"Nitrate and/or nitrite are the logical source of the NOS-independent NO, since they are the metabolic end-products of the NO-pathway that can be reduced to again form bioactive nitrogen oxides, including NO (Lundberg et al., 2008). Thus, hemoglobin, myoglobin, and xanthine oxidoreductase can transform nitrite to NO in various tissues and under different conditions (Chen et al., 2008; Lundberg, 2009). Cytochrome P450 reductase and cytochrome P450 can transform organic nitrate and nitrite to NO in vitro, respectively (Li et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: In the aorta of male spontaneously hypertensive (SHR), but not in that of normotensive Wistar-Kyoto (WKY) rats, contractions to phenylephrine obtained in the presence of L-NAME [inhibitor of nitric oxide synthase (NOS)] and indomethacin (inhibitor of cyclooxygenase) are inhibited by an unknown endothelium-derived factor. The present study aimed to identify the mechanism underlying this endothelium-dependent inhibition in the SHR aorta. Aortic rings, with and without endothelium, of male SHR and WKY were suspended in organ chambers in the presence of indomethacin and L-NAME for the measurement of isometric tension. Contractions to phenylephrine were smaller in SHR, but not WKY, preparations with than without endothelium. The endothelium-dependent, NOS-independent inhibition of phenylephrine-induced contraction was abolished by oxyhemoglobin [extracellular nitric oxide (NO) scavenger], carboxy-PTIO (NO scavenger) and ODQ (inhibitor of soluble guanylyl cyclase). It was unmasked not only by indomethacin but also by apocynin (antioxidant), but inhibited by diphenyleneiodonium (inhibitor of flavoproteins including cytochrome P450 reductase). The cytochrome P450 reductase protein expression was similar in SHR and WKY aortae. However, the level of nitrate and nitrite, substrates of cytochrome P450 reductase, were higher in SHR than WKY plasma and aortae. Therefore, in SHR but not WKY aortae, eNOS-independent NO is formed by cytochrome P450 reductase.
Journal of Pharmacology and Experimental Therapeutics 09/2012; 344(1). DOI:10.1124/jpet.112.198721 · 3.97 Impact Factor
"These studies demonstrate the complexity of endothelium derived NO in the setting of atherosclerosis but clearly illustrate the dysfunctional eNOS/NO pathway as an early marker or a common mechanism for various cardiovascular disorders and therefore provides an ideal target for therapeutic or preventive intervention including alternative NOS independent sources of NO. Stokes et al. have demonstrated that supplementing nitrite in the drinking water inhibits the adhesion and emigration of leukocytes to the vascular endothelium, one of the earliest events of atherogenesis suggesting this nitrate-nitrite-NO pathway may be useful in preventing chronic vascular disease. "
[Show abstract][Hide abstract] ABSTRACT: The nation's aging population is growing rapidly. By 2030, the number of adults age 65 and older will nearly double to 70 million. Americans are living longer and older adults can now live for many years with multiple chronic illnesses but with a substantial cost to health care. Twenty percent of the Medicare population has at least five chronic conditions i.e., hypertension, diabetes, arthritis, etc. Studies in experimental models and even humans reveal that constitutive production of nitric oxide (NO) is reduced with aging and this circumstance may be relevant to a number of diseases that plague the aging population. NO is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including, but not limited to, host defense, neuronal communication and the regulation of vascular tone. NO is one of the most important signaling molecules in our body, and loss of NO function is one of the earliest indicators or markers of disease. Clinical studies provide evidence that insufficient NO production is associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and severity of atherosclerosis, and also has a profound predictive value for disease progression including cardiovascular and Alzheimers disease. Thirty plus years after its discovery and over 13 years since a Nobel Prize was awarded for its discovery, there have been no hallmark therapeutic breakthroughs or even NO based diagnostics. We will review the current state of the science surrounding NO in the etiology of a number of different diseases in the geriatric patient. From these observations, it can be concluded that enzymatic production of NO declines steadily with increasing age in healthy human subjects. Implementing strategies to diagnose and treat NO insufficiency may provide enormous benefit to the geriatric patient.
[Show abstract][Hide abstract] ABSTRACT: The gaseous radical nitric oxide is involved in numerous physiologic and pathophysiological events important in anesthesiology and intensive care. Nitric oxide is endogenously generated from the amino acid l-arginine and molecular oxygen in reactions catalyzed by complex nitric oxide synthases. Recently, an alternative pathway for nitric oxide generation was discovered, wherein the inorganic anions nitrate (NO3) and nitrite (NO2), most often considered inert end products from nitric oxide generation, can be reduced back to nitric oxide and other bioactive nitrogen oxide species. This nitrate-nitrite-nitric oxide pathway is regulated differently than the classic l-arginine-nitric oxide synthase nitric oxide pathway, and it is greatly enhanced during hypoxia and acidosis. Several lines of research now indicate that the nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia. The fact that nitrate is abundant in our diet gives rise to interesting nutritional aspects in health and disease. In this article, we present an overview of this field of research with emphasis on relevance in anesthesiology and intensive care.
Francesco Impagnatiello, Carol B Toris, Minerva Batugo, Ganesh Prasanna, Valentina Borghi, Elena Bastia, Ennio Ongini, Achim H P Krauss
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