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1.
JA Clin Rep ; 10(1): 32, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787462

ABSTRACT

BACKGROUND: Previous reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam. Case presentation A 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups. CONCLUSION: Remimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia.

2.
Mol Pharmacol ; 85(1): 175-85, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24202912

ABSTRACT

S-Nitrosylation, the addition of a nitrosyl group to cysteine thiols, regulates various protein functions to mediate nitric oxide (NO) bioactivity. Recent studies have demonstrated that selectivity in protein S-nitrosylation signaling pathways is conferred through transnitrosylation, a transfer of the NO group, between proteins via interaction. We previously demonstrated that sensitivity to activation by synthetic NO-releasing agents via S-nitrosylation is a common feature of members of the transient receptor potential (TRP) family of Ca(2+)-permeable cation channels. However, strategies to confer subtype selectivity to nitrosylating agents targeted to TRP channels are yet to be developed. Here, we show selective activation of TRPA1 channels by novel NO donors derived from the ABBH (7-azabenzobicyclo[2.2.1]heptane) N-nitrosamines, which exhibit transnitrosylation reactivity to thiols without releasing NO. The NNO-ABBH1 (N-nitroso-2-exo,3-exo-ditrifluoromethyl-7-azabenzobicyclo[2.2.1]heptane) elicits S-nitrosylation of TRPA1 proteins, and dose-dependently induces robust Ca(2+) influx via both recombinant and native TRPA1 channels, but not via other NO-activated TRP channels. TRPA1 activation by NNO-ABBH1 is suppressed by specific cysteine mutations but not by NO scavenging, suggesting that cysteine transnitrosylation underlies the activation of TRPA1 by NNO-ABBH1. This is supported by the correlation of N-NO bond reactivity and TRPA1-activating potency in a congeneric series of ABBH N-nitrosamines. Interestingly, nonelectrophilic derivatives of ABBH also activate TRPA1 selectively, but less potently, compared with NNO-ABBH1. Thus, ABBH N-nitrosamines confer subtype selectivity on S-nitrosylation in TRP channels through synergetic effects of two chemical processes: cysteine transnitrosylation and molecular recognition of the nonelectrophilic moiety.


Subject(s)
Aza Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Calcium Channels/metabolism , Heptanes/pharmacology , Nerve Tissue Proteins/metabolism , Nitric Oxide Donors/pharmacology , Nitrosamines/pharmacology , Transient Receptor Potential Channels/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , HEK293 Cells , Heptanes/chemical synthesis , Heptanes/chemistry , Humans , Nitric Oxide Donors/chemical synthesis , Nitric Oxide Donors/chemistry , Nitrosamines/chemical synthesis , Nitrosamines/chemistry , Patch-Clamp Techniques , TRPA1 Cation Channel
3.
Circ Res ; 112(2): 327-34, 2013 Jan 18.
Article in English | MEDLINE | ID: mdl-23212582

ABSTRACT

RATIONALE: The clinical problem of loss of ß-adrenergic receptor (ß-AR) response, both in the pathogenesis of heart failure and during therapeutic application of ß-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of ß-AR signaling, G protein-coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied ß-ARs, and this modification promotes desensitization, internalization, and downregulation of ß-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. OBJECTIVE: We examine whether S-nitrosylation without NO generation inhibits desensitization of ß(2)-AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. METHODS AND RESULTS: We have developed water-soluble N-nitrosamines that have S-nitrosylating activity but lack NO-generating activity. These compounds, at least partly, rescue ß-AR from desensitization in HEK 293 cells expressing FLAG-tagged human ß(2)-AR and in rat cardiac myocytes. They inhibit isoproterenol-dependent phosphorylation and internalization of ß(2)-AR. Indeed, they nitrosylate GRK2 in vitro and in cells, and their S-nitrosylation of GRK2 likely underlies their inhibition of ß(2)-AR desensitization. CONCLUSIONS: Compounds that induce S-nitrosylation without NO release inhibit GRK2 and attenuate ß(2)-AR desensitization. Developing water-soluble drugs that specifically induce S-nitrosylation may be a promising therapeutic strategy for heart failure.


Subject(s)
Nitric Oxide , Nitrosamines/metabolism , Nitrosamines/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Water/physiology , Animals , HEK293 Cells , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Nitric Oxide/metabolism , Nitrosamines/chemistry , Rats , Solubility/drug effects , Water/chemistry
4.
Chemistry ; 18(4): 1127-41, 2012 Jan 23.
Article in English | MEDLINE | ID: mdl-22179925

ABSTRACT

Although many organic/inorganic compounds that release nitric oxide (NO) upon photoirradiation (phototriggered caged-NOs) have been reported, their photoabsorption wavelengths mostly lie in the UV region, because X-NO bonds (X=heteroatom and metal) generally have rather strong π-bond character. Thus, it is intrinsically difficult to generate organic compounds that release NO under visible light irradiation. Herein, the structures and properties of N-pyramidal nitrosamine derivatives of 7-azabicyclo[2.2.1]heptanes that release NO under visible light irradiation are described. Bathochromic shifts of the absorptions of these nitrosamines, attributed to HOMO (n)-LUMO (π*) transitions associated with the nonplanar structure of the N-NO moiety, enable the molecules to absorb visible light, which results in N-NO bond cleavage. Thus, these compounds are innate organic caged-NOs that are uncaged by visible light.


Subject(s)
Light , Nitric Oxide/chemistry , Nitrosamines/chemistry , Cyclization , Models, Molecular , Molecular Structure
5.
Bioorg Med Chem ; 19(8): 2726-41, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21435887

ABSTRACT

Nitrosamines are potent carcinogens and toxicants in the rat and potential genotoxins in humans. They are metabolically activated by hydroxylation at an α-carbon atom with respect to the nitrosoamino group, catalyzed by cytochrome P450. However, there has been little systematic investigation of the structure-mutagenic activity relationship of N-nitrosamines. Herein, we evaluated the mutagenicity of a series of 7-azabicyclo[2.2.1]heptane N-nitrosamines and related monocyclic nitrosamines by using the Ames assay. Our results show that the N-nitrosamine functionality embedded in the bicyclic 7-azabicylo[2.2.1]heptane structure lacks mutagenicity, that is, it is inert to α-hydroxylation, which is the trigger of mutagenic events. Further, the calculated α-C-H bond dissociation energies of the bicyclic nitrosamines are larger in magnitude than those of the corresponding monocyclic nitrosamines and N-nitrosodimethylamine by as much as 20-30 kcal/mol. These results are consistent with lower α-C-H bond reactivity of the bicyclic nitrosamines. Thus, the 7-azabicyclo[2.2.1]heptane structural motif may be useful for the design of nongenotoxic nitrosamine compounds with potential biological/medicinal applications.


Subject(s)
Bridged Bicyclo Compounds/pharmacology , Heptanes/pharmacology , Mutagens , Nitrosamines/antagonists & inhibitors , Animals , Humans , Hydroxylation , Mutagenicity Tests , Nitrosamines/toxicity , Rats , Structure-Activity Relationship
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