Peroxynitrite is a contractile agonist of cerebral artery smooth muscle cells

Elliott, Stephen J.; Lacey, David; Chilian, William M.; Brzezinska, Anna K.

doi:10.1152/ajpheart.1998.275.5.h1585

Cited by 45 publications

(57 citation statements)

References 14 publications

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“…These data were in agreement with studies in other arterial ring preparations from different animals [23,125,144], and are in agreement with the concept that the endothelium has no significant role in the modulation of PN responses [23]. However, these findings are in contrast to observations in a cerebral smooth muscle cell preparation and in middle cerebral arteries of the rat where PN induced contraction [195,196]. In this study, the PN-induced relaxation was reproducible without the development of tachyphylaxis, suggesting that the action of PN is reversible and does not cause vascular damage.…”

Section: Vasorelaxant Properties Of Peroxyni-tritesupporting

confidence: 92%

Potential Benefits of Peroxynitrite

Nossaman

Kadowitz²

2008

TOPHARMJ

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Peroxynitrite (PN) is generated by the reaction of nitric oxide (NO) and superoxide in one of the most rapid reactions in biology. Studies have reported that PN is a cytotoxic molecule that contributes to vascular injury in a number of disease states. However, it has become apparent that PN has beneficial effects including vasodilation, inhibition of platelet aggregation, inhibition of inflammatory cell adhesion, and protection against ischemia/reperfusion injury in the heart. It is our hypothesis that PN may serve to inactivate superoxide and prolong the actions of NO in the circulation. This manuscript reviews the beneficial effects of PN in the cardiovascular system. Keywords:Nitric oxide/*metabolism, nitric oxide synthase/metabolism/physiology, peroxynitrous acid/metabolism, reactive nitrogen species/metabolism, reactive oxygen species/metabolism, endothelium, vascular/drug effects/metabolism, muscle, smooth, vascular/drug effects/*metabolism, vasodilator agents/adverse effects, oxidative stress/*physiology, vasodilation/drug effects.

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Section: Vasorelaxant Properties Of Peroxyni-tritesupporting

confidence: 92%

Potential Benefits of Peroxynitrite

Nossaman

Kadowitz²

2008

TOPHARMJ

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“…35 In addition, studies on cell cultures suggest that homocysteine may also promote increased generation of ROS 18 -21 by downregulating antioxidant mechanisms, such 37 We found that ONOO Ϫ is a potent vasoactive agent that elicits substantial TxA 2 -mediated constriction in skeletal muscle arterioles ( Figure 4A), similar to its action in cerebral arteries. 34 Direct measurements of ONOO Ϫ metabolism have shown that ONOO Ϫ (formed from xanthine-oxidase-derived superoxide and NO) can be effectively scavenged by urate in biological systems. 31 The finding that urate prevented ONOO Ϫ -induced arteriolar constrictions ( Figure 4A) confirms that urate acts as a potent ONOO Ϫ scavenger under the present experimental conditions as well.…”

Section: Discussionmentioning

confidence: 99%

“…Immediately before each experiment, an aliquot of the stock solution was diluted into an ice-cold alkaline solution, 34 from which an appropriate volume was administered immediately in the organ bath. SQ 29,548 (Cayman Chemicals) was dissolved in ethanol; urate (Calbiochem) was dissolved in alkaline buffer.…”

Section: Methodsmentioning

confidence: 99%

Xanthine Oxidase–Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia

Bagi

Ungvári

Koller

2002

ATVB

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Abstract-We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter Ϸ170 m) from control and methionine diet-induced HHcy rats were measured by videomicroscopy. Key Words: homocysteine Ⅲ arterioles Ⅲ flow-induced constriction Ⅲ thromboxane A 2 Ⅲ reactive oxygen species Ⅲ xanthine oxidase I ncreased plasma concentration of the methionine metabolite homocysteine 1 is an independent risk factor for cardiovascular diseases, such as stroke, myocardial infarction, peripheral vascular disease, and atherosclerosis. 1,2 One of the mechanisms by which hyperhomocysteinemia (HHcy) elicits its adverse vascular effects is by altering endothelial function. Recent studies by other laboratories and ours showed that even mild HHcy (15 to 30 mol/L) is associated with significant impairment of endothelium-dependent acetylcholine-, histamine-, or bradykinin-induced vasoactive responses in large arteries and aorta of monkeys 3,4 and mice, 5-7 as well as in rat skeletal muscle arterioles. 8,9 Furthermore, we demonstrated that increases in intraluminal flow-related wall shear stress, the primary stimulus for the endothelial synthesis/release of nitric oxide (NO) and prostaglandins (PGs) in vivo, which maintain a dilated state of arterioles, elicit constrictions in arterioles of HHcy rats because of the simultaneous lack of NO mediation and enhanced thromboxane A 2 (TxA 2 ) release. 10 These findings have important clinical applications, because in humans, a similar degree of mild HHcy, either basal or transient after a methionine load, is associated with an impaired dilation or even constriction of arteries in response to a release of forearm occlusion. [11][12][13][14][15][16] The underlying mechanisms responsible for flow-induced endothelium-dependent constriction in HHcy, however, remained unknown.Flow-dependent skeletal muscle, arteriolar dilation is mediated by NO and dilator PGs, the synthesis/release of which can be substantially affected by reactive oxygen species (ROS). 17 Studies on endothelial cells in culture suggest that high levels of homocysteine may promote the generation of ROS. 18 -22 Previous studies demonstrated that ROS [in particular, superoxide produced by endothelial NAD(P)H oxidase and/or xanthine oxidase] may impair arteriolar functions in pathophysiological conditions, such as hypertension, 23 hypercholesterolemia, 24 and diabetes. 25 A role for oxidative stress in HHcy-induced endothelial dysfunction in humans is also supported by recent studies showing that oral administration of antioxidants (eg, vitamin C, vitamin E) prevented oral methionine load-induced impairment of dilation of conduit arteries to acetylcholine 26 and after release of forearm occlusion. 27,28

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“…-ATPase type-2 [11,[38][39][40][41]. In addition, peroxynitrite has been shown to induce degranulation of eosinophils, epithelial damage and AHR [33,34], as well as airway microvascular hyperpermeability [35] in guinea pigs.…”

Section: +mentioning

confidence: 99%

L-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

European Respiratory Journal

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ABSTRACT:Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NOsynthase (iNOS) at low L-arginine concentrations. L-Arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N v -hydroxy-nor-Larginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N v -nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginaseand polycation-induced attenuation of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.

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Peroxynitrite is a contractile agonist of cerebral artery smooth muscle cells

Cited by 45 publications

References 14 publications

Potential Benefits of Peroxynitrite

Potential Benefits of Peroxynitrite

Xanthine Oxidase–Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia

L-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

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