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

Abstract

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.

Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits

“…A weakness of the present study was that rabbit plasma GTN levels were not measured during acute or chronic transdermal application. However, if the GTN is absorbed from the patch at the same rate from rabbit ear skin as from human skin, then on a body weight basis (3 kg rabbit) GTN plasma levels should be at least 10 -20 times higher than that required to show haemodynamic tolerance in human subjects (Hogan et al, 1990;Levy et al, 1991;Parker et al, 1991;Parker & Parker, 1993;Cloarec-Blanchard et al, 1994 . This is a very similar sensitivity to that reported in rabbit aortic rings precontracted with phenylephrine, pEC5o (M) 7.23+0.48 (Du et al, 1991), and in dog coronary artery precontracted with K+ (pEC5o GTN 7.5) and U46619 (pECo GTN 7.43) (Angus & Brazenor, 1983).…”

An update on nitrate tolerance: can it be avoided?

“…Some authors have reported potentiation of nitrate-induced vasodilatation following treatment with either N-acetyl cysteine infusion69-72 or oral methionine.73 However, patients who had developed tolerance to four times daily ISDN showed no immediate recovery following N-acetyl cysteine infusion74 and oral methionine seemed unable to reverse the tolerance induced by intravenous nitroglycerin in heart failure.75 One study aimed specifically at tolerance to antianginal effects of the NG patch found equal tolerance to 10 mg/24 hours at 4 days whether a placebo or N-acetyl cysteine was given simultaneously. 76 Two nitrate drugs, sodium nitroprusside and molsidomine, are considered to lead directly to nitric oxide production without the need for sulphydryl group donors at an intermediate stage. 77 Therefore the fact that tolerance developed in a study of 10 patients with stable angina whether given ISDN or molsidomine seems to suggest that sulphydryl depletion alone may not be the only factor and that other mechanisms such as neurohumoral activation may also play an important role.78 Finally, current evidence suggests that during chronic nitrate exposure and tolerance plasma nitrate levels actually increase.…”