Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve

Background and purpose:

Amitriptyline is often prescribed as a first-line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage-dependent ion channels and also to act as an antagonist at ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C-fibre action potential.

Experimental approach:

Isolated axon fascicles were prepared from short segments of human sural nerve, and multiple measures of axonal excitability were recorded using computer-controlled threshold tracking software.

Key results:

Amitriptyline (EC₅₀ 2.6 µM) reduced the nicotine-induced increase in C-fibre excitability but only slightly altered the amplitude and latency to onset of the compound action potential. In contrast, tetrodotoxin produced a clear reduction in the amplitude and a prolongation of action potential onset latency but was without effect on the nicotine-induced increase in axonal excitability.

Conclusions and implications:

These data demonstrate that low concentrations of amitriptyline suppress the response of human peripheral C-type axons to nicotine by directly inhibiting nAChRs. Blockade of tetrodotoxin-sensitive, voltage-dependent sodium channels does not contribute to this effect. An inhibitory action of amitriptyline on nAChRs in unmyelinated nociceptive axons may be an important component of amitriptyline''s therapeutic effect in the treatment of neuropathic pain.     

Angiotensin type-1 receptor A1166C gene polymorphism correlates with oxidative stress levels in human heart failure

Oxidative stress plays a critical role in the pathogenesis of cardiovascular disease and diabetes. Studies in vascular cells and experimental animals have demonstrated that the angiotensin type-1 receptor (AT1R) contributes to formation of reactive oxygen species by activating nicotinamide-adenine dinucleotide phosphate oxidases, but the relevance of this pathway to human heart disease has not been established. Here we demonstrate that a polymorphism in the AT1R gene (A1166C), linked to increased receptor activity, is associated with elevated levels of oxidative stress markers in heart failure patients but not in healthy controls. Plasma protein carbonyls (PCs), a marker of oxidative protein modification, were 10-fold higher in heart-failure patients compared with controls [geometric means and 95% CIs for patients, 75 (57 to 100) pmol/mg; controls, 5 (4 to 7) pmol/mg; P<0.001]. Moreover, levels of PCs were 50-fold higher in patients homozygous for the polymorphism (CC) than in controls and significantly higher than the AA and AC genotype patient groups [CC: 273 (135-550); AC: 59 (35-98); AA: 65 (40-106) pmol/mg; P<0.001]. Levels of myeloperoxidase were also modestly increased in heart-failure patients [51 (46-57) ng/mL] compared with controls [37 (32-44) ng/mL; P<0.001], but were especially elevated in patients with a CC genotype [CC: 72 (58-89); AC: 52 (44-61); AA: 39 (34-46) ng/mL; P<0.001]. The AT1R genotype was demonstrated to be an independent predictor of both PCs and myeloperoxidase levels in heart-failure patients. These findings suggest that oxidative stress in human heart failure is regulated via angiotensin signaling and may involve the nicotinamide dinucleotide oxidase pathway.     

Implementation of an integrated emergency department acute atrial fibrillation pathway safely reduces cardioversions and hospitalisations: A comparative pre–post study

Objective

Atrial fibrillation/flutter (AF/AFL) accounts for high rates of ED presentations and hospital admissions. There is increasing evidence to suggest that delaying cardioversion for acute uncomplicated AF is safe, and that many patients will spontaneously revert to sinus rhythm (SR). We conducted a before-and-after evaluation of AF/AFL management after a change in ED pathway using a conservative ‘rate-and-wait’ approach, incorporating next working day outpatient clinic follow-up and delayed cardioversion if required.

Methods

We performed a before-and-after retrospective cohort study examining outcomes for patients who presented to the ED in Christchurch, New Zealand, with acute uncomplicated AF/AFL in the 1-year period before and after the implementation of a new conservative management pathway.

Results

A total of 360 patients were included in the study (182 ‘Pre-pathway’ vs 178 ‘Post-Pathway’). Compared to the pre-pathway cohort, those managed under the new pathway had an 81.2% reduction in ED cardioversions (n = 32 vs n = 6), and 50.7% reduction in all cardioversions (n = 65 vs n = 32). There was a 31.6% reduction in admissions from ED (n = 54 vs n = 79). ED length of stay (3.9 h vs 3.8 h, net difference −0.1 h, 95% confidence interval [CI] −0.6 to 0.3), 1-year ED AF representation (32.4% vs 26.4%, net difference −6.0% [95% CI −16.0% to 3.9%]), 1-year ED ischaemic stroke presentation (2.2% in both groups) and 7-day all-cause mortality rates (hazard ratio 1.05 [95% CI 0.6 to 1.9]) were all similar.

Conclusions

Using a conservative ‘rate-and-wait’ strategy with early follow-up for patients presenting to ED with AF/AFL can safely reduce unnecessary cardioversions and avoidable hospitalisations.