Apostolia Hatziefthimiou - Academia.edu (original) (raw)
Papers by Apostolia Hatziefthimiou
Mediat Inflamm, 1998
The airway epithelium is responsible for the production of a number of arachidonic acid and non-p... more The airway epithelium is responsible for the production of a number of arachidonic acid and non-prostanoid inhibitory factors. Epithelium synthesises nitric oxide (NO) which may be important in regulating the function of airways smooth muscles. We studied in vitro the effect of histamine (100 nM-100 microM) which increases the NO release on rabbit airway smooth muscles induced by 80 mM KC1 in the presence or not of 10(-5) Methylene blue (MB) (inactivator of guanylate cyclase) or N(G)-monomethyl L-arginine (L-NMMA), a NOS inhibitor. All experiments were done in tracheal muscle strips from 28 rabbits with epithelium and after epithelium removal. The additional use of histamine (1 microM) on KC1 contraction induced a relaxation of 10% of the initial contraction. The additional use of L-NMMA decreased the relaxation to 5% of initial contraction. MB rather than L-NMMA increased the contraction significantly (p<0.01). Epithelium removal increased the contraction induced by KC1 (80 mM) and histamine (1 microM) by about 30% (p<0.001). NO release especially from epithelium regulates the airways smooth muscle functions. Damage to the epithelium may contribute to an increase in airways sensitivity, observed in asthma.
Open Journal of Molecular and Integrative Physiology, 2013
is recognized as a worldwide pathogen, and the incidence of community-acquired infections (CA-MRS... more is recognized as a worldwide pathogen, and the incidence of community-acquired infections (CA-MRSA) is increased. A virulence factor has been found in most CA-MRSA infections, the Panton-Valentin leukocidin (PVL), which causes polymorphonuclear leukocytes lysis and acute uncontrolled inflammation and tissue injury. In this study we investigated the effect of bacterial supernatant of PVL positive or negative strains on airway smooth muscle obtained from rabbit trachea. MRSA that carry the PVL-gene, confirmed by PCR, is cultured on GP agar and colonies were transferred into casein casein yeast extract medium. The culture supernatants were removed after centrifugation and the presence of PVL was confirmed using an immunochromatographic test. Rabbit tracheal ASMC were isolated and incubated with PVL positive or negative bacterial supernatant (1:20 -1:2000) for 1 -3 days. The effect of PVL on the ASMC morphology or viability was estimated using microscope observations or indirect immunofluorescence with anti-Smooth muscle α-actin antibody and Dapi for DNA staining, and Trypan blue staining, respectively. ASMC incubated with PVL exhibit increased cell size, granular cytoplasm, and ruptured nuclei. Furthermore, PVL reduces cell number mainly in ASMC incubated in the presence of 10% FBS, therefore actively proliferating cells. These results show that apart from the known effect of PVL on immune cells and inflammation process, PVL has a direct toxic effect on airway smooth muscle cells.
The Journal of Antibiotics, 2010
The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tr... more The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tracheal smooth muscle cells (SMCs). The purpose of this study is to investigate the effect of azithromycin on human bronchial SMCs. Human bronchial SMCs were treated with azithromycin (10 À5 M) in the presence or absence of 10% fetal bovine serum (FBS). Cell number was estimated using the Cell Titer 96 AQ ueous One Solution Assay. Induction of autophagy was studied by observation of cell morphology in cells treated or not with the autophagy inhibitor, 3-methyladenine (3-MA), as well as by Lysotracker Red staining of lysosomes. Activation of apoptosis was assessed with flow cytometry after annexin staining. Incubation with azithromycin for 24, 48 or 72 h reduced viability in FBS-deprived cells, as well as cells cultured in FBS-containing medium. Azithromycin treatment resulted in the formation of cytoplasmic vacuoles that could not be prevented by 3-MA. Furthermore, 3-MA did not reverse the effect of azithromycin on the viability of SMCs. There was an increase in the number of lysosomes in cells treated with azithromycin. Finally, azithromycin increased the percentage of early apoptotic cells. In conclusion, azithromycin reduces the viability of human bronchial SMCs possibly by leading to apoptotic cell death.
Pacing and Clinical Electrophysiology, 2017
Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fi... more Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial-selective electrophysiologic properties, has recently been attempted as add-on therapy with AMIO to facilitate AF conversion. To establish the role of this combination therapy, we enrolled 173 consecutive patients (68 ± 10 years, 54% male) with recent-onset (<48-hour duration) AF who were eligible for pharmacologic cardioversion. Patients were randomized to intravenous AMIO (loading dose 5 mg/kg in 1 hour followed by 50 mg/h; n = 81), or AMIO plus a single oral dose of RAN 1 g (n = 92). Mean left atrial diameter did not significantly differ between groups, AMIO and AMIO + RAN (4.2 ± 0.5 cm vs 4.1 ± 0.4 cm, P = 0.18). The AMIO + RAN group compared with the AMIO-only group showed significantly shorter time to conversion (8.6 ± 2.8 hours vs 19.4 ± 4.4 hours, P < 0.0001) and higher conversion rate at 24 hours (98% vs 58%, P < 0.001). Left ventricular ejection fraction did not markedly vary between the two groups and ranged within moderately reduced values. No serious clinically evident adverse effects were observed in any of the patients receiving either AMIO or the combination treatment. Our data demonstrate faster sinus rhythm restoration and enhanced conversion rate of AF after AMIO plus RAN in patients with preserved ejection fraction and left atrial size, implicating a synergistic effect of the two agents.
Steroids, 2011
Airway disease distribution and/or severity exhibit sex differences suggesting that sex hormones ... more Airway disease distribution and/or severity exhibit sex differences suggesting that sex hormones are involved in the respiratory system physiology and pathophysiology. The implication of airway smooth muscle cells (ASMCs) in the physiology of the airways and the pathogenetic mechanism of airway remodeling is of great interest. Therefore, we studied the effect of testosterone and 17β-estradiol on ASMC proliferation and the mechanisms involved.Cell proliferation was estimated using the methyl-[3H]thymidine incorporation and Cell Titer 96® AQueous One Solution Assay methods. ASMC isolated from adult male or female rabbit trachea were incubated with testosterone (1 pM–1 μM) or 17β-estradiol (1 pM–1 μM), in the presence or absence of the androgen receptor antagonist flutamide (10 nM) or estrogen receptor antagonist ICI182780 (10 nM), as well as of the PI3K inhibitors LY294002 (20 μM) or wortmannin (1 μM), or the MAPK inhibitors PD98059 (100 μM) or U0126 (1 μM).After 24 h of incubation, testosterone and 17β-estradiol increased methyl-[3H]thymidine incorporation and cell number, in ASMC isolated from male or female animals. The induction of ASMC proliferation by testosterone or 17β-estradiol was inhibited by flutamide or ICI182780 respectively, as well as by LY294002, wortmannin, PD98059 or U0126.In conclusion, testosterone and 17β-estradiol have a mitogenic effect on ASMC, which is receptor-mediated and involves the MAPK and PI3K signaling pathways. Moreover, their effect is the same for ASMC from male and female animals. It is possible that gender-related differences in ASMC remodeling, may be influenced by the different patterns of sex steroid hormone secretion in males and females.▶ Testosterone and 17β-estradiol have a mitogenic effect on ASMC. ▶ The hormone effect is receptor-mediated. ▶ The MAPK and PI3K signaling pathways are activated by hormones. ▶ There appear no gender-related differences in airway remodeling concerning ASMC.
Amer J Physiol Lung Cell M Ph, 2007
Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch betwee... more Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1alpha. In addition, FBS stimulated the induction of HIF-1alpha by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1alpha. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1alpha by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1alpha in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1alpha might be implicated in airway hypercontractility.
American Journal of Respiratory Cell and Molecular Biology, Dec 20, 2012
ABSTRACT
Pulmonary Research and Respiratory Medicine - Open Journal, 2014
Acta cardiologica, 2015
Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the c... more Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of ...
ISRN inflammation, 2012
Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characteriz... more Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characterized by the presence in the airways of inflammation factors, growth factors and cytokines, which promote airway wall remodelling. The aim of this study was to investigate the effect of cytokines and growth factors on airway smooth muscle cell (ASMC) proliferation, phenotype and responsiveness. Incubation of serum starved human bronchial ASMCs with TNF- α , TGF, bFGF, and PDGF, but not IL-1 β , increased methyl-[(3)H]thymidine incorporation and cell number, mediated by the PI3K and MAPK signalling pathways. Regarding rabbit tracheal ASMC proliferation, TNF- α , IL-1 β , TGF, and PDGF increased methyl-[(3)H]thymidine incorporation in a PI3K- and MAPK-dependent manner. bFGF increased both methyl-[(3)H]thymidine incorporation and cell number. Moreover, incubation with TGF, bFGF and PDGF appears to drive human ASMCs towards a synthetic phenotype, as shown by the reduction of the percentage of c...
Journal of Cardiovascular Pharmacology and Therapeutics, 2012
Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attribu... more Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attributed to the inhibition of late Na(+) current and atrial-selective early Na(+) current. However, there are only limited data regarding its efficacy and mechanism of action against atrial flutter (Afl) and atrial fibrillation (AF) in intact animals. Therefore, we aimed to investigate the electrophysiologic mechanism of Ran in a rabbit model of inducible atrial tachyarrhythmias elicited by acetylcholine (ACh). Arrhythmias were produced in 19 rabbits by rapid atrial burst pacing during control, after intravenous ACh and after Ran + ACh administration. Recording of right atrial monophasic action potentials (MAPs) and programmed stimulation were utilized to determine the duration of atrial repolarization at various cycle lengths and voltage levels of action potential, including 75% of total MAP duration (MAPD75), effective refractory period (ERP), and postrepolarization refractoriness (PRR = ERP - MAPD75) prior to and after Ran. Control stimulation yielded no arrhythmias or maximal nonsustained runs of Afl/AF. Upon ACh, 17 of 19 rabbits exhibited sustained Afl and AF as well as mixed forms of Afl/AF, while 2 animals revealed none or short runs of nonsustained arrhythmias and were excluded from the study. High-frequency burst pacing during the first 30 minutes after Ran + ACh failed to induce any arrhythmia in 13 of 17 rabbits (76%), while 2 animals displayed sustained Afl/AF and 2 other animals nonsustained Afl/AF. At basic stimulation cycle length of 250 milliseconds, Ran prolonged baseline atrial ERP (80 ± 8 vs 120 ± 9 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) much more than MAPD75 (65 ± 7 vs 85 ± 7 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001), leading to atrial PRR which was more pronounced after Ran compared with control measurements (35 ± 11 vs 15 ± 10 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). This in vivo study demonstrates that Ran exerts antiarrhythmic activity by suppressing inducibility of ACh-mediated Afl/AF in intact rabbits. Its action may predominantly be related to a significant increase in atrial PRR, resulting in depressed electrical excitability and impediment of arrhythmia initiation.
Clinical Research in Cardiology, 2014
Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. The... more Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. There exist consistent experimental and clinical data suggesting that aldosterone antagonists (AAs) may exert beneficial effects regarding electrical and structural remodeling in failing myocardium. Recently, eplerenone (EPL) has been found to reduce the incidence of nonsurgical AF when added to guideline-recommended therapy in patients with systolic heart failure. Based on these findings, we primarily aimed to evaluate by retrospective analysis the impact of the two AAs, EPL and spironolactone (SPL), given at standard therapeutic doses in preventing new-onset POAF in patients the majority of which had a preoperative ejection fraction (EF) below 40%. A total of 332 patients (298 men/34 women, mean age 64.3 ± 9 years) without history of AF were included in this analysis; 132 of these patients received long-term EPL or SPL in addition to beta-blockade/statins therapy and 200 patients received neither EPL nor SPL. All patients underwent on-pump coronary artery bypass graft (80%) and/or valvular surgery (20%). In the nonAA group (EF = 35.8 ± 6%) 90/200 patients (45%) had POAF, while in the AA group (EF = 36.2 ± 5%) only 40/132 patients (30.3%) developed POAF (P < 0.01, χ (2) test). Multivariate logistic regression analysis revealed that only AAs and left atrial diameter significantly affected the development of POAF even when adjusted for other clinical variables (P < 0.05). In conclusion, AAs significantly reduced the incidence of POAF when added to standard heart failure therapy in patients undergoing on-pump cardiac surgery.
Mediat Inflamm, 1998
The airway epithelium is responsible for the production of a number of arachidonic acid and non-p... more The airway epithelium is responsible for the production of a number of arachidonic acid and non-prostanoid inhibitory factors. Epithelium synthesises nitric oxide (NO) which may be important in regulating the function of airways smooth muscles. We studied in vitro the effect of histamine (100 nM-100 microM) which increases the NO release on rabbit airway smooth muscles induced by 80 mM KC1 in the presence or not of 10(-5) Methylene blue (MB) (inactivator of guanylate cyclase) or N(G)-monomethyl L-arginine (L-NMMA), a NOS inhibitor. All experiments were done in tracheal muscle strips from 28 rabbits with epithelium and after epithelium removal. The additional use of histamine (1 microM) on KC1 contraction induced a relaxation of 10% of the initial contraction. The additional use of L-NMMA decreased the relaxation to 5% of initial contraction. MB rather than L-NMMA increased the contraction significantly (p<0.01). Epithelium removal increased the contraction induced by KC1 (80 mM) and histamine (1 microM) by about 30% (p<0.001). NO release especially from epithelium regulates the airways smooth muscle functions. Damage to the epithelium may contribute to an increase in airways sensitivity, observed in asthma.
Open Journal of Molecular and Integrative Physiology, 2013
is recognized as a worldwide pathogen, and the incidence of community-acquired infections (CA-MRS... more is recognized as a worldwide pathogen, and the incidence of community-acquired infections (CA-MRSA) is increased. A virulence factor has been found in most CA-MRSA infections, the Panton-Valentin leukocidin (PVL), which causes polymorphonuclear leukocytes lysis and acute uncontrolled inflammation and tissue injury. In this study we investigated the effect of bacterial supernatant of PVL positive or negative strains on airway smooth muscle obtained from rabbit trachea. MRSA that carry the PVL-gene, confirmed by PCR, is cultured on GP agar and colonies were transferred into casein casein yeast extract medium. The culture supernatants were removed after centrifugation and the presence of PVL was confirmed using an immunochromatographic test. Rabbit tracheal ASMC were isolated and incubated with PVL positive or negative bacterial supernatant (1:20 -1:2000) for 1 -3 days. The effect of PVL on the ASMC morphology or viability was estimated using microscope observations or indirect immunofluorescence with anti-Smooth muscle α-actin antibody and Dapi for DNA staining, and Trypan blue staining, respectively. ASMC incubated with PVL exhibit increased cell size, granular cytoplasm, and ruptured nuclei. Furthermore, PVL reduces cell number mainly in ASMC incubated in the presence of 10% FBS, therefore actively proliferating cells. These results show that apart from the known effect of PVL on immune cells and inflammation process, PVL has a direct toxic effect on airway smooth muscle cells.
The Journal of Antibiotics, 2010
The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tr... more The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tracheal smooth muscle cells (SMCs). The purpose of this study is to investigate the effect of azithromycin on human bronchial SMCs. Human bronchial SMCs were treated with azithromycin (10 À5 M) in the presence or absence of 10% fetal bovine serum (FBS). Cell number was estimated using the Cell Titer 96 AQ ueous One Solution Assay. Induction of autophagy was studied by observation of cell morphology in cells treated or not with the autophagy inhibitor, 3-methyladenine (3-MA), as well as by Lysotracker Red staining of lysosomes. Activation of apoptosis was assessed with flow cytometry after annexin staining. Incubation with azithromycin for 24, 48 or 72 h reduced viability in FBS-deprived cells, as well as cells cultured in FBS-containing medium. Azithromycin treatment resulted in the formation of cytoplasmic vacuoles that could not be prevented by 3-MA. Furthermore, 3-MA did not reverse the effect of azithromycin on the viability of SMCs. There was an increase in the number of lysosomes in cells treated with azithromycin. Finally, azithromycin increased the percentage of early apoptotic cells. In conclusion, azithromycin reduces the viability of human bronchial SMCs possibly by leading to apoptotic cell death.
Pacing and Clinical Electrophysiology, 2017
Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fi... more Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial-selective electrophysiologic properties, has recently been attempted as add-on therapy with AMIO to facilitate AF conversion. To establish the role of this combination therapy, we enrolled 173 consecutive patients (68 ± 10 years, 54% male) with recent-onset (<48-hour duration) AF who were eligible for pharmacologic cardioversion. Patients were randomized to intravenous AMIO (loading dose 5 mg/kg in 1 hour followed by 50 mg/h; n = 81), or AMIO plus a single oral dose of RAN 1 g (n = 92). Mean left atrial diameter did not significantly differ between groups, AMIO and AMIO + RAN (4.2 ± 0.5 cm vs 4.1 ± 0.4 cm, P = 0.18). The AMIO + RAN group compared with the AMIO-only group showed significantly shorter time to conversion (8.6 ± 2.8 hours vs 19.4 ± 4.4 hours, P < 0.0001) and higher conversion rate at 24 hours (98% vs 58%, P < 0.001). Left ventricular ejection fraction did not markedly vary between the two groups and ranged within moderately reduced values. No serious clinically evident adverse effects were observed in any of the patients receiving either AMIO or the combination treatment. Our data demonstrate faster sinus rhythm restoration and enhanced conversion rate of AF after AMIO plus RAN in patients with preserved ejection fraction and left atrial size, implicating a synergistic effect of the two agents.
Steroids, 2011
Airway disease distribution and/or severity exhibit sex differences suggesting that sex hormones ... more Airway disease distribution and/or severity exhibit sex differences suggesting that sex hormones are involved in the respiratory system physiology and pathophysiology. The implication of airway smooth muscle cells (ASMCs) in the physiology of the airways and the pathogenetic mechanism of airway remodeling is of great interest. Therefore, we studied the effect of testosterone and 17β-estradiol on ASMC proliferation and the mechanisms involved.Cell proliferation was estimated using the methyl-[3H]thymidine incorporation and Cell Titer 96® AQueous One Solution Assay methods. ASMC isolated from adult male or female rabbit trachea were incubated with testosterone (1 pM–1 μM) or 17β-estradiol (1 pM–1 μM), in the presence or absence of the androgen receptor antagonist flutamide (10 nM) or estrogen receptor antagonist ICI182780 (10 nM), as well as of the PI3K inhibitors LY294002 (20 μM) or wortmannin (1 μM), or the MAPK inhibitors PD98059 (100 μM) or U0126 (1 μM).After 24 h of incubation, testosterone and 17β-estradiol increased methyl-[3H]thymidine incorporation and cell number, in ASMC isolated from male or female animals. The induction of ASMC proliferation by testosterone or 17β-estradiol was inhibited by flutamide or ICI182780 respectively, as well as by LY294002, wortmannin, PD98059 or U0126.In conclusion, testosterone and 17β-estradiol have a mitogenic effect on ASMC, which is receptor-mediated and involves the MAPK and PI3K signaling pathways. Moreover, their effect is the same for ASMC from male and female animals. It is possible that gender-related differences in ASMC remodeling, may be influenced by the different patterns of sex steroid hormone secretion in males and females.▶ Testosterone and 17β-estradiol have a mitogenic effect on ASMC. ▶ The hormone effect is receptor-mediated. ▶ The MAPK and PI3K signaling pathways are activated by hormones. ▶ There appear no gender-related differences in airway remodeling concerning ASMC.
Amer J Physiol Lung Cell M Ph, 2007
Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch betwee... more Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1alpha. In addition, FBS stimulated the induction of HIF-1alpha by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1alpha. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1alpha by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1alpha in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1alpha might be implicated in airway hypercontractility.
American Journal of Respiratory Cell and Molecular Biology, Dec 20, 2012
ABSTRACT
Pulmonary Research and Respiratory Medicine - Open Journal, 2014
Acta cardiologica, 2015
Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the c... more Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of ...
ISRN inflammation, 2012
Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characteriz... more Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characterized by the presence in the airways of inflammation factors, growth factors and cytokines, which promote airway wall remodelling. The aim of this study was to investigate the effect of cytokines and growth factors on airway smooth muscle cell (ASMC) proliferation, phenotype and responsiveness. Incubation of serum starved human bronchial ASMCs with TNF- α , TGF, bFGF, and PDGF, but not IL-1 β , increased methyl-[(3)H]thymidine incorporation and cell number, mediated by the PI3K and MAPK signalling pathways. Regarding rabbit tracheal ASMC proliferation, TNF- α , IL-1 β , TGF, and PDGF increased methyl-[(3)H]thymidine incorporation in a PI3K- and MAPK-dependent manner. bFGF increased both methyl-[(3)H]thymidine incorporation and cell number. Moreover, incubation with TGF, bFGF and PDGF appears to drive human ASMCs towards a synthetic phenotype, as shown by the reduction of the percentage of c...
Journal of Cardiovascular Pharmacology and Therapeutics, 2012
Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attribu... more Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attributed to the inhibition of late Na(+) current and atrial-selective early Na(+) current. However, there are only limited data regarding its efficacy and mechanism of action against atrial flutter (Afl) and atrial fibrillation (AF) in intact animals. Therefore, we aimed to investigate the electrophysiologic mechanism of Ran in a rabbit model of inducible atrial tachyarrhythmias elicited by acetylcholine (ACh). Arrhythmias were produced in 19 rabbits by rapid atrial burst pacing during control, after intravenous ACh and after Ran + ACh administration. Recording of right atrial monophasic action potentials (MAPs) and programmed stimulation were utilized to determine the duration of atrial repolarization at various cycle lengths and voltage levels of action potential, including 75% of total MAP duration (MAPD75), effective refractory period (ERP), and postrepolarization refractoriness (PRR = ERP - MAPD75) prior to and after Ran. Control stimulation yielded no arrhythmias or maximal nonsustained runs of Afl/AF. Upon ACh, 17 of 19 rabbits exhibited sustained Afl and AF as well as mixed forms of Afl/AF, while 2 animals revealed none or short runs of nonsustained arrhythmias and were excluded from the study. High-frequency burst pacing during the first 30 minutes after Ran + ACh failed to induce any arrhythmia in 13 of 17 rabbits (76%), while 2 animals displayed sustained Afl/AF and 2 other animals nonsustained Afl/AF. At basic stimulation cycle length of 250 milliseconds, Ran prolonged baseline atrial ERP (80 ± 8 vs 120 ± 9 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) much more than MAPD75 (65 ± 7 vs 85 ± 7 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001), leading to atrial PRR which was more pronounced after Ran compared with control measurements (35 ± 11 vs 15 ± 10 milliseconds, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). This in vivo study demonstrates that Ran exerts antiarrhythmic activity by suppressing inducibility of ACh-mediated Afl/AF in intact rabbits. Its action may predominantly be related to a significant increase in atrial PRR, resulting in depressed electrical excitability and impediment of arrhythmia initiation.
Clinical Research in Cardiology, 2014
Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. The... more Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. There exist consistent experimental and clinical data suggesting that aldosterone antagonists (AAs) may exert beneficial effects regarding electrical and structural remodeling in failing myocardium. Recently, eplerenone (EPL) has been found to reduce the incidence of nonsurgical AF when added to guideline-recommended therapy in patients with systolic heart failure. Based on these findings, we primarily aimed to evaluate by retrospective analysis the impact of the two AAs, EPL and spironolactone (SPL), given at standard therapeutic doses in preventing new-onset POAF in patients the majority of which had a preoperative ejection fraction (EF) below 40%. A total of 332 patients (298 men/34 women, mean age 64.3 ± 9 years) without history of AF were included in this analysis; 132 of these patients received long-term EPL or SPL in addition to beta-blockade/statins therapy and 200 patients received neither EPL nor SPL. All patients underwent on-pump coronary artery bypass graft (80%) and/or valvular surgery (20%). In the nonAA group (EF = 35.8 ± 6%) 90/200 patients (45%) had POAF, while in the AA group (EF = 36.2 ± 5%) only 40/132 patients (30.3%) developed POAF (P < 0.01, χ (2) test). Multivariate logistic regression analysis revealed that only AAs and left atrial diameter significantly affected the development of POAF even when adjusted for other clinical variables (P < 0.05). In conclusion, AAs significantly reduced the incidence of POAF when added to standard heart failure therapy in patients undergoing on-pump cardiac surgery.