European Journal of Pharmacology

1999

DOI: 10.1016/s0014-2999(99)00328-3

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Antiatherosclerotic activity of drugs in relation to nitric oxide function

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Arnold G. Herman

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Increased Lipidperoxidation1

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Cited by 32 publications

(26 citation statements)

References 198 publications

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“…Finally, the use of antioxidants might prevent the oxidative breakdown of NO and protect liver endothelial cells from injury. 85,86 Nitrovasodilators were used in the treatment of portal hypertension, long before the discovery of NO, because of their capacity to lower portal pressure. 87 Although it is fashionable to state that these drugs replace endogenous NO, important differences between the endogenous L-arginine/NO pathway and exogenous nitrovasodilators most likely exist.…”

Section: Increased Lipidperoxidationmentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

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2002

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C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

“…Finally, the use of antioxidants might prevent the oxidative breakdown of NO and protect liver endothelial cells from injury. 85,86 Nitrovasodilators were used in the treatment of portal hypertension, long before the discovery of NO, because of their capacity to lower portal pressure. 87 Although it is fashionable to state that these drugs replace endogenous NO, important differences between the endogenous L-arginine/NO pathway and exogenous nitrovasodilators most likely exist.…”

Section: Increased Lipidperoxidationmentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

¹

,

²

2002

View full text Add to dashboard Cite

C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

“…NO in the vasculature, the eects of PETN might be related to the antioxiative, anti-adhesive, antiproliferative, anti-aggregative or anti-apoptotic eects of . NO (Kojda & Harrison, 1999;Bult et al, 1999). Oxidized LDL is believed to play a causative role in mediating vascular dysfunction in vivo and has been shown to be correlated with the severity of cardiovascular disease (Steinberg, 1995;Cox & Cohen, 1996;Esterbauer et al, 1997).…”

Section: Nomentioning

confidence: 99%

The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis

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²

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et al. 2001

British J Pharmacology

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1 Recent results suggested that long-term treatment with a low dose of the organic nitrate pentaerythritol tetranitrate (PETN, 6 mg kg 71 per day) for 16 weeks slightly decreases aortic superoxide production in normal rabbits. We sought to determine if PETN can preserve endothelium dependent relaxation (EDR) in atherosclerotic rabbits. 2 Three groups of 9 ± 10 New Zealand White rabbits received a cholesterol chow (0.75%) for 16 weeks. One group (CHOL16) served as control and two groups were fed for another 16 weeks a cholesterol-chow without (CHOL32) or with 6 mg PETN kg 71 per day (PETN32). 3 Isolated aortic rings of CHOL16 showed a typical impairment of EDR with a maximal relaxation at 1 mM acetylcholine of 28+16%. In CHOL32-rings EDR was completely impaired. In striking contrast, EDR in PETN32 (24+15%) was similar to that of CHOL16 indicating a protective eect of PETN on endothelial function. Vascular superoxide production measured with the lucigenin method was not dierent between the groups. 4 Aortic lesion formation in PETN32 was smaller than in CHOL32 (P50.008). The onset of copper-induced LDL-oxidation (lag-time) after 16 weeks of cholesterol feeding (214+9 min) was reduced in CHOL32 (168+24 min, P=0.035) but not in PETN32 (220+21 min). This indicates prevention of increased LDL oxidation by PETN. 5 The halfmaximal eective vasodilator concentrations of PETN (in 7logM) were identical in CHOL16 (7.9+0.1), CHOL32 (7.6+0.2) and PETN32 (7.7+0.2). Similar results were obtained with S-nitroso-N-acetyl-D,L-penicillamine. 6 These data suggest that PETN can reduce the progression of lesion formation, endothelial dysfunction and of LDL-oxidation in established atherosclerosis.

“…All major risk factors for atherosclerosis including hypercholesterolemia, hypertension, and smoking have been associated with impaired vascular NO synthesis (6). The underlying mechanisms are thought to involve reduced formation of NO due to a decrease in NOS expression or a limited availability of L-arginine, as well as increased degradation of NO by reaction with superoxide anions or oxidized low density lipoproteins (5,6). Recent studies indicate that under certain pathological conditions, decreased availability of tetrahydrobiopterin may also be responsible for dysfunction of endothelial nitric-oxide synthase.…”

mentioning

confidence: 99%

l-Ascorbic Acid Potentiates Endothelial Nitric Oxide Synthesis via a Chemical Stabilization of Tetrahydrobiopterin

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et al. 2001

Journal of Biological Chemistry

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Ascorbic acid has been shown to stimulate endothelial nitric oxide (NO) synthesis in a time-and concentrationdependent fashion without affecting NO synthase (NOS) expression or L-arginine uptake. The present study investigates if the underlying mechanism is related to the NOS cofactor tetrahydrobiopterin. Pretreatment of human umbilical vein endothelial cells with ascorbate (1 M to 1 mM, 24 h) led to an up to 3-fold increase of intracellular tetrahydrobiopterin levels that was concentration-dependent and saturable at 100 M. Accordingly, the effect of ascorbic acid on Ca 2؉ -dependent formation of citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) was abolished when intracellular tetrahydrobiopterin levels were increased by coincubation of endothelial cells with sepiapterin (0.001-100 M, 24 h). In contrast, ascorbic acid did not modify the pterin affinity of endothelial NOS, which was measured in assays with purified tetrahydrobiopterin-free enzyme. The ascorbate-induced increase of endothelial tetrahydrobiopterin was not due to an enhanced synthesis of the compound. Neither the mRNA expression of the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the activities of either GTP cyclohydrolase I or 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de novo synthesis pathway, were altered by ascorbate. Our data demonstrate that ascorbic acid leads to a chemical stabilization of tetrahydrobiopterin. This was evident as an increase in the half-life of tetrahydrobiopterin in aqueous solution. Furthermore, the increase of tetrahydrobiopterin levels in intact endothelial cells coincubated with cytokines and ascorbate was associated with a decrease of more oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in cells and cell supernatants. The present study suggests that saturated ascorbic acid levels in endothelial cells are necessary to protect tetrahydrobiopterin from oxidation and to provide optimal conditions for cellular NO synthesis.Endothelium-derived nitric oxide (NO) is a potent signaling molecule in the cardiovascular system participating in many processes such as vascular relaxation, inhibition of platelet aggregation, regulation of endothelial cell adhesivity, and preservation of the normal vessel wall structure (1). NO is generated from the conversion of L-arginine to L-citrulline by the enzymatic action of an NADPH-dependent NO synthase (NOS) 1 that requires Ca 2ϩ /calmodulin, FAD, FMN, and tetrahydrobiopterin as cofactors (2). The endothelial NOS isoform (eNOS) is constitutively expressed and activated upon an increase of intracellular Ca 2ϩ following cell stimulation with agonists such as thrombin and bradykinin or through serine phosphorylation subsequent to cell stimulation with shear stress or insulin (3, 4).Evidence is accumulating that NO determines the antiatherosclerotic properties of the endothelium (5). All major risk factors for atherosclerosis including hypercholesterolemia, hypertension...

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