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Using the patch-clamp technique, we determined that bretylium tosylate, a quaternary ammonium compound possessing immunomodulating activity, decreased the whole-cell K+ current in human T lymphocytes, in a dose-dependent manner, in the 0.05-5 mM extracellular concentration range. Bretylium tosylate prolonged the recovery from inactivation and accelerated the inactivation and deactivation of the K+ current but did not influence the kinetics of activation or the voltage dependence of activation and steady state inactivation of the K+ conductance. The percentage of drug-induced block was independent of membrane potential. K+ channel block by bretylium tosylate was partially and slowly removable by washing with drug-free extracellular solution. Bovine serum albumin (10 mg/ml) in the bath lifted the drug-induced block almost instantaneously, although not completely. In control experiments bovine serum albumin increased the inactivation time constant of the K+ channels but left the peak K+ current amplitude unaffected. On the basis of the experimental evidence, a gating-dependent allosteric interaction is suggested for the mechanism of drug action. The effective dose range, time of exposure, and reversibility of bretylium tosylate-induced K+ channel block correlated well with the same parameters of the drug-induced inhibition of T lymphocyte activation. The reported effects of bretylium tosylate on T cell mitogenesis can be regarded partly as a consequence of its blocking effects on voltage-gated K+ channels.

Backgroundrespiratory morbidity is common in patients with sickle cell anaemia (SCA). The quality of care and environmental factors might have an influence on their respiratory health.Aimsto compare spirometry lung function in children and adolescents attending sickle cell centres in UK and Italy.Methodsanthropometry and spirometry were undertaken in SCA-patients (SS,Sb0) aged 6–17 years. Exclusion criteria: SCArelated morbidity within the last two weeks and inability to perform an adequate spirometry. Portable spirometers (Pony FX, Cosmed-IT, Easy-on PC, NDD-CH) were used. Z-scores of anthropometric and spirometric data were derived, respectively, from CDC2000 and GLI-black equation (Quanjer, ERJ2012). Spirometry patterns were classified as normal, obstructive (zFEV1/FVC < 1.64) or restrictive (zFVC < 1.64 +zFEV1/ FVC 31.64). Differences between groups were assessed by ttests and considered statistically significant for p values<0.05.ResultsEighty-five subjects of African ancestry were included (n.46 UK; n.39 Italy; 42% girls; age-range: 6.2–17.9 years). Prevalence of obstructive pattern was higher in SCA-patients from UK, while a restrictive pattern was more common in subjects living in Italy (table). Mean FEV1/FVC was ~0.6 z-scores lower in SCA patients from UK (p<0.01). Age was negatively correlated (p<0.05) with both zFEV1(R20.19) and zFVC(R20.136).Conclusionobstructive lung disease is more common among paediatric subjects with SCA living in UK than in Italy. Differences in the level of ambient air pollution and prevalence of allergies, could have contributed to these findings. It seems that SCA patients from Italy develop earlier a restrictive picture. These results need further confirmation.Abstract G112(P) Table 1Mean (SD) values, unless otherwise specifiedIndexSickle cell UKSickle cell ITADiff between means (95% CI)n (%male)46 (54%)39 (61%)Age (years)11.8 (2.9)11.3 (3.5)0.5 (-0.9 to 1.9)Height z-score-0.11 (1.23)-0.08 (1.09)-0.03 (-0.53 to 0.47)BMI z-score-0.26 (1.20)-0.55 (1.17)0.29 (-0.24 to 0.82)FEV1 z-score-1.15 (1.09)-0.80 (0.97)-0.35 (-0.81 to 0.08)FVC z-score-0.79 (1.04)-0.71 (0.83)-0.08 (-0.53 to 0.32)FEV1/FVC z-score-0.87 (0.93)-0.27 (0.93)-0.60 (-1.0 to -0.019)Spirometry patternObstructive (% of total)10 (21.7%)3 (7.7%)Restrictive (% of total)5 (10.8%)8 (20.5%)