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• W2314548171 abstract "In this issue of the journal, Maffei et al. [1] describe the measurement of intracellular NO in rat arteries using the fluorescent probe, 4,5-diaminoflurescein diacetate (DAF–2). DAF-2 has been used for several years to quantify levels of NO in a range of cell culture systems but its use in tissues has been limited because of problems with non-specific fluorescence and, particularly, auto-fluorescence of the elastic lamina. By careful use of conditions and timing, the authors have minimized these problems. Having established their methodology, they go on to compare intracellular NO levels in arteries from Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) and report increased levels of basal NO in SHR. Such observations are consistent with previously reported increases in levels of endothelial nitric oxide synthese (eNOS) mRNA, and NOS activity in hypertensive rats [2–5]. In contrast to the increase in basal NO production, the authors suggest that NO production in response to acetylcholine stimulation is reduced in SHR. Addition of ascorbate further enhanced basal NO levels in the SHR and increased acetylcholine stimulated levels in SHR but not WKY rats. How can all these observations be reconciled? The authors interpret their results in terms of overproduction of reactive oxygen species in SHR and scavenging by ascorbate. Excessive formation of reactive oxygen species, in particular superoxide, is well documented in most forms of cardiovascular disease. In many models of hypertension, there is evidence that eNOS itself is a major source of superoxide [5,6]. Stimulation of the acetylcholine receptor leads to increases in intracellular calcium and activation of eNOS. In the hypertensive model, although some NO is produced, superoxide may be the predominant radical formed. This superoxide may react with NO. The net result is that much less NO is available to react with DAF-2 in SHR. The uncoupling of eNOS is believed to be consequent on reduced bioactivity of tetrahydrobiopterin [6,7]. eNOS is situated on the inner surface of caveola and NO is released intracellularly [8]. NO is a labile molecule and, as well as interacting with other intracellular molecules, readily diffuses to vascular smooth muscle and interacts with other extracellular agents. Superoxide, unlike NO, is not readily membrane permeable. However, there are numerous sources of superoxide and it may be formed both intracellularly and extracellularly [9,10]. Thus, a complex balance exists between NO production and scavenging in intracellular and extracellular compartments. Under normal physiological conditions, scavenging of NO by superoxide is minimal and superoxide generation is low, and what is produced is rapidly converted to hydrogen peroxide and subsequently water by superoxide dismutase and catalase, respectively. Under pathophysiological conditions, this nitric oxide/super oxide balance is perturbed. A family of superoxide dismutases (SODs) exist which scavenge superoxide in different cellular compartments. SOD1 or Cu/Zn SOD acts intracellularly, SOD2 (MnSOD) is the mitochondral form, while SOD3 (EC-SOD) acts extracellularly. EC-SOD is found in very large amounts in the interstitium of the human arterial wall but is almost undetectable in rat arteries [11]. Levels of EC-SOD appear to be critical when considering pathophysiology. Angiotensin II increases oxidative stress but also expression of EC-SOD [12]. Levels of EC-SOD are also reported to be increased by cytokines [13] and in atherosclerotic vessels [14]. In most cases, gene transfer of EC-SOD has proved more successful than transfer of Cu/Zn or MnSOD in improving endothelial function [15–18]. Ascorbic acid, similar to EC-SOD, will act extracellularly to scavenge superoxide. The decrease in levels of extracellular superoxide will facilitate passage of NO to the smooth muscle cell and thus increase its biological activity. However, Maffei et al. [1] show that ascorbate can also increase levels of intracellular NO. It is not obvious why intracellular levels of NO are higher in the presence of ascorbic acid. Is the distribution of NO between cellular compartments altered? Does ascorbate have a sparing effect on other enzyme systems which are able to scavenge superoxide intracellularly? Is there some leaching of DAF-2 into the extracellular space? Intracellular ascorbic acid can enhance eNOS activity by increasing tetrahydrobiopterin [19]. However, this is unlikely to account for the acute effects of ascobate reported by Maffei et al. The studies with ascorbic acid should also be considered in the wider context of antioxidant therapy in cardiovascular disease. Animal studies both in vitro and in vivo have almost uniformly demonstrated an antioxidant effect of vitamin administration and delayed progression or regression of atherosclerosis. This has not translated to man. Clinical trials of antioxidant therapy present a confused picture and, in the majority of trials, the results have been disappointing. However, most trials have focused on vitamin E rather than vitamin C, and epidemiological studies strongly sustain the antioxidant hypothesis [20,21]. Moreover some studies suggest that vitamin C can improve endothelial function in man. In one small study in pregnant women, the incidence of pre-eclampsia was significantly less in patients treated with vitamins C and E [22]. Vitamin C was also shown to improve endothelial function in two small studies, comprising 15 and 55 patients, with chronic heart failure [23,24]. Although the balance between extracellular levels of NO and superoxide are key in regulating NO dependent vasorelaxation, intracellular levels of the radicals are of equal biological importance. Peroxynitrite formed intracelluarly from reaction between NO and superoxide has widespread disruptive effects on cellular metabolism. It can inhibit antioxidant systems, cause nitration of tyrosine groups on proteins, interfere with signalling process and give rise to mitachrondrial DNA damage [9,25]. It is clear that we need to consider not only global levels of NO and superoxide under pathophysiological conditions, but also localization. Fluorescent probes such as DAF-2, 1,2-diaminoanthraquinone, hydroethidine and dichlorodihydrofluorescein (for measurement of NO, superoxide and peroxynitrite, respectively) have the potential to address this. As more methods become available for studying NO and superoxide, it becomes important to be aware of exactly what each method offers and even more important to define precisely the question to be addressed and the most appropriate methods for doing so." @default.
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• W2314548171 date "2002-06-01" @default.
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• W2314548171 title "Nitric oxide, oxidative stress and hypertension: a complex equation" @default.
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• W2314548171 doi "https://doi.org/10.1097/00004872-200206000-00008" @default.
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