N‐acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.

Hogan, J.C.; Mj, Lewis; Henderson, A. H.

doi:10.1111/j.1365-2125.1989.tb03522.x

Cited by 13 publications

(6 citation statements)

References 13 publications

(18 reference statements)

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“…In contrast to the other antioxidants tested, the sulphydryl donor N‐acetyl‐L‐cysteine was able to abolish tolerance development to the lowest level of GTN, while clearly tending to attenuate tolerance to the higher level. While a number of previous studies have failed to find improvement with N‐acetyl‐L‐cysteine in tolerant animals (Abdollah et al , 1987; Hütter et al , 1988; Münzel et al , 1989; Holtz et al , 1989) or man (Hogan et al , 1989), the present observations are in agreement with the results of Lawson et al (1991) and Newman et al (1990) that N‐acetyl‐L‐cysteine mitigates nitrate tolerance both in vitro and in vivo. Furthermore, given that N‐acetyl‐L‐cysteine was washed out before vasorelaxation to GTN was studied, the beneficial action of N‐acetyl‐L‐cysteine in the rat isolated aorta is clearly distinguishable from a simple reversal of tolerance due to the extracellular metabolism of GTN (see Fung et al , 1988; Levy et al , 1988; Hütter et al , 1988; Boesgaard et al , 1991).…”

Section: Discussionsupporting

confidence: 92%

Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro

Laight

Carrier

Änggård

1997

British J Pharmacology

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The role of reactive oxygen species (ROS) during the development of vascular cellular tolerance to glyceryl trinitrate (GTN), was studied in the rat isolated aorta. Nitrate tolerance induced by a 30 min incubation with GTN (30 or 100 μm) in vitro, was not affected by pretreatment with the intracellular superoxide anion scavenger, tiron (10 mm), or the intracellular scavenger of peroxynitrite anion and hydroxyl radical, dimethylsulphoxide (DMSO, 0.2% v v−1). In contrast, pretreatment with the intracellular sulphydryl donor, N‐acetyl‐l‐cysteine (NAC, 1 mm), significantly attenuated GTN‐induced tolerance. Pretreatment with a putative inhibitor of oxidant stress‐mediated, transcription factor NF‐κ B activation, pyrrolidine dithiocarbamate (PDTC, 50 μm), an inhibitor of gene activation by NF‐κB, dexamethasone (1 μm) or an inhibitor of protein synthesis, cycloheximide (10 μm), failed to affect tolerance development to GTN. Pretreatment with DMSO (0.2% v v−1) or PDTC (50 μm) depressed non‐tolerant vasorelaxation to GTN (1 nm1 μm) per se. Tiron (10 mm) abolished the reduction of ferricytochrome c by a superoxide anion generating system, assessed photometrically in vitro. In contrast, DMSO (0.2% v v−1), NAC (1 mm) and PDTC (50 μm) were without effect. Our data suggests that neither oxidant stress nor nuclear activation, is important in the development of cellular tolerance to GTN in rat isolated aortic smooth muscle. British Journal of Pharmacology (1997) 120, 1477–1482; doi:

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Section: Discussionsupporting

confidence: 92%

Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro

Laight

Carrier

Änggård

1997

British J Pharmacology

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“…The present study differed from the previous two studies in that it addressed the question whether oral administration of N-acetylcysteine might prevent the development of tolerance during transdermal glyceryl trinitrate treatment of patients with chronic stable angina. In this respect it is similar in design and findings to a previous report by us investigating the effects of N-acetylcysteine on nitrate tolerance in healthy volunteers (Hogan et al, 1989).…”

Section: Discussionsupporting

confidence: 86%

“…On this basis, prevention of reversal of nitrate tolerance might be achieved by repletion of sulphydryl groups from an exogenous source such as N-acetylcysteine. This has been demonstrated in vitro (Needleman et al, 1973) but in vivo studies have given conflicting results (Hogan et al, 1989;Packer et al, 1987;Parker et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

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Chronic administration of N‐acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris.

Hogan

Henderson

1990

Brit J Clinical Pharma

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1 Reduced availability of sulphydryl groups in vascular smooth muscle cells may contribute to the development of tolerance to the action of the organic nitrovasodilators. 2 Eight patients with stable angina were treated with 10 mg of transdermal glyceryl trinitrate per 24 h, together with 400 mg N-acetylcysteine, a sulphydryl group donor, or matching placebo three times daily in a double-blind randomised crossover manner for two periods of 4 days with intervening washout period of 3 days off these drugs. Other therapy remained unaltered during the study. 3 Blood pressure, heart rate and symptom-limited treadmill walking time were measured in the pre-treatment control state and 4 h after starting treatment on day 1 and day 4 of each glyceryl trinitrate treatment period. 4 The changes seen on day 1 were attenuated by day 4 to an equal extent in N-acetylcysteine and placebo treatment periods. 5 These results suggest that chronic oral administration of N-acetylcysteine fails to prevent the development of tolerance to the anti-anginal or haemodynamic effects of glyceryl trinitrate.

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“…Consistent with this proposal, supplementation with sources of sulphydryl groups has been shown to suppress tolerance to glyceryl trinitrate (GTN), for example (see Katz, 1990;Newman et al, 1990). However, it should be noted that other studies have not confirmed these results (Gruetter & Lemke, 1983;Stewart et al, 1988;Hogan et al, 1989). Nonetheless, sulphydryl depletion as an explanation for organic nitrate tolerance has led to the proposal that sulphydryl-containing angiotensinconverting enzyme (ACE) inhibitors might be particularly useful in conjunction with organic nitrates, since they could combat both the biochemical and physiological bases of tolerance (Katz, 1990).…”

Section: Introductionmentioning

confidence: 95%

Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats

Phillips

Gardiner

Kemp

et al. 1991

British J Pharmacology

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1 A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics. 2 Infusion of glyceryl trinitrate (GTN, 0. mgkg-' min 1, i.v.) for 10min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed. 3 In the presence of captopril (2mg kg-1 bolus, and 1 mg kg-h -1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin-angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg'-bolus, and 1 mg kg -h'-infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols. 4 Administration of molsidomine alone (1 mg kg', i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation. 5 In the presence of captopril or enalaprilat, molsidomine evoked renal and mesenteric vasodilatations in association with hypotension, indicating that activation of the renin-angiotensin system contributed to the lack of vasodilator responses to administration of molsidomine alone. However, since the effects of enalaprilat were more marked than those of captopril (in spite of the dose of both drugs being supramaximal for inhibition of angiotensin-converting enzyme), other factors must have been involved. 6 In a separate experiment, pretreatment with the nitric oxide synthesis inhibitor, N0-nitro-L-arginine methyl ester (1 mg kg-1 h-1, i.v.), enhanced the mesenteric vasodilator effect of molsidomine. Collectively, these results are consistent with in vitro data showing that endogenous nitric oxide can inhibit the vasodilator effects of nitric oxide derived from molsidomine, and that the sulphydryl groups of captopril can protect endogenous nitric oxide from inactivation by oxygen-derived free radicals, thereby enhancing the inhibitory effect of endogenous nitric oxide on the vasodilator responses to exogenous nitric oxide derived from molsidomine (or GTN).

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N‐acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.

Cited by 13 publications

References 13 publications

Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro

Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro

Chronic administration of N‐acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris.

Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats

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