Nicotine And Alcohol Promote Nitric Oxide

[DaveFoster]

Nitric oxide-mediated pathogenesis during nicotine and alcohol consumption. - PubMed - NCBI

"Nitric oxide (NO) is formed by different cell types in response to a variety of physiological and patho-physiological stimuli. The intake of nicotine and/or alcohol has patho-physiological effects on organ function, and the progression of alcohol-/tobacco-related diseases seem to be directly influenced by NO-mediated mechanisms. Nicotine has an adverse influence on blood vessel functionality, repair and maintenance. Chronic nicotine exposure augments atherosclerosis by enhancing the production of proinflammatory cytokines by macrophages which then activate atherogenic NF-kB target genes in aortic lesions. Alcohol produces NO which speeds up the apoptosis of neutrophils. Alcohol sensitizes the liver to endotoxemic shock. Nitrosative stress and increased basal levels of NO contribute to tumour growth. The progression of disease seems to be directed via a definite NO-mediated mechanism. This review gives an insight into how intake of tobacco and alcohol may affect quality of life."

Both nicotine and alcohol function as tumor promoters, and the latter leads to higher levels of endotoxin; in addition to heavy PUFA-laden starch, alcohol promotes hepatic steatosis (fatty liver), cirrhosis (liver damage) and liver cancer.

 

[Such_Saturation]

It's like a series of strawmans strung togheter

 

[DaveFoster]

It's like a series of strawmans strung togheter

In regards to proinflammatory cytokines, NF-kB, and NO being implicated in CVD?

 

[Such_Saturation]

In regards to proinflammatory cytokines, NF-kB, and NO being implicated in CVD?

Yeah well I'm not one to criticize an abstract wording, but it's pretty far out... like "Chronic nicotine exposure augments atherosclerosis" "alcohol produces NO" are pretty vague and contextless

 

[DaveFoster]

Yeah well I'm not one to criticize an abstract wording, but it's pretty far out... like "Chronic nicotine exposure augments atherosclerosis" "alcohol produces NO" are pretty vague and contextless

The role of nicotine in the pathogenesis of atherosclerosis

"Smoking is a major preventable risk factor for atherosclerosis. Exposure to cigarette smoke activates a number of mechanisms predisposing to atherosclerosis, including thrombosis, insulin resistance and dyslipidemia, vascular inflammation, abnormal vascular growth and angiogenesis, as well as loss of endothelial homeostatic and regenerative functions 1–3. The pathophysiologic mechanisms by which tobacco smoke accelerates vascular disease are manifold and complex, in part because the smoke contains over 4000 different chemicals 4. Of these, the polycyclic aromatic hydrocarbons, oxidizing agents, particulate matter, and nicotine, have been identified as potential contributing factors to atherogenesis. In addition to its role as the habituating agent in tobacco, nicotine also accelerates vascular disease. By inducing the release of catecholamines, nicotine increases heart rate and blood pressure. These adverse hemodynamic effects are associated with progression of atherosclerosis. Furthermore, nicotine-induced catecholamine release increases platelet aggregability 3. Platelets contribute to the growth of plaque through the accretion of thrombus, as well as through the release of growth factors (such as platelet derived relaxing factor) that induce vascular smooth muscle cell proliferation. In addition to these actions mediated by activation of the sympathetic nervous system, nicotine has direct actions on the cellular elements participating in plaque formation."

"The effects of nicotine on cells within the vessel wall are mediated by cholinergic receptors. There are two major types of cholinergic receptors, the muscarinic and the nicotinic 5. Whereas acetylcholine stimulates both receptor types, nicotine preferentially stimulates the nicotinic receptor. The muscarinic receptors are 7-transmembrane spanning G protein-gated receptors. By contrast, the nicotinic acetylcholine receptors (nAChRs) are each composed of 5 subunits, arranged in a barrel-like configuration to form a channel in the cell membrane. Activation of the nAChRs by endogenous acetylcholine, or exogenous nicotine, increases permeability of these ligand-gated channels to cations. There are 16 different isoforms (α1–α10, β1–β4, δ, γ. and ɛ) of the subunits, which form homomeric or heteromeric channels. The combinatorial association of various α− and β− subunits result in functionally diverse nAChR subtypes that have different ligand affinity, cation permeability, and signaling 6,7. The nAChRs were first identified in excitable cells, but later were identified in many other cell types including vascular 8–11 and immune cells 12."

"The “muscle-type” nAChR, first found in the neuromuscular junction of skeletal muscle, consists of the specific assembly of five polypeptide subunits (α1, β1, δ, and ɛ in a 21:1 ratio). These subunits have since been described in other cell types, including endothelial cells 13. In this issue of Atherosclerosis, Zhang and colleagues provide evidence that the muscle-type nAChR may play a direct role in regulating vascular smooth muscle cell proliferation and migration. They first observed that the expression of the α1 subunit was increased 4-fold in the aortae of ApoE deficient mice fed a Western diet (by comparison to the aortae from mice fed normal chow), and was localized in vascular smooth muscle cells and some macrophages. They did not determine if the expression of the other subunits of the classical “muscle-type” nAChR was increased. However, it is known that silencing of the α1 subunit abrogates the function of the muscle type nAChR. Accordingly, to determine if the increased expression of the α1 subunit was of pathophysiological importance, they used a hydrodynamic approach to introduce hairpin nAChR α1-siRNA into the abdominal aorta in vivo. Their approach provided for a significant and sustained (16 weeks) silencing of the subunit in the aorta. Downregulation of the α1 subunit was associated with a dramatic reduction (by 80%) in the atherosclerotic lesion area in the abdominal aorta."

"During the development of the atherosclerotic lesion, proliferating vascular smooth muscle cells (vsmc; or a vsmc progenitor) migrate into the intima and undergo phenotypic modulation into myofibroblasts and osteoblast-like cells. There they elaborate extracellular matrix (collagen and osteopontin), and even take up lipid to resemble macrophage-derived foam cells. In this study, silencing of the α1 subunit was associated with an 80% reduction in myofibroblasts in the lesion, and a reduction in expression of TGFβ, a vsmc mitogen. Furthermore, in the aortic root, quantification of Masson stained or von Kosa stained sections revealed that silencing of the α1 subunit was associated with a reduction in the extracellular matrix accumulation (collagen and osteopontin) and an attenuation of calcification. These findings are consistent with the authors’ hypothesis that activation of the “muscle-type” nAChR induces the proliferation and migration of vascular smooth muscle cells into the intima, mediated in part by TGFβ."

Bascially, nicotine activates the a1 subunit, which increases extracellular matrix accumulation of collagen and osteopontin.

The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice. - PubMed - NCBI

"Nitric oxide (NO) is now known to control both mitochondrial respiration and organelle biogenesis. Under conditions of ethanol-dependent hepatic dysfunction, steatosis is increased, and this is associated with increased expression of inducible nitric oxide synthase (iNOS). We have previously shown that after chronic exposure to ethanol, the sensitivity of mitochondrial respiration to inhibition by NO is enhanced, and we have proposed that this contributes to ethanol-dependent hypoxia. This study examines the role of iNOS in controlling the NO-dependent modification of mitochondrial function. Mitochondria were isolated from the livers of both wild-type (WT) and iNOS knockout (iNOS-/-) mice that were fed an isocaloric ethanol-containing diet for a period of 5 weeks. All animals that consumed ethanol showed some evidence of fatty liver; however, this was to a lesser extent in the iNOS-/- mice compared to controls. At this early stage in ethanol-dependent hepatic dysfunction, infiltration of inflammatory cells and the formation of nitrated proteins was also decreased in response to ethanol feeding in the iNOS-/- animals. Mitochondria isolated from wild-type ethanol-fed mice showed a significant decrease in respiratory control ratio and an increased sensitivity to NO-dependent inhibition of respiration relative to their pair-fed controls. In contrast, liver mitochondria isolated from iNOS-/- mice fed ethanol showed no change in the sensitivity to NO-dependent inhibition of respiration. In conclusion, the hepatic response to chronic alcohol-dependent cytotoxicity involves a change in mitochondrial function dependent on the induction of iNOS."

 

[Such_Saturation]

The role of nicotine in the pathogenesis of atherosclerosis

"Smoking is a major preventable risk factor for atherosclerosis. Exposure to cigarette smoke activates a number of mechanisms predisposing to atherosclerosis, including thrombosis, insulin resistance and dyslipidemia, vascular inflammation, abnormal vascular growth and angiogenesis, as well as loss of endothelial homeostatic and regenerative functions 1–3. The pathophysiologic mechanisms by which tobacco smoke accelerates vascular disease are manifold and complex, in part because the smoke contains over 4000 different chemicals 4. Of these, the polycyclic aromatic hydrocarbons, oxidizing agents, particulate matter, and nicotine, have been identified as potential contributing factors to atherogenesis. In addition to its role as the habituating agent in tobacco, nicotine also accelerates vascular disease. By inducing the release of catecholamines, nicotine increases heart rate and blood pressure. These adverse hemodynamic effects are associated with progression of atherosclerosis. Furthermore, nicotine-induced catecholamine release increases platelet aggregability 3. Platelets contribute to the growth of plaque through the accretion of thrombus, as well as through the release of growth factors (such as platelet derived relaxing factor) that induce vascular smooth muscle cell proliferation. In addition to these actions mediated by activation of the sympathetic nervous system, nicotine has direct actions on the cellular elements participating in plaque formation."

"The effects of nicotine on cells within the vessel wall are mediated by cholinergic receptors. There are two major types of cholinergic receptors, the muscarinic and the nicotinic 5. Whereas acetylcholine stimulates both receptor types, nicotine preferentially stimulates the nicotinic receptor. The muscarinic receptors are 7-transmembrane spanning G protein-gated receptors. By contrast, the nicotinic acetylcholine receptors (nAChRs) are each composed of 5 subunits, arranged in a barrel-like configuration to form a channel in the cell membrane. Activation of the nAChRs by endogenous acetylcholine, or exogenous nicotine, increases permeability of these ligand-gated channels to cations. There are 16 different isoforms (α1–α10, β1–β4, δ, γ. and ɛ) of the subunits, which form homomeric or heteromeric channels. The combinatorial association of various α− and β− subunits result in functionally diverse nAChR subtypes that have different ligand affinity, cation permeability, and signaling 6,7. The nAChRs were first identified in excitable cells, but later were identified in many other cell types including vascular 8–11 and immune cells 12."

"The “muscle-type” nAChR, first found in the neuromuscular junction of skeletal muscle, consists of the specific assembly of five polypeptide subunits (α1, β1, δ, and ɛ in a 21:1 ratio). These subunits have since been described in other cell types, including endothelial cells 13. In this issue of Atherosclerosis, Zhang and colleagues provide evidence that the muscle-type nAChR may play a direct role in regulating vascular smooth muscle cell proliferation and migration. They first observed that the expression of the α1 subunit was increased 4-fold in the aortae of ApoE deficient mice fed a Western diet (by comparison to the aortae from mice fed normal chow), and was localized in vascular smooth muscle cells and some macrophages. They did not determine if the expression of the other subunits of the classical “muscle-type” nAChR was increased. However, it is known that silencing of the α1 subunit abrogates the function of the muscle type nAChR. Accordingly, to determine if the increased expression of the α1 subunit was of pathophysiological importance, they used a hydrodynamic approach to introduce hairpin nAChR α1-siRNA into the abdominal aorta in vivo. Their approach provided for a significant and sustained (16 weeks) silencing of the subunit in the aorta. Downregulation of the α1 subunit was associated with a dramatic reduction (by 80%) in the atherosclerotic lesion area in the abdominal aorta."

"During the development of the atherosclerotic lesion, proliferating vascular smooth muscle cells (vsmc; or a vsmc progenitor) migrate into the intima and undergo phenotypic modulation into myofibroblasts and osteoblast-like cells. There they elaborate extracellular matrix (collagen and osteopontin), and even take up lipid to resemble macrophage-derived foam cells. In this study, silencing of the α1 subunit was associated with an 80% reduction in myofibroblasts in the lesion, and a reduction in expression of TGFβ, a vsmc mitogen. Furthermore, in the aortic root, quantification of Masson stained or von Kosa stained sections revealed that silencing of the α1 subunit was associated with a reduction in the extracellular matrix accumulation (collagen and osteopontin) and an attenuation of calcification. These findings are consistent with the authors’ hypothesis that activation of the “muscle-type” nAChR induces the proliferation and migration of vascular smooth muscle cells into the intima, mediated in part by TGFβ."

Bascially, nicotine activates the a1 subunit, which increases extracellular matrix accumulation of collagen and osteopontin.

The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice. - PubMed - NCBI

"Nitric oxide (NO) is now known to control both mitochondrial respiration and organelle biogenesis. Under conditions of ethanol-dependent hepatic dysfunction, steatosis is increased, and this is associated with increased expression of inducible nitric oxide synthase (iNOS). We have previously shown that after chronic exposure to ethanol, the sensitivity of mitochondrial respiration to inhibition by NO is enhanced, and we have proposed that this contributes to ethanol-dependent hypoxia. This study examines the role of iNOS in controlling the NO-dependent modification of mitochondrial function. Mitochondria were isolated from the livers of both wild-type (WT) and iNOS knockout (iNOS-/-) mice that were fed an isocaloric ethanol-containing diet for a period of 5 weeks. All animals that consumed ethanol showed some evidence of fatty liver; however, this was to a lesser extent in the iNOS-/- mice compared to controls. At this early stage in ethanol-dependent hepatic dysfunction, infiltration of inflammatory cells and the formation of nitrated proteins was also decreased in response to ethanol feeding in the iNOS-/- animals. Mitochondria isolated from wild-type ethanol-fed mice showed a significant decrease in respiratory control ratio and an increased sensitivity to NO-dependent inhibition of respiration relative to their pair-fed controls. In contrast, liver mitochondria isolated from iNOS-/- mice fed ethanol showed no change in the sensitivity to NO-dependent inhibition of respiration. In conclusion, the hepatic response to chronic alcohol-dependent cytotoxicity involves a change in mitochondrial function dependent on the induction of iNOS."

A compelling case, I'm on both though so I'll suspend judgement

 

[DaveFoster]

A compelling case, I'm on both though so I'll suspend judgement

 

[schultz]

A compelling case, I'm on both though so I'll suspend judgement

I applaud your excellent use of the cool guy emoticon!

 

[Diokine]

It's a fairly convoluted topic - I think on one hand there is pretty clear evidence that smoking cigarettes is unequivocally bad for you. With nicotine, though, the picture is not so clear. Agonism of vagal nerve nicotinic AcH receptors has been shown to reduce sensitivity to TNF and other inflammatory cytokines, leading to attenuation of the inflammatory cascade.

My personal feeling is that low doses of nicotine can be an effective sympathetic stimulant and moderately theraputic.