance of nitric oxide in regulating resting blood flow:
• In the clinical study, “Role of Nitric Oxide in the Regulation of Microvascular Perfusion in Human Skin In Vivo”, Dr. Clough determined the role that nitric oxide played in resting blood flow in normal human skin. (14) She found that local inhibition of nitric oxide activity (intradermal injection of L-NAME) caused significant constriction of skin blood vessels, and decreased blood flux by an average of 41%!
• In the clinical study, “Inhibitors of Nitric Oxide Synthase in Human Skin”, Drs. Goldsmith and colleagues found that local inhibition of nitric oxide activity (intradermal injection of L-NAME) caused potent constriction of normal skin blood vessels, and significantly decreased blood flow through these vessels. (8)
These studies are of great relevance to rosacea sufferers. If topical nitric oxide inhibitors can constrict blood vessels and decrease skin blood flow in normal human subjects, then the effects could be dramatic in rosacea sufferers who have dilated, inflamed blood vessels. These studies indicate the great potential for topical nitric oxide inhibitors in reducing chronic facial redness, inflammation, and telangiectasia.
2. Nitric oxide production is enhanced every time there is an increase in blood flow through the facial skin: This is one of the most exciting aspects of nitric oxide physiology. Every time that blood flow is enhanced through skin blood vessels the inside of the blood vessel wall ‘senses’ the increased shear force across it this triggers local production of nitric oxide causing even greater blood flow. (13, 15-18) Let me stress this point. No matter what the flushing trigger is (i.e., food, beverages, heat, exercise, stress, skincare products, neural triggers, environmental insults, overheating, embarrassment, etc.), every time that a flush occurs facial blood vessels ‘sense’ this increase in blood flow this triggers increased production of nitric oxide from the wall of the blood vessel significantly increasing the intensity and duration of facial flushing. Therefore, nitric oxide inhibitors could significantly reduce the frequency, intensity, and duration of most forms of facial flushing.
3. Nitric oxide production is enhanced in areas of skin that experience chronic increases in blood flow: Over time, chronically increased skin blood flow can enhance nitric oxide production in two ways: (1) It can increase the number of enzymes that produce nitric oxide, and (2) It can increase the sensitivity of nitric oxide release from these blood vessels. (17, 19-22) Both of these changes can make facial flushing more frequent and intense. These findings are important because most rosacea sufferers experience chronic increases in facial blood flow.
4. Nitric oxide production is enhanced in areas of skin where physical damage has occurred to blood vessels: In vascular disorders where there is physical damage to the blood vessel wall, nitric oxide production from the damaged vessel is greatly increased, resulting in substantial dilation. (21-23) These findings are clearly relevant to rosacea sufferers because most sufferers incur extensive structural damage to their facial blood vessels.
5. Nitric oxide production is increased during exposure to external heat (local warming of the skin): In a recent clinical study, “Role of Nitric Oxide in the Vascular Effects of Local Warming of the Skin in Humans”, Dr. Dean Kellogg and colleagues demonstrated that nitric oxide was a key mediator of skin flushing to local heating. (24) In this study, they warmed small areas of human skin and demonstrated that they could block most of the heat-induced skin flushing by local nitric oxide blockade (intradermal injection of L-NAME). Consistent with these findings, a study by Dr. Goldsmith and colleagues, “Inhibitors of Nitric Oxide Synthase in Human Skin”, also demonstrated that nitric oxide inhibitors could significantly reduce skin flushing to local warming. (8) These findings are very exciting because many rosacea sufferers report uncontrollable facial flushing to warm environments.
6. Nitric oxide production is enhanced during body overheating (i.e., increased internal body temperature): In a recent clinical study, “Nitric Oxide and Cutaneous Active Vasodilation during Heat Stress in Humans”, Dr. Dean Kellogg and colleagues demonstrated that nitric oxide is a key mediator of skin flushing during body heating. (25) Consistent with this, a second study found that increased internal body temperature triggers nitric oxide-mediated skin flushing. (26) A third study demonstrated that thermoregulatory shunt vessels of the human skin produce significant concentrations of nitric oxide, and that blockade of nitric oxide from these vessels caused a significant decrease in blood flow (33% decrease in red cell flux). (27) Taken together, these findings indicate that nitric oxide inhibitors can reduce skin flushing to internal body heating, one of the most powerful triggers for rosacea flushing.
7. Nitric oxide production is augmented during exercise: Multiple studies indicate that nitric oxide is a key mediator of exercise-induced skin flushing. (26, 28) Although the body response to exercise is quite complex, nitric oxide inhibitors could greatly reduce the intensity and duration of facial flushing to exercise.
8. Nitric oxide production is increased in areas of skin irritation (i.e., irritant or allergic dermatitis): Very recently, several human clinical studies have shown that nitric oxide is intimately involved in irritant and allergic dermatitis. (10-12) These findings are important to rosacea sufferers who experience facial flushing to topical skincare products. Is it possible that nitric oxide inhibitors could allow rosacea sufferers to use normal skincare products again?
9. Nitric oxide production is augmented in areas of skin that are exposed to sunlight (UV radiation): In a clinical study, “Inhibitors of Nitric Oxide Synthase in Human Skin”, Dr. Goldsmith and colleagues demonstrated that nitric oxide inhibition significantly decreased UVB-induced skin flushing. (8) These researchers also demonstrated that this effect was long lasting (blood flow was reduced for over 24 hours). This could be very helpful to rosacea sufferers, both in decreasing sunlight-induced flushing, and reducing the secondary damage that usually accompanies this inflammatory response.
10. Nitric oxide production is increased when receptors on the blood vessel wall are activated: The inner wall of facial blood vessels contain receptors that bind dozens of substances in the body. Upon activation, these receptors can stimulate the production of nitric oxide. (13, 29) Some important substances that are known to trigger nitric oxide release include:
• Dilators such as histamine, bradykinin, prostaglandins, and cytokines. (14)
• Neurotransmitters such as acetylcholine, norepinephrine, epinephrine, Substance P, CGRP, VIP, and neurokinin A. (8, 30)
• Substances such as ATP, ADP, angiotensin II, arachidonic acid, vasopressin, neurotensin,
5-HT, and thrombin. (30)
11. Nitric oxide production is increased when circulating hormones bind to receptors on the inner wall of blood vessels: Circulating hormones (normal hormones and stress hormones) can also bind to receptors on the inner blood vessel wall, triggering the production of nitric oxide. (31-34)
12. Nitric oxide production is increased during periods of stress: In a superb medical article on nitric oxide and skin disorders, Dr. Quereshi and colleagues state, “We have all experienced patients whose skin disease is exacerbated by stress.” (1) These physicians then speculate that stressful conditions trigger nitric oxide release in the skin, resulting in flare-ups. More specifically, they suggest that the body response to stress increases neural and hormonal activity this, in turn, stimulates nitric oxide production in the skin causing dilation of facial blood vessels and skin flushing.
Nitric Oxide Inhibitors:
One of the Most Exciting Prospects for Future Therapy of Flushing and Rosacea Symptoms
As the reader can see from the above, nitric oxide could be one of the key mediators in facial flushing and rosacea progression. Blocking the release of nitric oxide from facial blood vessels could markedly reduce facial redness, and decrease many forms of facial flushing.
Over the last six years, most of my biomedical research has focused on the study of nitric oxide and blood vessels. Nitric oxide is arguably one of the most important mediators of blood vessel diameter and blood flow; in fact, in 1992 it was elected the molecule of the year by the prestigious American Academy of Science. It is my professional opinion that nitric oxide is one of the keys to our underlying flushing disorder. Topical nitric oxide inhibitors have the potential to:
• Markedly reduce chronic facial redness and inflammation.
• Suppress many forms of active facial flushing.
• Significantly decrease all rosacea symptoms including facial telangiectasia, papules, pustules, burning sensations, rhinophyma, and swelling.
Formulation of a low-dose, time-released nitric oxide inhibitor could be one of the single biggest advancements in rosacea treatment. It could be a direct blow into the heart of the rosacea beast.
Nitric Oxide Inhibitors for Different
Nitric Oxide-Producing Enzymes
Nitric oxide is generated by a group of enzymes called nitric oxide synthases. Medical researchers have identified three basic nitric oxide synthases:
• Constitutive nitric oxide synthase – which is found in the walls of blood vessels and skin cells.
• Inducible nitric oxide synthase – which can also be found in the walls of blood vessels and skin cells.
• Neuronal nitric oxide synthase – which is only found in nerve endings.
Although each enzyme produces the same end product (nitric oxide), they are all unique in structure and function. Therefore, one blocker does not effectively block all of the nitric oxide synthases. Recently, biomedical researchers have developed specific blockers for each group of enzymes. (8, 35, 36) This is an exciting area of vascular research that may become central to rosacea research and treatment in the near future.
Two of the most exciting flushing therapies include: (1) Blocking the production of nitric oxide (a potent dilator released from facial blood vessels and nearby cells), and (2) Blocking the action of dilator nerves supplying facial blood vessels.
NITRIC OXIDE INHIBITORS
Nitric oxide is a powerful dilator substance that is produced by enzymes located in and around skin blood vessels (nitric oxide synthase enzymes). Clinical studies demonstrate that nitric oxide is intimately involved in many inflammatory skin disorders including rosacea, psoriasis, atopic dermatitis, irritant dermatitis, and allergic dermatitis. (1-9)
In the facial skin, nitric oxide is produced from:
• The inner wall of blood vessels
• Epidermal and dermal cells
• Dilator nerves around blood vessels
After nitric oxide is produced from these cells it diffuses to nearby blood vessels and binds to receptors on vascular smooth muscle cells causing potent dilation and substantial increases in blood flow. Topical medications that block nitric oxide production hold the potential to reduce rosacea redness and inhibit many forms of facial flushing.
Nitric Oxide’s Role in Facial Flushing and
Rosacea Progression
There is considerable speculation that nitric oxide plays an important role in facial flushing and rosacea progression. (1-3) Below are a few medical descriptions on this important topic:
• In a superb medical article in the Archives of Dermatology (1996), Drs. Qureshi and colleagues, from Massachusetts General Hospital, USA, speculate that nitric oxide may be involved in the pathogenesis of facial redness, facial flushing, and rosacea. (1) They state, “Whatever the cause for erythema in the skin, whether excessive sun exposure or an inflammatory process, the final mediator may be nitric oxide. Inhibitors of nitric oxide production may thus provide a valuable mode of therapy to relieve symptoms of flushing and erythema in the skin.” These medical experts also pose the ultimate question, “Could the erythema that is so difficult to treat in patients with rosacea be reversed with nitric oxide synthase inhibitors?”
• In the medical article, “Nitric Oxide and its Implications in Skin Homeostasis and Disease: A Review”, Drs. Bruch-Gerharz and colleagues discuss the therapeutic actions of topical nitric oxide inhibitors. (3) They suggest that rosacea may be one of the most important targets for nitric oxide inhibitor therapy. They further state that topical nitric oxide inhibitors, “May be available in the near future.”
• In a recent clinical study in the Journal of Investigative Dermatology (1997), titled, “Influence of NO-Synthase Antagonists in Rosacea Patients”, Dr. Sauermann and colleagues detailed their findings on the effect of topical nitric oxide inhibitor therapy on rosacea patients. (2) They found that treatment with a topical nitric oxide inhibitor (1% L-NAME cream, 2 times daily for 3 weeks), resulted in significant improvement of vascular symptoms in all rosacea patients. These findings are very exciting, indicating the great potential for topical nitric oxide inhibitors in the treatment of rosacea.
Nitric oxide’s Role in Inflammatory
Skin Disorders
Numerous clinical studies demonstrate that nitric oxide also plays an important role in other inflammatory skin disorders. These studies indicate that nitric oxide is one of the key mediators of skin flushing and inflammation. (3-7, 10, 11)
• In a recent medical article in the Journal of Investigative Dermatology (1999), Drs. Ormerod and colleagues demonstrated that nitric oxide can cause significant flushing and inflammation in human skin. (4) They indicate that their results are consistent with other studies demonstrating that increased nitric oxide production is involved in psoriasis, atopic dermatitis, irritant dermatitis, allergic dermatitis, lupus erythematous, sunburn-induced flushing, nerve-mediated flushing, and skin swelling. They conclude that topical nitric oxide inhibitors may be of therapeutic use in many forms of skin inflammation.
• In a recent controlled clinical study in the International Journal of Dermatology (1995), titled, “Clinical Application of Nitric Oxide Synthase Inhibitor for Atopic Dermatitis”, Dr. Morita and colleagues detailed their preliminary findings on the effect of a topical nitric oxide inhibitor in 15 patients with an inflammatory skin disorder. (7) They found that treatment with a topical nitric oxide inhibitor (1% NLA cream, 2 times daily for 4 weeks), resulted in significant improvement in skin redness in 66% of the cases, and reduced uncomfortable skin sensations in 80% of the patients. No side effects were noted in any patients.
• In a superb clinical study on patients with atopic and allergic dermatitis, Dr. Rowe and colleagues demonstrated that nitric oxide synthase was abnormally high in areas of inflamed skin. (5) The greatest areas of nitric oxide synthase expression were in the walls of blood vessels and immediately outside the vessels. These investigators concluded that increased nitric oxide production could be central to skin flushing and inflammation in these disorders.
• In a controlled clinical study on patients with psoriasis, nitric oxide production was abnormally high in all areas of skin redness; in fact, it was up to 10 times higher than that found in normal human skin. (6)
• In a recent clinical study, medical researchers irritated the skin of humans with a soap detergent (sodium lauryl sulphate), and then measured nitric oxide synthase expression. (12) Skin biopsies taken from the subjects showed dramatic increases in nitric oxide synthase expression in all areas of skin irritation. These medical researchers indicated that increased nitric oxide production under these conditions was responsible for the irritant reaction. They concluded that topical nitric oxide inhibitors might block skin flushing associated with irritant and contact dermatitis.
Nitric Oxide’s Role in Skin Flushing
Nitric oxide is intimately involved in many forms of skin flushing because it is produced in great concentrations from the inner wall of skin blood vessels. Nitric oxide is produced continuously to ensure adequate blood flow to the skin, and can be generated in response to a wide variety of stimuli such as chronic skin inflammation, blood vessel damage, increased blood flow conditions, external warming of the skin, environmental insults, internal body overheating, exercise, skin irritation, sunlight, nerve activation, hormones, stress, and in response to dozens of normally produced substances within the body. These findings strongly suggest that even though rosacea sufferers may have different underlying triggers for facial redness, flushing, and rosacea progression, nitric oxide may be one of the key final mediators in causing the vascular response. Below are some important findings on this subject:
1. Nitric oxide is continuously produced from the inner wall of blood vessels in the skin: During resting conditions, the inside of the blood vessel wall continuously produces low levels of this potent dilator to ensure adequate blood flow. (13) Two superb studies have recently demonstrated the importance of nitric oxide in regulating resting blood flow:
• In the clinical study, “Role of Nitric Oxide in the Regulation of Microvascular Perfusion in Human Skin In Vivo”, Dr. Clough determined the role that nitric oxide played in resting blood flow in normal human skin. (14) She found that local inhibition of nitric oxide activity (intradermal injection of L-NAME) caused significant constriction of skin blood vessels, and decreased blood flux by an average of 41%!
• In the clinical study, “Inhibitors of Nitric Oxide Synthase in Human Skin”, Drs. Goldsmith and colleagues found that local inhibition of nitric oxide activity (intradermal injection of L-NAME) caused potent constriction of normal skin blood vessels, and significantly decreased blood flow through these vessels. (8)
These studies are of great relevance to rosacea sufferers. If topical nitric oxide inhibitors can constrict blood vessels and decrease skin blood flow in normal human subjects, then the effects could be dramatic in rosacea sufferers who have dilated, inflamed blood vessels. These studies indicate the great potential for topical nitric oxide inhibitors in reducing chronic facial redness, inflammation, and telangiectasia.
2. Nitric oxide production is enhanced every time there is an increase in blood flow through the facial skin: This is one of the most exciting aspects of nitric oxide physiology. Every time that blood flow is enhanced through skin blood vessels the inside of the blood vessel wall ‘senses’ the increased shear force across it this triggers local production of nitric oxide causing even greater blood flow. (13, 15-18) Let me stress this point. No matter what the flushing trigger is (i.e., food, beverages, heat, exercise, stress, skincare products, neural triggers, environmental insults, overheating, embarrassment, etc.), every time that a flush occurs facial blood vessels ‘sense’ this increase in blood flow this triggers increased production of nitric oxide from the wall of the blood vessel significantly increasing the intensity and duration of facial flushing. Therefore, nitric oxide inhibitors could significantly reduce the frequency, intensity, and duration of most forms of facial flushing.
3. Nitric oxide production is enhanced in areas of skin that experience chronic increases in blood flow: Over time, chronically increased skin blood flow can enhance nitric oxide production in two ways: (1) It can increase the number of enzymes that produce nitric oxide, and (2) It can increase the sensitivity of nitric oxide release from these blood vessels. (17, 19-22) Both of these changes can make facial flushing more frequent and intense. These findings are important because most rosacea sufferers experience chronic increases in facial blood flow.
4. Nitric oxide production is enhanced in areas of skin where physical damage has occurred to blood vessels: In vascular disorders where there is physical damage to the blood vessel wall, nitric oxide production from the damaged vessel is greatly increased, resulting in substantial dilation. (21-23) These findings are clearly relevant to rosacea sufferers because most sufferers incur extensive structural damage to their facial blood vessels.
5. Nitric oxide production is increased during exposure to external heat (local warming of the skin): In a recent clinical study, “Role of Nitric Oxide in the Vascular Effects of Local Warming of the Skin in Humans”, Dr. Dean Kellogg and colleagues demonstrated that nitric oxide was a key mediator of skin flushing to local heating. (24) In this study, they warmed small areas of human skin and demonstrated that they could block most of the heat-induced skin flushing by local nitric oxide blockade (intradermal injection of L-NAME). Consistent with these findings, a study by Dr. Goldsmith and colleagues, “Inhibitors of Nitric Oxide Synthase in Human Skin”, also demonstrated that nitric oxide inhibitors could significantly reduce skin flushing to local warming. (8) These findings are very exciting because many rosacea sufferers report uncontrollable facial flushing to warm environments.
6. Nitric oxide production is enhanced during body overheating (i.e., increased internal body temperature): In a recent clinical study, “Nitric Oxide and Cutaneous Active Vasodilation during Heat Stress in Humans”, Dr. Dean Kellogg and colleagues demonstrated that nitric oxide is a key mediator of skin flushing during body heating. (25) Consistent with this, a second study found that increased internal body temperature triggers nitric oxide-mediated skin flushing. (26) A third study demonstrated that thermoregulatory shunt vessels of the human skin produce significant concentrations of nitric oxide, and that blockade of nitric oxide from these vessels caused a significant decrease in blood flow (33% decrease in red cell flux). (27) Taken together, these findings indicate that nitric oxide inhibitors can reduce skin flushing to internal body heating, one of the most powerful triggers for rosacea flushing.
7. Nitric oxide production is augmented during exercise: Multiple studies indicate that nitric oxide is a key mediator of exercise-induced skin flushing. (26, 28) Although the body response to exercise is quite complex, nitric oxide inhibitors could greatly reduce the intensity and duration of facial flushing to exercise.
8. Nitric oxide production is increased in areas of skin irritation (i.e., irritant or allergic dermatitis): Very recently, several human clinical studies have shown that nitric oxide is intimately involved in irritant and allergic dermatitis. (10-12) These findings are important to rosacea sufferers who experience facial flushing to topical skincare products. Is it possible that nitric oxide inhibitors could allow rosacea sufferers to use normal skincare products again?
9. Nitric oxide production is augmented in areas of skin that are exposed to sunlight (UV radiation): In a clinical study, “Inhibitors of Nitric Oxide Synthase in Human Skin”, Dr. Goldsmith and colleagues demonstrated that nitric oxide inhibition significantly decreased UVB-induced skin flushing. (8) These researchers also demonstrated that this effect was long lasting (blood flow was reduced for over 24 hours). This could be very helpful to rosacea sufferers, both in decreasing sunlight-induced flushing, and reducing the secondary damage that usually accompanies this inflammatory response.
10. Nitric oxide production is increased when receptors on the blood vessel wall are activated: The inner wall of facial blood vessels contain receptors that bind dozens of substances in the body. Upon activation, these receptors can stimulate the production of nitric oxide. (13, 29) Some important substances that are known to trigger nitric oxide release include:
• Dilators such as histamine, bradykinin, prostaglandins, and cytokines. (14)
• Neurotransmitters such as acetylcholine, norepinephrine, epinephrine, Substance P, CGRP, VIP, and neurokinin A. (8, 30)
• Substances such as ATP, ADP, angiotensin II, arachidonic acid, vasopressin, neurotensin,
5-HT, and thrombin. (30)
11. Nitric oxide production is increased when circulating hormones bind to receptors on the inner wall of blood vessels: Circulating hormones (normal hormones and stress hormones) can also bind to receptors on the inner blood vessel wall, triggering the production of nitric oxide. (31-34)
12. Nitric oxide production is increased during periods of stress: In a superb medical article on nitric oxide and skin disorders, Dr. Quereshi and colleagues state, “We have all experienced patients whose skin disease is exacerbated by stress.” (1) These physicians then speculate that stressful conditions trigger nitric oxide release in the skin, resulting in flare-ups. More specifically, they suggest that the body response to stress increases neural and hormonal activity this, in turn, stimulates nitric oxide production in the skin causing dilation of facial blood vessels and skin flushing.
Nitric Oxide Inhibitors:
One of the Most Exciting Prospects for Future Therapy of Flushing and Rosacea Symptoms
As the reader can see from the above, nitric oxide could be one of the key mediators in facial flushing and rosacea progression. Blocking the release of nitric oxide from facial blood vessels could markedly reduce facial redness, and decrease many forms of facial flushing.
Over the last six years, most of my biomedical research has focused on the study of nitric oxide and blood vessels. Nitric oxide is arguably one of the most important mediators of blood vessel diameter and blood flow; in fact, in 1992 it was elected the molecule of the year by the prestigious American Academy of Science. It is my professional opinion that nitric oxide is one of the keys to our underlying flushing disorder. Topical nitric oxide inhibitors have the potential to:
• Markedly reduce chronic facial redness and inflammation.
• Suppress many forms of active facial flushing.
• Significantly decrease all rosacea symptoms including facial telangiectasia, papules, pustules, burning sensations, rhinophyma, and swelling.
Formulation of a low-dose, time-released nitric oxide inhibitor could be one of the single biggest advancements in rosacea treatment. It could be a direct blow into the heart of the rosacea beast.
Nitric Oxide Inhibitors for Different
Nitric Oxide-Producing Enzymes
Nitric oxide is generated by a group of enzymes called nitric oxide synthases. Medical researchers have identified three basic nitric oxide synthases:
• Constitutive nitric oxide synthase – which is found in the walls of blood vessels and skin cells.
• Inducible nitric oxide synthase – which can also be found in the walls of blood vessels and skin cells.
• Neuronal nitric oxide synthase – which is only found in nerve endings.
Although each enzyme produces the same end product (nitric oxide), they are all unique in structure and function. Therefore, one blocker does not effectively block all of the nitric oxide synthases. Recently, biomedical researchers have developed specific blockers for each group of enzymes. (8, 35, 36) This is an exciting area of vascular research that may become central to rosacea research and treatment in the near future.