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NITRIC OXCIDE.
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Essay Subject:
Technical discussion of the discovery of how nitric oxide acts in the human body. Its value in treating cardiovascular disease.... More...
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Paper Abstract:
Technical discussion of the discovery of how nitric oxide acts in the human body. Its value in treating cardiovascular disease.
Paper Introduction:
In 1998, three American scientists were awarded the Nobel prize for Physiology and Medicine for their discovery that nitric oxide, a common gas in air pollution, transmits signals within the human body (Maugh, 1998). The discovery was hailed as one of the most important in the history of cardiovascular medicine, and was predicted to lead the way to treating high blood pressure and heart attacks. It led to the development of Viagra, to a new treatment for newborns with dangerously high blood pressure in their lungs, and to drugs for the treatment of shock.
The signaling function of nitric oxide influences virtually every organ system in the body. The discovery that nitric acid produced by one cell could alter the function of other cells is an entirely new principle for signaling in biological systems. Previ
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999-1 . Some data suggest that insulin resistanceimpairs the effects of dilating factors on blood vessels, allowingconstricting factors to predominate. L-arginine improves the coronaryblood flow response to acetylcholine in patients with normal coronaryarteries and hypercholesterolemia. (2 ). A292. E., Ying, J., Davis, P. H. References Busse, R., & Fleming, I. Wiley, K. The coronary artery vascular dilation in response toacetylcholine is predominantly caused by increased production of nitricoxide, and even in the absence of atherosclerosis, patients with at leastone known risk factor for coronary artery disease show reduced resting andstimulated bioavailability of nitric oxide from the coronary circulation.When the reduced bioavailability of nitric oxide is stimulated byacetylcholine, the contrasting action of endothelium becomes dominant andvasoconstriction could result. (1997). Nitric oxide prevents p21degradation in vascular smooth muscle cells. Lancet, 349, pp. Studieshave revealed that human erythrocytes have a nitric oxide synthase whoseactivation might be involved in the regulation of rheological properties oferythrocytes. Nitric oxide, nitric oxidesynthase, and hypertensive vascular disease. Tracey, K. Curr. Origins ofcoronary artery ectasia. These researchers studied 15 patientswith chronic stable angina, coronary artery disease, and a positivetreadmill exercise test to see the effects of L-arginine. Ten patientsreceived intracoronary infusion of saline followed by intracoronaryinfusion of L-arginine. Theseeffects are associated with an apparent decrease in the production ofbioactive nitric oxide and concomitant increase in the generation of oxygen-derived free radicals such as superoxide anions. The nitrates and nitric oxide are the most common drugs used intreating cardiovascular disease because of their vasodilatory effects. Allowing the infants to breathe trace amounts of nitric oxidecauses blood vessels in their lungs to relax so the infants can breathenormally (Maugh, 1998). L., Davis, M. The signaling function of nitric oxide influences virtually everyorgan system in the body. Studies by one of the scientists on how nitroglycerin and other drugsused to dilate blood vessels functioned led to the discovery that theypromoted the release of nitric oxide. Although vasodilators such as nitrates improve pulmonary hypertension,they do not improve exercise tolerance in these patients. The researchers demonstrated that p21 messenger RNA levels in rataortic smooth muscle cells treated with S-nitroso-N-acetylpenicillamine oradenoviral i-nitric oxide synthase gene transfer, and p21 protein levelsunder similar conditions. Glasser, S. In this study, L-arginine induced a significant dilation in coronary stenosis segments,suggesting that the endothelial intracellular availability and/ormobilization of L-arginine is defective in atherosclerotic coronaryarteries. Young, M. Rep., 1, pp.88-95. 1129-113 . In five patients, D-arginine was used instead of L-arginine. Res.Commun., 275, pp. Los Angeles Times, p. These conditions either reduce the production of nitricoxide, hasten its breakdown, or both. Coronary stenosis dilatation induced by L-arginine. They haveenlarged, non-stenotic coronary arteries which may be ectatic. The gene transferof the inducible nitric oxide synthase gene to injured arteries inhibitsthe development of intimal hyperplasia. While the enzymaticsource of endothelial oxygen has been debated, it may be that theendothelial nitric oxide synthase is itself an important producer ofoxygen. p21 induces G(OJ)/G(1) cell cycle arrest,leading to an inhibition of vascular smooth muscle cell proliferation.Because nitric oxide induces such a dramatic upregulation of p21 andbecause p21 is a universal inhibitor of the cell cycle, researchersinvestigated how nitric oxide upregulates p21 protein expression invascular smooth muscle cells. Inhaled nitricoxide has been used to treat patients with primary pulmonary hypertension.These researchers studied patients with vascular heart disease, dilatedcardiomyopathy, and myocardial infarction. The infusions did not affect systolic blood pressure. Both SNAP and DETA/NO causeda significant rightward shift in the ET-1 concentration-response curve.All four NO-donors were found to completely reverse an establishedcontraction to a submaximal concentration ET-1:SNAP>DEA/NO>SIN-!>DETA/NO.These data suggest that these agents can physiologically antagonize theeffects of ET-1 in human arteries and may be useful therapeutic agents inthe treatment of cardiovascular disease. 1. Nitric oxide synthase catalyzes the conversion of arginine tocitrulline, with the concomitant generation of nitric oxide (Young, Ying,Davis and Taegtmeyer, 2 ). (1998). The guanylLydrazones, a new class ofdrugs which inhibit TNF and NO in monocytes and retain their cytokine-suppressive activity are being investigated as possible treatments forthis disease. Its active metabolites - isosorbide mononitrateand isosorbide dinitrate- are available in short- and long-acting oralformulations. Novel nitric oxide donorsreverse endothelin-1-mediated constriction in human blood vessels. Maugh, T. The amount of nitric oxide in theartery wall seems to decrease in the presence of several risk factors forheart disease, including high cholesterol, high blood pressure, smoking,and diabetes. These data indicatethat one mechanism by which nitric oxide upregulates p21 protein expressionis through the prevention of p21 protein degradation by the ubiquitin-proteasome pathway in association with increased protein tyrosine andserine/threonine phosphatase activity. Two of the scientists then worked on EDRF and discovered it to be nitricoxide. Diabetes, 49, p. Patient Care,32, pp. (1996). Arginine is a semi-essential amino acid which serves as a substratefor the enzyme nitric oxide synthase, which converts arginine to citrullineand nitric oxide, and thereby reduces vascular tone. J., & Bove, A. Researchers examining the impact of insulin resistance on the bloodvessels have found that people with elevated insulin often have abnormalresponses to nitric oxide. Theysuggests the greater effect of nitric oxide on the fluidity in essentialhypertension suggests that nitric oxide might actively participate in theregulation of rheological behavior of erythrocytes and have a crucial rolein the improvement of microcirculation in hypertension. scientists win Nobel medicineprize. A 15-foldincrease in mortality is found in this population of workers. The discovery that nitric acid produced by onecell could alter the function of other cells is an entirely new principlefor signaling in biological systems. Studies showed that fasting increases endothelial nitric oxide synthaseexpression in skeletal muscle, but had no significant effects on the heart. At the same time, another one of thescientists= studies showed that naturally occurring chemicals such asacetylcholine also stimulate the release of a signaling molecule thatcaused muscles of blood vessels to relax, and this molecule was named EDRF. TNF, a cytokine produced by macrophages, cardiac myocytes, and othercells, can directly suppress cardiac function. Dilatedcardiomyopathy is identified by the onset of decreased myocardialcontractility with ventricular dilation and failure (Tracey, 1996). (1998). NA. E., & Davenport, A. These researchers showed that nitric oxide increases themembrane fluidity and decreases the rigidity of cell membranes. Because the redox state of endothelial cells and the activation ofredox-sensitive transcription factors is regulated by the balance betweennitric oxide and oxygen production, endothelial nitric oxide synthase maybe the crucial enzyme determining the anti- or prohypertensive andeventually proatherogenic state of the vascular wall. Macrophages, cardiacmyocytes and other cells produce nitric oxide after exposure to TNF, andcompetitive inhibitors of iNOS reversed the cardiac suppression mediated bycytokines, suggesting another pathway by which inflammatory mediators cansuppress cardiac contractility and another possible treatment strategy.Although the triggers which activate TNF and NO synthesis are unknown,investigation of their inhibitors in this disease may be beneficial.Oligocorticoids which can partly inhibit both TNF and NO but have limitedbenefits in dilated cardiomyopathy. A., & Taegtmeyer, H. J. 1812-1813. (1999). They assessed ubiquinated p21 in these sametreatment groups by immunoprecipitation of p21 from rat aortic smoothmuscle cells. Tousoulis, D., Davies, G., Tentolouris, C., Crake, T., & Toutouzas, P. Researchers hope that these discoveries will lead to thedevelopment of drugs to treat hypertension, and even improve blood flowthrough blocked arteries. Antianginamedication was stopped 24 hours prior to the testing, but patients wereallowed to use sublingual glyceryl nitrate if necessary. Prospects for therapy of nitrate tolerance.Lancet, 353, pp. 1545-1546. The preciseincidence of tolerance to nitrates is unknown, but seems to occur almostinvariably with dose regimens that sustain plasma tissue nitrateconcentrations for more than 24 hours. Two proteins, tumornecrosis factor (TNF) and inducible nitric oxide synthase (NOS) have beenimplicated as the molecular basis for dilated cardiomyopathy and may beresponsible for the development of depressed myocardial contractility andincrease cardiac thrombus formation. The mechanism of tolerance isunknown also. Chronic relaxation could lead to coronary artery ectasia.Munitions workers exposed chronically to nitrites suffer arterial spasm,myocardial infarctions, and an out-of-proportion incidence of sudden death,but have no evidence of coronary stenosis at angiography. Biochem. In normotensive states, the vascular endothelium produces mainlynitric oxide and prostacyclin, and the vasodilator and growth inhibitoryinfluence predominates (Busse and Fleming, 1999). L-arginine administration was associated with significant dilation ofstenoses but there were no changes when D-arginine was used. It has seven modes of delivery: oral,sublingual, buccal, transdermal, lingual aerosol spray, topical ointment,and intravenous infusion. farmers exposed to herbicides (Sorrell, Davisand Bove, 1996). (2 ). Navigating the nitrate maze. Sorrell, V. Augmenting the activity of the nitric oxide synthase pathway isthus a possible therapeutic avenue in the treatment of atherosclerosis andischemic heart disease. J. Nitrate therapy is now indicated for myocardial infarctionas well as the standard treatment for prophylaxis and treatment of anginapectoris. J.Cardiovasc. Itoften leads to severe morbidity and mortality because of progressivecongestive heart failure or to embolic complications. Previously known signaling agentswere typically complex molecules that must bind to specific receptors oncell membranes to elicit a response, but nitric oxide is a light gas whichcan pass through membranes, causing chemical changes directly in the cells=interior (Maugh, 1998). The common thread in all theseinstances is exposure to nitrites and the potential stimulation of nitricoxide. It has alsobeen suggested that some Vietnam veterans with coronary artery ectasia wereexposed to agent orange, an herbicide. Endothelial nitric oxide synthase is aprimary nitric oxide synthase isoform regulating vascular tone, contractilefunction and metabolism in muscles, and decreased activity has been linkedwith vascular disease and contractile dysfunction associated with diabetes. Insulin resistance and heart disease. (1999). A study compared theability of the nitric oxide donors 3-morpholinylsydnonimine (SIN-1) andnitroso-N-acetylpenicillamine (SNAP) with nitric oxide donors(NONOates)diethylamine NONOate(DEA/NO) and diethylenetriamine NONOate(DETA/NO) in order to physiologically antagonize ET-1-mediated constrictionin human internal mammary arteries in vitro. The discovery has also allowed physicians totreat pulmonary hypertension in newborns, a breathing disorder that can befatal. The patients inhaled nitricoxide, which reduced pulmonary arterial pressure and pulmonary vascularresistance in a dose-dependent manner without altering systemic bloodpressure or cardiac output. Repairing the broken heart of dilatedcardiomyopathy. Pharmacol., 36, pp. (1996). Saunders, C. Patients with congestive heart failure often have pulmonary congestionwhich causes ventilation-perfusion mismatch and leads to shallow and rapidventilation (Matsumoto, Momomura, Hirata, Aoyagi, Sugiura and Omata, 1997). Nitricoxide improves membrane fluidity of erythrocytes in essential hypertension:an electron paramagnetic resonance investigation. High fat feeding significantly increased endothelial nitric oxide synthaseexpression in skeletal muscle, again with no significant effects on theheart. Acetylcholine stimulates nitric oxide, and so herbicidesmay be responsible for locally increased nitric oxide concentrations.Nitric oxide stimulates the relaxation of vascular smooth muscle via theguanylate cyclase pathway and release of calcium from the endoplasmicreticulum. Lancet, 347, pp. Strategies can be used to avoid developing tolerance to nitrates,including administration of exogenous sulphydryl donors, blockade ofneurohormonal vasoconstriction, diuresis, and intermittent dose regimens.Administration of angiontensin-converting enzyme may prevent thedevelopment of tolerance by blocking vasoconstriction and sodium retentioncaused by the nitrate-induced reflex activation of the renin-angiotensinsystem. In vascular smooth muscle cells, nitric oxide prevents p21 degradationvia the ubiquitin-proteasome pathway (Henderson, 2 ). Nitric oxide is involved in many cardiovascular diseases. Many patients suffering from angina receive chronicglycerylnitrate therapy, but so far no one has linked this to coronaryartery ectasia. In hypertension, thereis a shift towards enhanced constriction and vascular hypertrophy. Harvard Heart Letter,9, p. Peripheral arterial dilation induced by nitrates contributes tothe beneficial effects by reducing left ventricular afterload. P. Nitroglycerin is now available in several forms for different routesof administration (Saunders, 1998). S. 23-51. P. Matsumoto, A., Momomura, S., Hirata, Y., Aoyagi, T., Sugiura, N., &Omata, M. An increase in p21 protein expression induced by nitric oxide wasassociated with less of the ubiquinated form of p21. A. It is suggested that abnormal responses tonitric oxide may be responsible, in part, for the heart disease seen indiabetes. (1997). 136-137. One mechanism by which nitricoxide may inhibit this process is through the upregulation of the cyclin-dependent kinase inhibitor p21. Tsuda, K., Kimura, K., Nishio, L., & Masuyama, Y. During exercise while inhaling nitric oxide,patients demonstrated increased peak oxygen uptake and peak work load, butoxygen uptake and work load at the anaerobic threshold remained unchanged.These results suggest that inhalation of nitric oxide improves the functionof patients with congestive heart failure. In 1998, three American scientists were awarded the Nobel prize forPhysiology and Medicine for their discovery that nitric oxide, a common gasin air pollution, transmits signals within the human body (Maugh, 1998).The discovery was hailed as one of the most important in the history ofcardiovascular medicine, and was predicted to lead the way to treating highblood pressure and heart attacks. Care needs to be taken in the administration ofnitric oxide because too much dilation of blood vessels throughout the bodycan induce fatal shock. This impairs the ability of the bloodvessels to supply additional oxygen and nutrients to the heart when it isstressed, e.g. Henderson, C. during exercise. People exposed to toxins which are acetylcholinesterase inhibitorsoften develop ectasia, e.g. 3 U. Lancet, 347, pp. (2 , April). Inhaled nitric oxide and exercise capacity incongestive heart failure. However, theclinical value of longterm nitrate therapy is limited by the development oftolerance to the hemodynamic actions of the drug and its clinical effects.Nitrate-induced venous dilation reduces venous return and left-ventricularpreload, decreasing myocardial oxygen needs and improving left ventricularemptying. (2 ).Differential effects of nutritional status on cardiac and skeletal muscleendothelial nitric oxide synthase gene expression. Biophys. Organic nitrates are widely used for the chronic treatment of ischemicheart disease and congestive heart failure (Glasser, 1999). (1998, October). L-arginine, a substrate in the production of endothelium-derivednitric oxide, may stimulate the release of nitric oxide (Tousoulis, Davies,Tentolouris, Crake and Toutouzas, 1997). W. Lancet, 349,pp. The percentage change in luminal diameter from baseline werecalculated. Coronary artery ectasia affects about two percent of the generalpopulation and may be due to an imbalance between the beneficial effects ofnitric oxide on coronary dilation and the potentially detrimental effectsof chronic overstimulation by this relaxation factor (Sorrell, Davis andBove, 1996). These studies showed that nutritional status has considerableinfluence on skeletal muscle endothelial nitric oxide synthase, butexpression in heart muscle remains constant through varying nutritionalconditions. Hypertens. Cardiovascular disease is associated with elevated circulating levelsof endothelin-1 (ET-1)(Wiley and Davenport, 2 ). Gene Therapy Weekly, p. The directvasodilatory effects of nitrates on the coronary circulation increasemyocardial perfusion, improving myocardial oxygen supply. 946-954. These two proteins have a centralrole in the mediation of tissue responses to inflammation. It led to the development of Viagra, toa new treatment for newborns with dangerously high blood pressure in theirlungs, and to drugs for the treatment of shock. It has been shown that rheological abnormality might be an etiologicalfactor in hypertension (Tsuda, Kimura, Nishio and Masuyama, 2 ). NA. S151-S152. In atherosclerosis, cholesterol builds up in the walls of arteries,and it has been shown that nitric oxide may help to reduce the resultantinflammation (Insulin resistance, 1998). S.
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