Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide.

Salvemini, Daniela; Mollace, Vincenzo; Pistelli, Alessandra; Änggård, Erik; Vane, John R.

doi:10.1073/pnas.89.3.982

Cited by 77 publications

(61 citation statements)

References 26 publications

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“…Besides the well established metabolism of GTN to NO by SMC, EC can also make this conversion (Benjamin et al, 1991;Feelisch & Kelm, 1991;Salvemini et al, 1992 from GTN by SMC or EC is mediated by an enzymatic mechanism has now been substantiated. Thus we (Salvemini et al, 1992) and others (Feelisch & Kelm, 1991) have demonstrated that boiled SMC or EC from bovine or porcine aortae lose about 80-90% of their capacity to form NO from GTN. Furthermore, in bovine coronary SMC the metabolic activation of GTN to NO is also enzymatic and is associated with the plasma membrane (Chong & Fung, 1990); the subcellular location for the metabolism of GTN to NO in EC is at present not known.…”

Section: Discussionmentioning

confidence: 99%

“…However, the enzymatic pathway which converts GTN into its active principle NO in SMC or EC is distinct from the one that forms NO from L-Arg and it is not regulated by NO release from L-Arg via the enzyme NO-synthase (Salvemini et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…GTN (1-10 10-6 M) induced a concentration-dependent relaxation (Table 1) which was not affected by SBP, metyrapone or SKF-525A (Table 1). The tissues were preconstricted with phenylephrine (5 x 10-6-i0-5 M) to produce approximately a 90-100% of maximal contraction and when the state of contraction of the tissue was stable a cumulative dose-response curve to GTN (10-1o-10-6M) was con- This increase in cyclic GMP is attenuated by oxyHb indicating NO formation (Salvemini et al, 1992). The increase in the levels of cyclic GMP in tolerant SMC or EC by GTN (20011M) was much smaller (Figure 4a and b).…”

Section: Organ Bath Studiesmentioning

confidence: 99%

“…Apart from the metabolism of GTN to NO by SMC (Benjamin et al, 1991;Feelish & Kelm, 1991;Salvemini et al, 1992) we and others (Feelish & Kelm, 1991;Salvemini et al, 1992) (GST) and glutathione reductase . Recent 'PI Macmillan Press Ltd, 1993 evidence in hepatic and renal cells has suggested that the cytochrome P4m enzyme system is involved in the formation of NO from GTN (Servent et al, 1989;Schroder & Schrdr, 1992).…”

Section: Introductionmentioning

confidence: 99%

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Conversion of glyceryl trinitrate to nitric oxide in tolerant and non‐tolerant smooth muscle and endothelial cells

Salvemini

Pistelli

Vane

1993

British J Pharmacology

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Exposure of smooth muscle cells (SMC) to glyceryl trinitrate (GTN, 75–600 μm) for 30 min led to a concentration‐dependent increase in nitrite (NO2−), one of the breakdown products of nitric oxide (NO). This was not affected by 30 min pretreatment of the cells with 0.5 mm of sulphobromophthalein (SBP) an inhibitor of glutathione‐S‐transferase (GST), by metyrapone or SKF‐525A inhibitors of cytochrome P450. These experiments were confirmed by organ bath studies using rabbit aortic strips denuded of endothelium and contracted with phenylephrine. Thus, a 30 min incubation of the strips with 0.5 mm SPB, metyrapone or SKF‐525A did not affect the relaxations in response to GTN (10−10−10−6 m). Potentiation of the anti‐platelet effect of GTN (44 μm) by endothelial cells (EC, 40 × 103 cells) was not affected by prior incubation of EC with SBP, metyrapone or SKF‐525A (all at 0.5 mm). Potentiation of the antiplatelet activity of GTN (11–352 μm) by small numbers of SMC (24 × 103 cells) or EC (40 × 103 cells) treated with indomethacin (10 μm) was attenuated when the SMC or EC were treated in culture with a high concentration of GTN (600 μm) for 18 h beforehand (referred to as ‘tolerant’ cells). In addition, tolerant SMC produced far less NO2− than non‐tolerant SMC. Exposure of non‐tolerant SMC or EC (105 cells) to GTN (200 μm) for 3 min increased (3–4 fold) the levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). This increase was much less (≤ 1 fold) in the tolerant SMC or EC (105 cells). The basal levels of cyclic GMP were similar in normal or tolerant SMC or EC. Sodium nitroprusside (80 μm) or atrial natriuretic factor (ANF, 10−7 m) increased the levels of cyclic GMP in normal or tolerant SMC or EC to the same extent. The anti‐platelet effects of GTN (44 μm) were potentiated by the sulphydryl donor N‐acetylcysteine (NAC, 0.5 mm). Incubation of GTN (150–1200 μm) for 30 min with NAC (0.1–1 mm) led to a concentration‐dependent increase in NO2− formation. The reduced ability of tolerant SMC or EC to potentiate the anti‐platelet activity of GTN was restored by NAC (0.5 mm). These anti‐aggregatory effects were abolished by concurrent co‐incubation with oxyhaemoglobin (10 μm) indicating that they were due to NO release. Thus, in SMC or EC, metabolism of GTN to NO does not depend on glutathione‐S‐transferase or the cytochrome P450 system. Furthermore, when compared to normal cells, tolerant SMC or EC metabolize GTN to NO less effectively as assessed by the reduced capacity to potentiate the antiplatelet effects of GTN, to release NO2− and to increase the level of cyclic GMP. This decrease in NO formation shows that tolerance to GTN is mainly due to impaired biotransformation of GTN to NO. NAC, by directly forming NO from GTN, compensates for this failing mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Organ Bath Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conversion of glyceryl trinitrate to nitric oxide in tolerant and non‐tolerant smooth muscle and endothelial cells

Salvemini

Pistelli

Vane

1993

British J Pharmacology

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“…The Griess reagent (aqueous solution of 1% sulphanilic acid and 0.1% N-1-naphthylethylendiamine dihydrochloride in 2.5% H3PO4) forms a stable chromophore with NO2, absorbing at 546 nm A. The values were determined by comparison with standard concentrations of sodium nitrite and expressed as net amounts of NO ml-' (Salvemini et al, 1992). A possible involvement of the L-arginine-NO pathway in the response of the coronary vessels to RLX was also investigated in guinea-pig isolated hearts by studying the effect of NG-monomethyl-L-arginine (L-NMMA), which is a powerful inhibitor of nitric oxide-synthase (NOS).…”

Section: Evaluation Of No Productionmentioning

confidence: 99%

Relaxin‐induced increased coronary flow through stimulation of nitric oxide production

Bani-Sacchi

Bigazzi²,

Bani

et al. 1995

British J Pharmacology

150

125

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1 Relaxin (RLX) is a multifunctional hormone which, besides its role in pregnancy and parturition, has also been shown to influence the cardiovascular system. In this study, we investigated the effect of RLX on coronary flow of rat and guinea-pig hearts, isolated and perfused in a Langendorff apparatus. RLX was either added to the perfusion fluid at a concentration of 5 x 109 M for a 20-min perfusion, or given as a bolus into the aortic cannula at concentrations of 10-9 M, 5 x io-9 M and 10-8 M dissolved in 1 ml of perfusion fluid. 2 RLX, given either for a 20-min perfusion or as a bolus in the aortic cannula to guinea-pig and rat isolated hearts, increased the coronary flow and the amount of nitrite, a stable end-product of nitric oxide (NO) metabolism, that appeared in the perfusates in a concentration-dependent fashion. 3 The increase in coronary flow and in nitrite in the perfusates induced by RLX was significantly reduced by pretreatment with the nitric oxide synthase (NOS) 4 The effects of RLX on coronary flow and nitrite amounts in the perfusates were compared with those induced by the endothelium-dependent vasodilator agent, acetylcholine (ACh, I0--I0-M), and by the endothelium-independent vasodilator agent, sodium nitroprusside (SNP, I0--10-6 M). The results obtained show that RLX is more effective than ACh and SNP in increasing coronary flow. 5 The results of this study show that RLX increases coronary flow through stimulation of NO production; hence this hormone should be regarded as a novel agent capable of improving myocardial perfusion.

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Synthesis of a Series of Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group and Pharmacological Evaluation on Isolated Rat Aortas

Nallet¹,

Mégard²,

Arnaud

et al. 1998

Eur. J. Org. Chem.

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As part of our research into new organic nitrates for the treatment of angina pectoris, we have investigated a series of hexitol and aminodeoxyhexitol mononitrate derivatives containing a sulfur group. Since the depletion of tissue stores of sulfhydryl groups appears to play an important role in the development of this phenomenon, the addition of a sulfur group to a nitrate derivative could prevent the development of nitrate tolerance during a long‐term treatment. Before studying the duration of action, and the possible influence on tolerance phenomenon, it was important to check the vasorelaxing effects of our compounds compared to those of commercial organic nitrates of similar structures such as isosorbide mononitrate or isosorbide dinitrate. All the compounds were tested on isolated rat aortas; some of these products exhibited an interesting activity.

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Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide.

Cited by 77 publications

References 26 publications

Conversion of glyceryl trinitrate to nitric oxide in tolerant and non‐tolerant smooth muscle and endothelial cells

Conversion of glyceryl trinitrate to nitric oxide in tolerant and non‐tolerant smooth muscle and endothelial cells

Relaxin‐induced increased coronary flow through stimulation of nitric oxide production

Synthesis of a Series of Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group and Pharmacological Evaluation on Isolated Rat Aortas

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