Nitric oxide animal models

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

Nitric oxide may be the active moiety of STZ that induces diabetes in this animal model. STZ contains a nitroso moiety and may release nitric oxide by a process analogous to the nitric oxide donor compounds SIN-1 and nitroprusside. Turk et al. (1993) have shown that incubation of rat islets with STZ at concentrations that impair insulin secretion results in the generation of nitrite and the accumulation of cGMP. STZ also inhibits mitochondrial aconitase activity of islets to a degree similar to that achieved by IL-1. These findings provide the first evidence that STZ impairs islet function by liberating nittic oxide. 

In animal models and some human studies, ginkgo has been shown to increase blood flow, reduce blood viscosity, and promote vasodilation, thus enhancing tissue perfusion. Enhancement of endogenous nitric oxide (see Chapter 19) and antagonism of platelet-activating factor may be involved. 

PCP inhibits brain nitric oxide synthase irreversibly (Osawa and Davila, 1993 Jewett et al., 1996 Klamer et al., 2005). Depending upon its levels, nitric oxide acts as a neuroprotective or neurodestructive molecule (Lipton, 1993 Lipton et al., 1998). NMDA receptor antagonists that have treated ischemic injury of the brain in animal models with some benefit are presented in Tables 10.1 and 10.2. All studies on their use in humans have been unsuccessful because they not only block normal neuronal function, but also produce serious side effects such as headache, anxiety, agitation, nausea, vomiting, hallucinations, dizziness, and coma (Schehr, 1996 Koroshetz and Moskowitz, 1996 Ratan et al., 1994). Clinical trials of NMDA antagonists for stroke and traumatic brain injury have been abandoned (Kemp and McKeman, 2002 Lees et al., 2000 Sacco et al., 2001). 

Nitric oxide also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, THl cells (see Chapter 56 Immunopharmacology) respond by synthesizing nitric oxide. Inhibition of NOS and knockout of the NOS-2 gene can markedly impair the protective response to injected parasites in animal models. 

Bisphosphonates (particularly clodronate) have been shown to have anti-inflammatory effects in animal models of rheumatoid arthritis (RA), as well as in arthritis in humans. In adjuvant- and antigen-induced arthritis in rats, clodronate suppresses the inflammatory articular lesions in the inflamed joints [29], whilst in human RA, clodronate decreases the levels of interleukin (ILJ-1, tumor necrosis factor-alpha (TNFaand /1-microglobulin in the circulation [30]. In vitro, clodronate inhibits cytokine and nitric oxide (NO) release and inducible nitric oxide synthase (iNOS) expression in macrophage-like cells. 

The molecular mechanism linking the inflammatory response to redox equilibria and modification of nitric oxide production will be explored in an animal model system of septic shock, a generalized inflammation induced by bacterial lipopolisaccharide (LPS). It is known that endotoxemia induces a complex interplay between the activation of nuclear transcription factors such as nuclear factor kappa B (NFkB) and a cascade-activation of various enzymatic activities, mostly mediators of the inflammatory response with particular attention to the variation of the inducible form of nitric oxide synthase (iNOS). 

In comparison to the n-6 series, much less attention has been paid to the involvement of n-3 fatty acids in diabetic neuropathy, although the beneficial effects offish-oil supplements, a rich source of these fatty acids, in the prevention of atherosclerosis and hypertension in animal models and patients with vascular complications is well known (Lands et al. 1992). Proposals for the mechanisms by which n-3 fatty acids act include serving as precursors of vasoactive prostanoids and acting as shmulants for production of relaxing factors, such as nitric oxide (Lands etal. 1992 Boulanger 1990 McVeigh etal. 1993). 

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