Studies on compensatory reflexes and tolerance to glyceryl trinitrate (GTN)

Rush, M.L.; Lang, W.J.; Rand, M. J.

doi:10.1016/0014-2999(71)90004-5

Cited by 25 publications

(6 citation statements)

References 17 publications

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“…The present study is the first evidence that arterial depression tolerance to subcutaneously administered NTG is facilitated by microinjection of small doses of NTG or an exogenous NO donor in the PH, an important autonomic regulation site in the brain. Development of acute NTG tolerance in these studies is consistent with the results of previous studies using animal models [21][22][23] and humans. 5,7 Tolerance responses to arterial pressure depression were prevented by a bilateral microinjection of guanethidine, a noradrenergic blocker, into the PH.…”

Section: Effect Of Dea/no and Guanethidine In The Ph On The Tolerance Responses To Ntgsupporting

confidence: 90%

Effects of Nitric Oxide and Noradrenergic Activation in the Posterior Hypothalamus on Arterial Pressure Tolerance to Nitroglycerin in Rats

Guettler

2008

J Cardiovasc Pharmacol Ther

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The effects of nitric oxide (NO) and noradrenergic activation in the posterior hypothalamus on arterial pressure tolerance induced by subcutaneous injection of nitroglycerin (NTG) was investigated in anesthetized Sprague-Dawley rats. Intravenous injections of NTG (3, 10, and 30 microg/kg) and sodium nitroprusside (1, 3, and 10 microg/kg) produced dose-dependant decreases in arterial blood pressure. Tolerance to NTG was produced by subcutaneous administration of 4.0 mg of NTG as 4 separate hourly injections of 1.0 mg each, affecting the dose-dependent response of NTG IV injection. The 4 high-dose NTG pulse injections produced a marked shift in the dose-response curves for arterial pressure depression induced by intravenous injection of the challenge doses of NTG, but did not alter hypotensive responses to sodium nitroprusside. The tolerance responses to arterial pressure depression were enhanced by a bilateral microinjection of NTG (1 nmol) and by diethylamine NONOate (1 nmol), an NO donor, into the posterior hypothalamus. Bilateral microinjection of guanethidine (1.5 nmol), a noradrenergic blocker, into the posterior hypothalamus inhibits NTG tolerance in a period of time within 2 hours. We conclude that exogenous NO and noradrenergic activation in the posterior hypothalamus play an important role in arterial pressure tolerance to systemically administered NTG.

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Section: Effect Of Dea/no and Guanethidine In The Ph On The Tolerance Responses To Ntgsupporting

confidence: 90%

Effects of Nitric Oxide and Noradrenergic Activation in the Posterior Hypothalamus on Arterial Pressure Tolerance to Nitroglycerin in Rats

Guettler

2008

J Cardiovasc Pharmacol Ther

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“…(2) Inhibition of catecholamine synthesis does not alter tolerance induction or maintenance; (3) Carotid body compensatory reflexes are unaltered in tolerant rats; and (4) Lack of cross tolerance between NTG and other, chemically unrelated, vasodilators such as papaverine and histamine (Needleman & Johnson 1975). Rush et al (1971) suggested that acute and chronic tolerance to NTG may be due to different mechanisms. Acute tolerance in dogs, produced by infusion of NTG (1 mg/kg for 1 h), could be prevented by pretreatment with guanethidine and it was suggested that altered sympathetic compensatory reflexes were the cause of acute tolerance.…”

Section: Mechanistic Studiesmentioning

confidence: 99%

Tolerance to organic nitroesters in experimental animals. An assessment of in vitro and in vivo investigations

Axelsson

Ahlner

Ljusegren

1986

Acta Pharmacologica et Toxicologica

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This paper will present a short survey of the literature dealing with nitrate tolerance in experimental animals. Tolerance towards organic nitroesters has been experimentally established in animal models both in vivo and in vitro. However the dose of drug used to provoke tolerance has invariably been very high, which makes it difficult to apply experiences from animal experiments to the clinical setting. Several different hypothesis has been put forward in order to explain the mechanism of tolerance. Today, most evidence seem to point towards an altered metabolism of cGMP as a possible cause of tolerance. Cyclic GMP is the second messenger suggested to mediate the vasodilatory effect of organic nitroesters. The proposed role of critical tissue sulfhydryl groups in mediating the smooth muscle relaxant effect of nitroglycerin (NTG) have made experiments concerning reversal and prevention of tolerance to center on the use of various sulfhydryl reactive compounds. The results of these experiments are as yet ambigous. Several studies show the existence of cross tolerance between NTG and various other vasodilatory organic nitroesters. In contrast no cross tolerance between NTG and chemically unrelated vasodilator drugs has been observed. The endogenous vasodilators acetylcholine and atrial natriuretic factor are known to induce cGMP increases. In view of this, their effect on NTG‐tolerant bovine mesenteric arteries was investigated. However no cross‐tolerance appears to exist under in vitro conditions.

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“…[1][2][3][4][5] Proposed mechanisms of this phenomenon of tolerance include alterations in intracellular nitrate metabolism6,7 or the activation of neurohumoral systems counteracting the vasodilator potency of nitrates. [8][9][10][11] In vitro findings stressed the critical role of intracellular sulfhydryl groups in activation of guanylate cyclase6.12,'3 and nitrate tolerance development.…”

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confidence: 99%

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

et al. 1989

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N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of Nacetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n=12) during long-term nitroglycerin treatment (1.5 ,g/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/ kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n=17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 ,ug/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 ,M) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from Nacetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin. (Circulation 1989;79:188-197) D uring continued administration of organic nitrates, their anti-ischemic effects are severely blunted. 1-5 Proposed mechanisms of this phenomenon of tolerance include alterations in intracellular nitrate metabolism6,7 or the activation of neurohumoral systems counteracting the vasodilator potency of nitrates.8-11 In vitro findings stressed the critical role of intracellular sulfhydryl groups in activation of guanylate cyclase6.12,'3 and nitrate tolerance development.These observations led to the study of the interactions between nitroglycerin and the sulfhydryl donor N-acetylcysteine (NAC) in nontolerant and tolerant

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Studies on compensatory reflexes and tolerance to glyceryl trinitrate (GTN)

Cited by 25 publications

References 17 publications

Effects of Nitric Oxide and Noradrenergic Activation in the Posterior Hypothalamus on Arterial Pressure Tolerance to Nitroglycerin in Rats

Effects of Nitric Oxide and Noradrenergic Activation in the Posterior Hypothalamus on Arterial Pressure Tolerance to Nitroglycerin in Rats

Tolerance to organic nitroesters in experimental animals. An assessment of in vitro and in vivo investigations

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

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