Abstract. Cyclosporine belongs to the group of the most commonly used immunosuppressants. Hypertension occurs in approximately 30% of patients treated with this drug. However, the pathogenesis of this occurrence has not been explained to date. The purpose of our study was to clarify the mechanisms leading to the evolution of hypertension induced by cyclosporine A (CsA). We examined the changes in transmission within receptors and around the receptors. We also aimed to elucidate the mechanisms responsible for averting arterial hyperresponsiveness induced by the drug. Experiments were performed on isolated and perfused tail arteries of Wistar rats. Tissues surrounding the artery were removed and the proximal segment (length of 2-3 cm) was used for cannulation. Cannulated arteries were placed in a 20-ml glass chamber (vertical position). The contraction force in our model was measured by an increased degree of perfusion pressure with a constant flow rate (approximately 1 ml/min). The results showed that in the presence of CsA, the concentration-response curves/phenylephrine (PHE) curve shifted to the left. Cyclosporine increased the reactivity of the arteries to PHE. This effect was directly linked to the increase in the receptor reserve. The analysis of the reactivity of vascular smooth muscle showed that CsA increased the influx of calcium ions from the extracellular to the intracellular area. No difference was found between the contraction triggered by Bay-K8644 in the presence of CsA and the control probe. The increase in perfusion pressure induced by CsA was blocked by L-type calcium channel blockers (nifidipine and diltiazem). The results from our experiments show that CsA increases the reactivity of vessels to the effect of catecholamines. CsA also enhances signal transmission between G-protein coupled receptors (GPCRs) and calcium channels. The activation of protein kinase C also plays a significant role in this process. Our results suggest that the best choice for the pharmacotherapy of hypertension induced by CsA would be calcium channel antagonists.

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Our results strongly support the idea that main difference between effects on smooth muscle contractility of calcineurin-dependent immunosuppressants: CsA and tacrolimus is related to the different level of extracellular calcium influx to the cytoplasm. The elucidation of these mechanisms may permit the identification of new therapeutic strategies against CsA-induced hypertension.

Abstract. the pathogenesis of viral bronchiolitis is poorly understood. the aim of this study was to analyze interleukin (il)-15, il-18 and interferon (iFn)-γ concentrations and the activity of nK cells and cd4 + and cd8 + lymphocytes in 23 children not older than 30 months of age with acute viral bronchiolitis using blood samples drawn within the first 24 h of their hospital admission, in comparison to a healthy group. in children with bronchiolitis, the mean concentrations of il-15, il-18 and iFn-γ were 9.39±11.55, 884.03±645.44 and 17.92±27.14 pg/ml, respectively, and were significantly higher than those in the control group [2.34±0.61 pg/ml (p<0.05), 248.69±98.73 pg/ml (p<0.001) and 2.75±1.72 pg/ml (p<0.005), respectively]. in the bronchiolitis group, mean z-scores were -1.15±1.9 for cd4 + cells and -0.9±1.23 for cd8 + cells; these scores were significantly lower than those of the general polish population (p<0.001 and <0.01, respectively). however, the mean z-score of the ratio of cd4 + /cd8 + and the nK cell count in children with bronchiolitis did not differ significantly from those of the controls. in conclusion, cytokines such as il-15, il-18 and iFn-γ play a role in the pathogenesis of bronchiolitis in children. IntroductionBronchiolitis in children is a serious self-limiting disease (mortality rate <1%) of respiratory tract infections. however, in high-risk groups such as children with bronchopulmonary dysplasia, congenital heart disease or cystic fibrosis, mortality increases to 5-10%. the leading cause of bronchiolitis are viral infections, with the most common agent being respiratory syncytial virus infection (rSV) (60-80% of cases) (1-4). during rSV infection, the cytokine cascade is activated, leading to the activation of th1 and th2 lymphocytes. thus, an increase in the concentrations of cytokines such as interleukin (il)-2, -6, -10, -12, -13 and a decrease in interferon (iFn)-γ and il-4 concentrations are observed (5-12). during non-rSV viral infections, the th1 type response of the immunologic system with an increase in the iFn-γ concentration is commonly observed (5,8,13,14).il-15 and il-18 are relatively newly discovered cytokines that are produced principally by macrophages during immune response. il-15 has multiple biological properties, including the induction of the production of other cytokines and the inhibition of T-cell apoptosis (15,16). IL-18 is a pro-inflammatory cytokine with pleiotropic properties and plays a crucial role in the maintenance of th1-cell response. this cytokine activates nK cells, leads to eosinophilia and increases histamine concentrations (17)(18)(19)(20). there are various reports indicating that, during viral infection, il-15, il-18 and iFn-γ concentrations are elevated (21). a secondary increase in nK cell activity has also been reported (22). however, the role of il-15 and il-18 in viral bronchiolitis in children remains unknown. the aim of this study was to analyze il-15, il-18 and iFn-γ concentrations and the activity of nK cells as well as cd4 + and cd8 +...