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  • Author: M. Kocmálová x
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Open access

M. Kocmálová and I. Kazimierová

Abstract

The present in vitro study was focused on the differences in expression and activity of calcium release-activated calcium (CRAC) channels of human term-pregnant and non-pregnant myometrium. The expression of Orai1 protein, as a functional subunit of CRAC channel, was significantly higher than in non-pregnant myometrium. Lower Orai1 protein expression did not influence the amplitude of contractile response of term-pregnant myometrium, but higher Orai1 expression observed in non-pregnant myometrium was related to the different influence of CRAC blocker on contraction frequency.

Open access

M. Kocmalova, J. Marcinek, M. Kalman, S. Franova and M. Sutovska

Relationship Between Potassium Ion Channels and Airways Defence Reflexes Influenced by Experimentally Induced Allergic Inflammation in Guinea Pigs

Previously, we declared important role of ATP-sensitive (KATP) and calcium-sensitive (BKCa) potassium ion channels in cough and other defence reflexes of the airways coupled with reactivity of airways smooth muscle (ASM) and suggested their potential use as antitussives and antiasthmatic drugs.

The aim of presented studies was prove whether openers of potassium ion channels, KATP - pinacidil and BKCa - NS 1619, inhibit the cough reflex and modulate the ASM reactivity in conditions of experimental allergic inflammation of the airways in guinea pigs and if their influence on airways defence reflexes is changed by developing airways inflammation. Presented studies were realized in 4 partial experimental procedures with unsensitized guinea pigs and animal on 7th, 14th and 21th day of sensitization. Allergic inflammation of airways was induced by repetitive exposure of guinea pigs to ovalbumine and the degree of allergic inflammation was determined by histological analysis of tracheal and pulmonary samples. The cough reflex was induced by 0, 3 M citric acid aerosol for 3 min interval in which total number of coughs was counted. ASM reactivity in vivo was expressed as values of specific airway resistance (R. V) calculated by Pennock.

The cough response on the citric acid was significantly increased on 7th and 14th days of sensitization. The experiments showed persistent cough suppressive effect of pinacidil almost similar to codeine. The antitussive activity of NS 1619 remained only on 7th day of sensitization similar to its effect in group of unsensitized animals. Sensitization by ovalbumine gradually increased the values of R. V on bronchoprovoking agent citric acid. Pinacidil suppressed R. V values of both, unsensitized and sensitized animals, more significantly than salbutamol. In unsensitized guinea pigs, NS 1619 significantly reduced R. V values, but allergic inflammation attenuated its bronchodilatory activity on 7th and 14th days. Histological analysis of specimens showed increasing signs of allergic inflammation during sensitization procedure as well as significant proinflammatory effect of pinacidil and NS 1619. Introduction of non-selective KATP agonists in clinical practice is strongly limited due to proinflammatory effect, but KATP of ASM represents a rational therapeutic target for novel drugs - tissue selective agonists of KATP.

Open access

J. Sutovsky, M. Kocmalova, M. Benco, I. Kazimierova, L. Pappova, A. Frano and M. Sutovska

Abstract

Background: Degenerative spine disorders (DSD) are the most frequent reason of morbidity in adults. Commonly DSD includes degenerative disorders of intervertebral discs (IVDs), spinal stenosis and degenerative spondylolisthesis (SL). There is increasing evidence about significant role of cytokines in DSD pathogenesis, symptomathology and progression, but their protective levels remain still unknown.

Material and Methods: The aim of presented study was to provide quantitative and qualitative analysis of cytokine, chemokine and growth factors levels in individual parts of IVDs - annulus fibrosus (AF) and nucleus pulposus (NP) - separately and in facet joints (FJ) subchondral bone of patients with DSD and in controls - healthy subjects during a multiorgan procurement procedure. Bio-Plex® assay was used to measure concentrations of 27 different cytokines in tissue of patients with DSD. Their concentrations in tissues of healthy subjects during a multiorgan procurement procedure represented protective levels.

Results: The Bio-Plex® assay revealed significant differences between the patients suffered from degenerated and herniated IVDs and from lumbar SL and controls in cytokines, chemokines and growth factor profiles suggested that pro-inflammatory changes of both NP and AF were dominated in herniated IVDs, whereas the same tissue of lumbar SL patients exhibited much more complex changes in cytokine levels suggested o only ongoing inflammation (IL-6, IL-8, MCP-1, TNF-α), abut also antiinflammatory processes (IL-ra, IL-10) or connective tissue remodeling (PDGF-bb, IL-17, VEGF). The different mediators were found elevated in lumbar SL samples of subchondral FJ bone. These also confirmed ongoing inflammation, accelerated bone resorption and formation and increased fibroblasts activity in FJ bone.

Conclusion: The study supported the significant involvement of several cytokines, chemokines and growth factors in the pathogenesis of DSD. These cytokines should represent future potential targets for new biological treatment able to slow DSD progression as well as factor determining prognosis of DSD.

Open access

M. Kocmálová, J. Ľupták, J. Barboríková, I. Kazimierová, M. Grendár and J. Šutovský

Abstract

Background: This study specified the role of several significant ion channels regulating the metabolism of calcium ions in contraction and relaxation of human detrusor muscle in order to identify possible target for future drugs that are capable of treating diseases resulting from impaired detrusor activity, e.g. overactive bladder. Although this disease can be successfully treated with muscarinic receptor antagonists or β3 agonist, many patients may not be suitable for chronic therapy, especially due to the relatively high side effects of the treatment.

Material and Methods: The study used the isolated detrusor tissue samples, which were obtained from the macroscopic healthy tissue of urinary bladder from 19 patients undergoing a total prostatectomy because of localized prostate cancer. Each biological sample was prepared into 8 strips. We used oxybutynin and mirabegron as control drugs and several blockers of specific subtypes calcium and potassium ion channels as tested substances. The contractility of bladder was investigated by an organ tissue bath method in vitro and contraction was induced by carbachol.

Results: The amplitude of contraction was successfully decreased by positive control drugs and, from tested agents, the comparable effect had the substance capable of influencing IP3 receptors and Orai-STIM channels and combination consisting of drugs possessing an inhibitory effect on IP3 receptors, L- and T-type voltage-gated calcium channels and Orai-STIM channels.

Conclusion: The present work represents a new finding about handling Ca2+ in urinary bladder contraction and pointed to a dominant role of IP3 receptor-mediated pathway in the regulation of Ca2+ metabolism, which may represent a future strategy in pharmacotherapy of impaired detrusor activity.

Open access

L. Pappová, I. Kazimierová and M. Kocmálová

Abstract

Aim: N-acetylcysteine is the prototype of mucolytic agents. The aim of this study was to evaluate the acute and chronic effect of inhaled and oral N-acetylcysteine on airway reactivity, cough reflex and ciliary beat frequency and parameters of mentioned defense mechanisms were assessed in physiological conditions.

Methods: An experiment was performed using healthy guinea pigs treated with inhaled (0.6 M; 5min) and oral N-acetylcysteine (20 mg/kg), administrated either acutely as a single dose or chronically during 7 days. The cough reflex and specific airway resistance were assessed by in vivo method, using a double chamber plethysmograph box. The ciliary beat frequency was evaluated in in vitro conditions on tracheal brushed samples using light microscope coupled to high speed video camera.

Results: Inhaled and oral N-acetylcysteine, either administrated as a single dose or during 7 days, have shown a tendency to decrease sensitivity of the cough reflex and increase the airway reactivity. Acute administration of inhaled and oral N-acetylcysteine had no statistically relevant effect on the ciliary beat frequency, whereas chronic administration of both inhaled and oral N-acetylcysteine led to a marked reduction in the ciliary beat frequency.

Conclusion: Chronic administration of oral and inhaled N-acetylcysteine had a negative impact on the ciliary beat frequency, which represents one of the key factors determining the rate of mucociliary clearance. Thus, administration of N-acetylcysteine is less likely to increase the expulsion of mucus by ciliary movement. In addition, the observed tendency of inhaled and oral N-acetylcysteine to increase the airway reactivity may limit its use in conditions with severe airflow obstruction.