Nitric oxide in the pathogenesis of diffuse pulmonary fibrosis

By studying the responses of nitric oxide in pulmonary fibrosis, the role of inducible nitric oxide synthase in diffuse pulmonary fibrosis as caused by lipopolysaccharide (LPS) treatment was investigated. When compared to rats treated with LPS only, the rats pretreated with 1400W (an iNOS-specific inhibitor) were found to exhibit a reduced level in: (i) NOx (nitrate/nitrite) production, (ii) collagen type I protein expression, (iv) soluble collagen production, and (iv) the loss of body weight and carotid artery PO2. In the pulmonary fibroblast culture, exogenous NO from LPS-stimulated secretion by macrophages or from a NO donor, such as DETA NONOate, was observed to induce the expression of TIMP-1, HSP47, TGF-beta1, and collagen type I as well as the phosphorylation of SMAD-2. After inhalation of NO for 24 h, an up-regulation of collagen type I protein was also noted to occur in rat pulmonary tissue. The results suggest that the NO signal pathway enhanced the expression of TGF-beta1, TIMP-1, and HSP47 in pulmonary fibroblasts, which collectively demonstrate that the NO signal pathway could activate the SMAD-signal cascade, by initiating a rapid increase in TGF-beta1, thereby increasing the expression of TIMP-1 and HSP47 in pulmonary fibroblasts, and play an important role in pulmonary fibrosis.     

Nitric oxide regulation of lingual blood flow in the rat.

The purpose of this study was to determine the role of nitric oxide in the maintenance of basal lingual blood flow in the anesthetized rat. By using laser-Doppler flowmetry, blood flow was measured from the tongue before and after treatment with the nonselective inhibitor of nitric oxide synthase, L-NAME (0.2, 2.0, and 20 mg/kg), or the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (40 mg/kg). Other groups of rats were treated with saline, D-NAME (2.0 mg/kg), L-arginine (200 mg/kg), L-arginine + L-NAME (200 + 2.0 mg/kg), or the 7-nitroindazole vehicle. L-NAME produced a dose-related depression in blood flow in the tongue (concurrent with increased arterial blood pressure), which was attenuated by prior administration of L-arginine. Lingual blood flow depression was not seen after administration of the inactive stereoisomer, D-NAME. In addition, the neuronally specific nitric oxide synthase inhibitor, 7-nitroindazole, failed to produce a significant depression of lingual blood flow. These results suggest that the tonic release of nitric oxide from the vascular endothelium plays an important role in maintaining basal blood flow in the tongue and that neuronally released nitric oxide is not involved in maintaining basal circulation in this vascular bed.     

Views on the autoimmunity hypothesis for Chagas disease pathogenesis

Initially, the notion that the pathogenesis of Chagas disease has an autoimmune component was based on the finding that sera from Trypanosoma cruzi-infected patients or laboratory animals contain antibodies that recognize both parasite and host tissue antigens. Subsequent work suggested that T lymphocytes from chagasic patients and animals also displayed such cross-reactivity. However, the autoimmunity hypothesis has remained controversial because of experimental pitfalls, incomplete or inadequate controls, difficulties in reproducing some key results, and a lack of persuasive evidence that the cross-reactive antibodies or lymphocytes can truly effect the multifaceted pathological features of Chagas disease. Whether the immunologic autoreactivities described to date cause chagasic pathology or result from it is another unresolved question. Discussed herein are the most recent contributions to this topic and the reservations they have raised.     

Nitric oxide as a signal in blood vessels.

In the five years since the discovery that nitric oxide is produced as a signal in blood vessels, a great deal has been discovered about the processes involved. This article reviews current knowledge about the vascular cell synthesis, effects and subsequent destruction of this messenger molecule.     

Nitric oxide: Involvement in the nervous control of cardiovascular function

Identification of nitric oxide (NO) as a neurotransmitter in the CNS resulted in initiation of numerous studies aimed at elucidating the roles of NO not only at a cellular level, but also in regulation of the activity of specific physiological systems coordinated by the brain. In this lecture, we will discuss the state of current knowledge about cellular events in the brain realized with the involvement of NO, distribution of NO-producing neurons in cerebral structures providing central cardiovascular control, peculiarities of NO production, and mechanisms underlying NO-mediated neuromodulatory effects on cardiovascular function. Activation of the NO system in the lower brainstem modulates a variety of neuronal pathways; NO was shown to induce GABA and glutamate releases within the medulla. The NO system in the brain is activated in the states of homeostatic imbalance, including hypertension and stress.Neirofiziologiya/Neurophysiology, Vol. 36, Nos. 5/6, pp. 466–478, September–December, 2004.This revised version was published online in April 2005 with a corrected cover date and copyright year.     

Nitric oxide and sympathoexcitatory cardiovascular neurons of the ventrolateral medulla in cats

In acute experiments on cats, the effects of injections of nitric oxide (NO) donors and an inhibitor of its synthesis into the sympathoexcitatory neuronal structures in the ventrolateral medulla (VLM) were studied to examine their effects on the peripheral mechanisms of the cardiovascular control. Unilateral injections of NO donors, nitroglycerine (1.3–5.2 nmol) or sodium nitroprusside (1.1–4.6 nmol) into the sites of the sympathoexcitatory neurons residing in the VLM induced the lowering of the systemic arterial pressure (SAP) in a dose-depended fashion. Two types of the hypotensive responses have been distinguished. In the first type responses, lowering of the SAP level was mainly due to a decrease in the peripheral vascular resistance (PVR), while the heart rate (HR) and stroke volume (SV) were only slightly reduced. In the second type responses, the drop in SAP level resulted mainly from a decrease in the HR and myocardial contractivity. These effects were induced by the limitation of the descending excitatory influences to the heart and vessels from the VLM sympathoexcitatory systems. An increase in the NO concentrations in the neuronal structures located 2.5–4.5 mm caudally to the trapezold bodies resulted in the first type responses, while that in the sites immediately adjacent to the caudal sympathoinhibitory area (0.5–1.5 mm rostrally to the XIIth cranial nerve roots) was associated with the second type of reactions. Stimulation of the endogenous NO release from the neurons after injections of L-arginine induced the same cardiovascular shifts as exogenic NO did, and attenuation of NO synthesis following injections of NO antagonist L-NMMA into the VLM neuronal structures evoked hemodynamic shifts of a reverse direction. Injections of NO donors inhibited the reflex responses induced by the activation of the carotid sinus receptors. Our data give further evidence for NO involvement in the inhibitory control of the cardiac activity and vascular tone through those VLM sympatoexcitatory neurons, which are involved in the system of central neurogenic cardiovascular control and the activity of which prevent the development of hypertension.Neirofiziologiya/Neurophysiology, Vol. 28, No. 2/3, pp. 111–120, March–June, 1996.     

The antioxidant hypothesis of cardiovascular disease: epidemiology and mechanisms

Plasma levels of major essential antioxidants were determined in representative random samples of middle-aged men from 16 European study populations which differed up to 6-fold in age-specific mortality from ischaemic heart disease (IHD). In 12 study populations having total plasma cholesterol in the medium range (5.7-6.2 mmol/l) and usual blood pressure, both these classical risk factors lacked a significant correlation to IHD mortality, whereas the absolute level of vitamin E (alpha-tocopherol) showed a strong inverse correlation (r2 = 0.63, P = 0.002). On evaluation of all study populations, cholesterol and diastolic blood pressure had a moderate direct association with IHD, but their importance still remained inferior to that of vitamin E as an inversely associated, presumably protective factor. In stepwise regression and multiple regression analysis, the IHD mortality of the study populations was predictable to 62% by lipid-standardized vitamin E, to 79% by vitamin E and total cholesterol, to 83% after inclusion of lipid-standardized vitamin A (retinol) and to 87% by all the above parameters plus diastolic blood pressure. In conclusion, in the present study the plasma status of vitamin E is the most important factor to explain cross-cultural differences of IHD mortality. This finding is consistent with the hypothesis of the prevention of arteriosclerosis by antioxidant protection against peroxidative lipoprotein modification, but does not exclude additional effects of antioxidant vitamins, e.g. on the cellular or immunological level.     

Nitric oxide effect on the hemoglobin-oxygen affinity.

The biological roles of nitric oxide (NO)-hemoglobin (Hb) derivatives are obscure. It is proposed that NO can function as an allosteric regulator of hemoglobin oxygen-binding properties. We aimed to estimate the effects of NO donors and NO-synthase substrate (L-arginine) on hemoglobin-oxygen affinity (HOA) in experiments in vitro with the various ratios between NO formed and Hb and various oxygen pressures. HOA index (p50), blood pH, plasma and red blood cell (RBC) concentrations of nitrite/nitrate and methemoglobin amounts were measured after the experiments. In our experiments, blood incubation with NO donors (glyceryltrinitrate, molsidomine, sodium nitroprusside, S-nitrosocysteine) or NO-synthase substrate (L-arginine) did not change HOA even at NO:Hb ratio of 1:1. At the same time our results showed that oxygenated blood incubation with S-nitrosocysteine induced an oxyhemoglobin dissociation curve shift leftwards. This indicates a leading role of met-Hb in a modification of Hb oxygen-binding properties. However other NO-modified forms of hemoglobin (S-nitroso- and nitrosylhemoglobin) also may be involved in the regulation of HOA. The results obtained indicate that nitric oxide can be the allosteric effector of hemoglobin, increasing or decreasing its oxygen affinity - possibly, through the generation of different NO-Hb derivatives.     

The role of adiponectin in pathogenesis of metabolic syndrome and cardiovascular disease

The aim of this review is to present the up-to-date data about adiponectin and it's role in pathogenesis of cardiovascular disease. Adiponectin is a hormone derived from adipose tissue which regulates energy metabolism, and plays an important role in the pathogenesis of insulin resistance. Serum levels of adiponectin are reduced in obesity, hypertension, metabolic syndrome and type 2 diabetes. Moreover, plasma adiponectin concentration is inversely associated with LDL-cholesterol, TG and is positively related to HDL-cholesterol. Recent studies have indicated that adiponectin has antiinflammatory and antiatherogenic properties. Review of the data confirmed the hypothesis that adiponectin plays an important role in pathogenesis of cardiovascular disease.     

Nitric oxide in septic shock.

Septic shock is a major cause of death following trauma and is a persistent problem in surgical patients throughout the world. It is characterised by hypotension and vascular collapse, with a failure of the major organs within the body. The role of excessive nitric oxide (NO) production, following the cytokine-dependent induction of the inducible nitric oxide synthase (iNOS), in the development of septic shock is discussed. Emphasis is placed upon the signal-transduction process by which iNOS is induced and the role of NO in cellular energy dysfunction and the abnormal function of the cardiovascular system and liver during septic shock.     

Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications

Traditional Chinese medicine (TCM) has been used for centuries to treat and prevent certain ailments and diseases. Although TCM has served as mainstream medical care throughout Asia for many generations, it is considered an alternative medical system in much of the Western world. Because many TCMs are used primarily for cardiovascular indications characterized by a nitric oxide (NO) insufficiency, we hypothesized that some, if not all, of these TCMs have a robust NO bioactivity that may act to restore NO homeostasis. We tested a group of convenience samples of TCMs obtained in the United States for endogenous nitrite, nitrate, nitroso, and nitrite reductase activity as well as their ability to relax isolated aortic rings. The results from this study reveal that all of the TCMs tested reveal NO bioactivity through their inherent nitrite and nitrate content and their ability to reduce nitrite to NO. Many of the TCM extracts contain a nitrite reductase activity greater by 1000 times that of biological tissues. Repletion of biological nitrite and nitrate by these extracts and providing a natural system for NO generation in both endothelium-dependent and -independent mechanisms may account for some of the therapeutic effects of TCMs.     

Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis

Nitric oxide (NO) is an important mediator in both health and disease. In addition to its effects on vascular tone and platelet function, it plays roles in inflammation and pain perception that may be of relevance in osteoarthritis. Many patients with osteoarthritis take nonsteroidal anti-inflammatory drugs (NSAIDs) long term for pain control. Over recent years concern has been raised about the possible cardiovascular side effects of NSAIDs. The reasons for this possible increased cardiovascular risk with NSAIDs are not yet entirely clear, although changes in blood pressure, renal salt handling and platelet function may contribute. Recently, drugs that chemically link a NSAID with a NO donating moiety (cyclo-oxygenase-inhibiting NO-donating drugs [CINODs]) were developed. NO is an important mediator of endothelial function, acting as a vasodilator and an inhibitor of platelet aggregation, and having anti-inflammatory properties. The potential benefits of CINODs include the combination of effective analgesic and anti-inflammatory actions with NO release, which might counterbalance any adverse cardiovascular effects of NSAIDs. Effects of CINODs in animal studies include inhibition of vasopressor responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation. CINODs may also reduce ischemic damage to compromised myocardial tissue. In addition, endothelial dysfunction is a recognized feature of inflammatory arthritides, and therefore a drug that might provide slow release of NO to the vasculature while treating pain is an attractive prospect in these conditions. Further studies of the effects of CINODs in humans are required, but these agents represent a potential exciting advance in the management of osteoarthritis.     

Nitric oxide modulates the cardiovascular effects elicited by acetylcholine in the NTS of awake rats

Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 +/- 5 mmHg before L-NAME to 9 +/- 4 mmHg, 10 min after L-NAME, and HR fell by 100 +/- 26 bpm before L-NAME to 20 +/- 10 bpm, 10 min after L-NAME (both P < 0.05). Microinjection of the selective inhibitor of neuronal nitric oxide synthase (nNOS), 1-(2-trifluoromethylphenyl) imidazole (TRIM; 13.3 nmol in 100 nl), in the NTS also reduced responses to ACh: MAP fell from 42 +/- 3 mmHg before TRIM to 27 +/- 6 mmHg, 10 min after TRIM (P < 0.05). TRIM also tended to reduce ACh-induced bradycardia, but this effect was not statistically significant. ACh-induced hypotension and bradycardia returned to control levels 30-45 min after NOS inhibition. Control injections with D-NAME and saline did not affect resting values or the response to ACh. In conclusion, injection of ACh into the NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.     

Nitric oxide function and signalling in plant disease resistance

Nitric oxide (NO) is one of only a handful of gaseous signalling molecules. Its discovery as the endothelium-derived relaxing factor (EDRF) by Ignarro revolutionized how NO and cognate reactive nitrogen intermediates, which were previously considered to be toxic molecules, are viewed. NO is now emerging as a key signalling molecule in plants, where it orchestrates a plethora of cellular activities associated with growth, development, and environmental interactions. Prominent among these is its function in plant hypersensitive cell death and disease resistance. While a number of sources for NO biosynthesis have been proposed, robust and biologically relevant routes for NO production largely remain to be defined. To elaborate cell death during an incompatible plant-pathogen interaction NO functions in combination with reactive oxygen intermediates. Furthermore, NO has been shown to regulate the activity of metacaspases, evolutionary conserved proteases that may be intimately associated with pathogen-triggered cell death. NO is also thought to function in multiple modes of plant disease resistance by regulating, through S-nitrosylation, multiple nodes of the salicylic acid (SA) signalling pathway. These findings underscore the key role of NO in plant-pathogen interactions.     

Nitric oxide and blood pressure in mice lacking extracellular-superoxide dismutase

Nitric oxide is a major vasorelaxant and regulator of the blood pressure. The blood vessels contain several active sources of the superoxide radical, which reacts avidly with nitric oxide to form noxious peroxynitrite. There are large amounts of extracellular-superoxide dismutase (EC-SOD) in the vascular wall. To evaluate the importance of EC-SOD for the physiology of nitric oxide, here we studied the blood pressure in mice lacking the enzyme. In chronically instrumented non-anaesthetized mice there was no difference in mean arterial blood pressure between wild-type controls and EC-SOD mutants. Extensive inhibition of nitric oxide synthases with N -monomethyl- l -arginine however resulted in a larger increase in blood pressure, and infusion of the nitric oxide donor nitrosoglutathione caused less reduction in blood pressure in the EC-SOD null mice. We interpret the alterations to be caused by a moderately increased consumption of nitric oxide by the superoxide radical in the EC-SOD null mice. One role of EC-SOD may be to preserve nitric oxide, a function that should be particularly important in vascular pathologies, in which large increases in superoxide formation have been documented.     

The effects of protein intake on blood pressure and cardiovascular disease

PURPOSE OF REVIEW: Investigators, especially those from western countries, have commonly assumed that there is either no association or a direct association of protein intake with elevated blood pressure and atherosclerosis. In contrast, recent observational studies and clinical trials have suggested that increased protein intake, particularly protein from plant sources, might actually reduce blood pressure and prevent cardiovascular disease. RECENT FINDINGS: In epidemiological studies, an increased intake of protein has been associated with lower blood pressure and an attenuated increase in blood pressure over time. Furthermore, such studies also suggest that the beneficial effects of increased protein intake result from an increased consumption of protein from plant rather than animal sources. In several predominantly small trials, an increased intake of soy protein lowered blood pressure. With respect to clinical outcomes, reports from large cohort studies suggest that increased protein intake is associated with a reduced risk of ischemic heart disease and perhaps intraparenchymal hemorrhage. In other reports, a higher protein intake is one characteristic of a dietary pattern associated with a reduced risk of ischemic heart disease. The mechanisms by which protein could exert its beneficial effects include an increased intake of biologically active amino acids, peptides, or highly correlated nutrients. SUMMARY: Recent evidence suggests that an increased intake of protein, particularly plant protein, may lower blood pressure and reduce the risk of cardiovascular disease. However, the data are not sufficiently compelling to advocate an increased consumption of protein.