Dissociation of nitrovasodilator-induced relaxation from cyclic GMP levels during in vitro nitrate tolerance

doi:10.1016/0014-2999(90)90136-T

European Journal of Pharmacology

Volume 176, Issue 1, 25 January 1990, Pages 91-95

https://doi.org/10.1016/0014-2999(90)90136-T Get rights and content

Abstract

The effects of nitroglycerin tolerance on relaxation and cyclic GMP accumulation by nitroglycerin, nitric oxide and S-nitroso-N-acetylpenicillamine were examined in isolated rate aortic rings. Cyclic GMP accumulation by nitroglycerin, S-nitroso-N-acetylpenicillamine and nitric oxide was diminished in nitroglycerin-tolerant aorta. In contrast, only relaxation by nitroglycerin, but not S-nitroso-N-acetylpenicillamine and nitric oxide, was attenuated. These data suggest that cyclic GMP levels might represent an inadequate index for mechanistic studies of nitroglycerin relaxation tolerance.

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Cited by (27)

Nitric oxide in respiratory diseases
2002, Pharmacology and Therapeutics
Citation Excerpt :
An increase in the polarity and bulk of SNO compounds would decrease SNO penetration across cell membranes. The highly polar SNAP, GSNO, S-nitroso-N-acetyl-cysteine and S-nitroso-cysteine and the bulky and polar S-nitroso-coenzyme A are all found to be potent relaxants of rat aortic rings (Kowaluk & Fung, 1990a). In isolated human bronchial smooth muscle, the high molecular weight SNO compound S-nitroso-BSA was no less potent than the lower molecular weight SNO compounds (Gaston et al., 1994a).
The formation and modulation of nitric oxide (NO) in the lungs is reviewed. Its beneficial and deleterious roles in airways diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis, and in animal models is discussed. The pharmacological effects of agents that modulate NO production or act as NO donors are described. The clinical pharmacology of these agents is described and the therapeutic potential for their use in airways disease is considered.
Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryltrinitrate-tolerant rat femoral arteries
2000, European Journal of Pharmacology
Organic nitrates, such as glyceryltrinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6,tetra-O-acetyl-β-d-glucopyranose (RIG200) and S-nitroso-N-valeryl-d-penicillamine (d-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N^ω-nitro-l-arginine methyl ester (l-NAME). Perfusion pressure was measured during 20 h treatment with supramaximal concentrations of NO donor (10 μM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2–20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20 h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.
Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryl trinitrate-tolerant rat femoral arteries
2000, European Journal of Pharmacology
Organic nitrates, such as glyceryl trinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6,tetra-O-acetyl-β-d-glucopyranose (RIG200) and S-nitroso-N-valeryl-d-penicillamine (d-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N^ω-nitro-l-arginine methyl ester (l-NAME). Perfusion pressure was measured during 20-h treatment with supramaximal concentrations of NO donor (10 μM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2–20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20-h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.
Effects of guanylyl cyclase and protein kinase G inhibitors on vasodilatation in non-tolerant and tolerant bovine coronary arteries
1999, European Journal of Pharmacology
The effects in bovine coronary arteries of the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) were examined in order to establish the relative importance of the enzyme (a) in the vasodilator actions of glyceryl trinitrate and S-nitroso-N-acetylpenicillamine and (b) in induction of tolerance to these agents. ODQ strongly inhibited responses to both relaxants with IC₅₀'s of the order of 0.5 μM; in contrast, the protein kinase G inhibitor, 8-bromoguanosine-3′,5′-monophosphorothioate (Rp-8-Br-cGMPS) had little effect on the responses. Tolerance after pre-incubation with glyceryl trinitrate (10 μM) was unaffected by co-pre-incubation with ODQ (1.0 μM), but similar experiments with S-nitroso-N-acetylpenicillamine were inconclusive because tolerance was associated with depressed contractile activity. It is concluded that in bovine coronary arteries soluble guanylyl cyclase is essential for vasorelaxation to both glyceryl trinitrate and S-nitroso-N-acetylpenicillamine but is unimportant for induction of tolerance to glyceryl trinitrate. Our results add weight to the hypothesis of impaired biotransformation rather than guanylyl cyclase desensitisation as the mechanism of in vitro nitrate tolerance.
Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function
1999, Journal of Pediatrics
Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs, nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13 healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0-320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide metabolites nitrate and nitrite (mean ± SEM: 3.7 ± 0.5 μmol/L vs 4.8 ± 0.9 μmol/L). S-nitrosolation– mediated bioreactivities may be impaired by depletion of the CF airway SNO reservoir. (J Pediatr 1999;135:770-2)
Contribution of activation of K<sup>+</sup> channels to glyceryl trinitrate-induced relaxation of rabbit aorta
1995, General Pharmacology
- 1.
  1. Possible contribution of K⁺ channel opening to the relaxation by glyceryl trinitrate (GTN) was examined using isolated rabbit aorta.
- 2.
  2. While glibenclamide and apamin failed to affect relaxation by GTN, both charybdotoxin (ChTx) and iberiotoxin (IbTx) effectively attenuated GTN-induced relaxation.
- 3.
  3. The increase in cGMP produced by GTN was not attenuated by ChTx and IbTx.
- 4.
  4. The inhibitory effect of ChTx on GTN-induced relaxation was not reduced in the presence of zaprinast, indicating that cGMP but not GMP was responsible for activation of the K⁺ channel.
- 5.
  5. Okadaic acid, a selective inhibitor of protein phosphatase 2A, had no effect on the relaxation by GTN. These results indicate that, though small in degree, activation of a ChTx-sensitive K⁺ channel (large conductance Ca²⁺-activated K⁺ channel) is involved in the GTN-induced relaxation in rabbit aorta.

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Short communicationDissociation of nitrovasodilator-induced relaxation from cyclic GMP levels during in vitro nitrate tolerance

Abstract

European J. Pharmacol.

European J. Pharmacol.

Pharmacol. Rev.

Biochem. Pharmacol.

An unusually stable thionitrite from N-acetyl-D,L-penicillamine; X-ray crystal and molecular structure of 2-(acetylamino)-2-carboxyl-1,1-dimethylethyl thionitrite

J.C.S. Chem. Commun.

Short communication
Dissociation of nitrovasodilator-induced relaxation from cyclic GMP levels during in vitro nitrate tolerance