Role of <scp>L</scp>‐arginine in the vascular actions and development of tolerance to nitroglycerin

Abou-Mohamed, Gamal; Kaesemeyer, Wayne H.; Caldwell, Ruth B.; Caldwell, Robert W.

doi:10.1038/sj.bjp.0703293

Cited by 61 publications

(56 citation statements)

References 37 publications

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“…In this study we test and con®rm the hypothesis that eNOS is a site of O 2 .7 synthesis in endothelial cells activated by GTN when L-arginine is limited. The results of this study amplify our recent ®ndings that agonists of eNOS increase superoxide production when L-arginine is restricted (Ogonowski et al, 2000) and that L-arginine is depleted by GTN, indicating a component of nitroglycerin tolerance that is Larginine dependent (Abou-Mohamed et al, 2000).…”

Section: Introductionsupporting

confidence: 79%

Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate

Kaesemeyer

Ogonowski

Jin

et al. 2000

British J Pharmacology

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Tolerance to glyceryl trinitrate (GTN) involves superoxide (O2.−) production by endothelial cells. Nitric oxide synthase (NOS) produces O2.− when L‐arginine (L‐arg) is limited. The purpose of this study was to test the hypothesis that GTN stimulates NOS to increase O2.− synthesis in endothelial cells when L‐arg is limited. Production of O2.− by bovine aortic endothelial cells (BAEC, passages 3–5) was determined by spectrophotometrically measuring superoxide dismutase‐inhibited reduction of ferricytochrome C to ferrocytochrome C. Cells were incubated in buffer without L‐arg. O2.− production was measured using BAEC either untreated or treated with L‐NAME or L‐arg alone or following treatment with GTN (10−9 to 10−6 M) for 30 min or DPTA NONOate (10−7 and 10−6 M) alone or with GTN or DPTA NONOate after pretreatment with nitro‐L‐arginine methyl ester (L‐NAME), L‐arg or their inactive enantiomers, D‐NAME or D‐arg (all 5×10−4 M) (n=6–7/group). L‐NAME alone produced a 69% reduction in O2.− levels. Treatment with L‐arg alone had no effect. Cells treated with GTN alone exhibited an increase in O2.−. This effect was prevented by pretreatment with either L‐NAME or L‐arg, and was unaffected by D‐NAME or D‐arg. We observed a dose‐response relationship in O2.− production to GTN over a range of 10−9 to 10−7 M. The NO donor, DPTA‐NONOate, unlike GTN, did not have a significant effect on O2.− production. In conclusion, endothelial NOS is a site of O2.− synthesis in endothelial cells activated by GTN. British Journal of Pharmacology (2000) 131, 1019–1023; doi:10.1038/sj.bjp.0703665

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Section: Introductionsupporting

confidence: 79%

Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate

Kaesemeyer

Ogonowski

Jin

et al. 2000

British J Pharmacology

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“…34,35 We found no change in platelet NOS activity in the present studies. A decrease in platelet steady-state cGMP has been previously described in response to the continuous administration of organic nitrates.…”

Section: Discussioncontrasting

confidence: 32%

Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

et al. 2002

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Background-The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. Methods and Results-We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O 2 ·Ϫ ] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O 2 ·Ϫ production from 1.0Ϯ1.17 to 2.52Ϯ0.88 pmol/10 8 platelets and 13.2Ϯ4.8 to 72.5Ϯ34.4 pmol/10

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“…Another possible mechanism is GTN reducing in the cellular uptake of L-arginine, the precursor of NO. In this connection, there is recent evidence that GTN suppresses the uptake of L-arginine by cultured bovine endothelial cells after 1-4 h of treatment (41). The above two mechanisms are not mutually exclusive and may both contribute to the GTN-induced reduction of plasma NOx in patients with diabetes (diagram in Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect of Diabetes on Nitric Oxide Metabolism During Cardiac Surgery

Matata

Galiñanes

2001

Diabetes

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The metabolism of nitric oxide (NO) during cardiac surgery is unclear. We studied the effect of diabetes on NO metabolism during cardiac surgery in 40 subjects (20 with diabetes and 20 without diabetes). The patients were randomized to receive an infusion of physiological saline or nitroglycerin (GTN) at 1 g ⅐ kg -1 ⅐ min -1 starting 10 min before the initiation of cardiopulmonary bypass and then continuing for a period of 4 h. Blood and urine samples were collected at several time points for up to 8 h. NO metabolites were determined by the measurement of nitrate/nitrite (NOx, mol/mmol creatinine) and cyclic guanosine monophosphate (cGMP, nmol/mmol creatinine) in plasma and urine. Plasma insulin levels were also determined at selected time points. Plasma NOx levels before surgery were significantly elevated in the group with diabetes compared with the group without diabetes (P < 0.001), and values were further increased during surgery in the former (P ‫؍‬ 0.005) but not in the latter (P ‫؍‬ 0.8). The greater plasma NOx values in patients with diabetes were matched by commensurate elevations in plasma cGMP levels (P ‫؍‬ 0.01). Interestingly, infusion of GTN, an NO donor, significantly reduced plasma NOx (P < 0.001) and its urine elimination (P < 0.001) in patients with diabetes without reducing plasma cGMP levels (P ‫؍‬ 0.89). Cardiac surgery increased plasma insulin in patients with and without diabetes; this increase was delayed by the infusion of GTN, but it was not related to the changes in NO production. In conclusion, NO production during cardiac surgery is increased in patients with diabetes, and this elevation can be blunted by the infusion of GTN in a rapid and reversible manner. Diabetes 50: [2603][2604][2605][2606][2607][2608][2609][2610] 2001 D iabetes is recognized as a major independent risk factor for cardiovascular disease (1). In addition, patients with diabetes undergoing cardiac surgery have a greater rate of perioperative complications and increased mortality than those without diabetes (2,3), but the reason for this is unknown. Diabetes is associated with altered endothelial vascular responses (4), and modifications in nitric oxide (NO) metabolism may play a role. This thesis finds support in the observation that diabetes affects basal NO metabolism (5). We have also recently demonstrated (6) that the provision of exogenous NO during cardiac surgery influences oxidative stress and the inflammatory response to cardiopulmonary bypass (CPB), effects that are more prominent in patients with diabetes than in those without diabetes. NO, synthesized by NO synthase (NOS) from a terminal guanidino group of L-arginine (7), relaxes vascular smooth muscle and inhibits platelet aggregation and adhesion via the second messenger cyclic guanosine monophosphate (cGMP) (8), and it has also been implicated in the pathophysiology of a number of cardiovascular diseases, including atherosclerosis (9), septic shock (10), inflammation (11), oxidative stress (12), and ischemia/reperfusion injury (13). NO is rapidl...

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Role of L‐arginine in the vascular actions and development of tolerance to nitroglycerin

Cited by 61 publications

References 37 publications

Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate

Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate

Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance

Effect of Diabetes on Nitric Oxide Metabolism During Cardiac Surgery

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