High doses of digoxin increase the myocardial nuclear factor-kB and CaV1.2 channels in healthy mice. A possible mechanism of digitalis toxicity.

BACKGROUND: Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. METHODS: To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. RESULTS: Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. CONCLUSIONS: These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.

Comparative evaluation of the effect of tricyclic antidepressants on inducible nitric oxide synthase expression in neuropathic pain model.

The analgesic effect of acute i.p. administration of amitriptyline (norepinepherine and serotonin reuptake inhibitor), clomipramine (serotonin reuptake inhibitor) and desipramine (norepinepherine reuptake inhibitor) was studied in chronic constriction injury (CCI) model of sciatic nerve in rats and mRNA and protein expression of inducible nitric oxide synthase (iNOS) were also investigated. Acute treatment with amitriptyline and clomipramine produced antinociceptive effects after sciatic nerve injury and blockade of norepinephrine reuptake using desipramine did not demonstrate antinociceptive effects. The antinociceptive effect of amitriptyline, not clomipramine, was augmented by the selective iNOS inhibitor, aminoguanidine. Amitriptyline inhibited iNOS mRNA and protein expression in cerebellum and hippocampus. However, desipramine altered neither iNOS expression at mRNA level nor at post-transcriptional level. Based on our experimental findings, we conclude that the analgesic effect of the dual norepinepherine and serotonin reuptake inhibitor, amitriptyline, is partially due to inhibition of central iNOS.