Birthweight trends and their explanatory factors in Hungary between 1999 and 2018: an analysis of the Hungarian Tauffer registry.

BACKGROUND: The increasing birthweight trend stopped and even reversed in several high income countries in the last 20 years, however the reason for these changes is not well characterized. We aimed to describe birthweight trends of term deliveries in Hungary between 1999 and 2018 and to investigate potential maternal and foetal variables that could drive these changes. METHODS: We analysed data from the Hungarian Tauffer registry, a compulsory anonymized data collection of each delivery. We included all singleton term deliveries in 1999-2018 (n = 1,591,932). We modelled birthweight trends separately in 1999-2008 and 2008-2018 in hierarchical multiple linear regression models adjusted for calendar year, newborn sex, maternal age, gestational age at delivery, and other important determinants. RESULTS: Median birthweights increased from 3250/3400 g (girl/boy) to 3300/3440 g from 1999 to 2008 and decreased to 3260/3400 g in 2018. When we adjusted for gestational age at delivery the increase in the first period became more pronounced (5.4 g/year). During the second period, similar adjustment substantially decreased the rate of decline from 2.5 to 1.4 g/year. Further adjustment for maternal age halved the rate of increase to 2.4 g/year in the first period. During the second period, adjustment for maternal age had little effect on the estimate. CONCLUSIONS: Our findings of an increasing birthweight trend (mostly related to the aging of the mothers) in 1999-2008 may forecast an increased risk of cardiometabolic diseases in offsprings born in this period. In contrast, the decreasing birthweight trends after 2008 may reflect some beneficial effects on perinatal morbidity. However, the long-term effect cannot be predicted, as the trend is mostly explained by the shorter pregnancies.

Birthweights showed an increase followed by a decrease in several high income countries in the last 20 years, however the reasons for these changes is not well described. Thus, we aimed to investigate birthweight trends and their potential explanatory factors in Hungary between 1999 and 2018. We used registry data of all deliveries from Hungary in 1999­2018 (n = 1 591 932). Birthweights increased from 3250/3400 g (girl/boy) to 3300/3440 g from 1999 to 2008 and decreased to 3260/3400 g until 2018. Maternal age explained approximately half of increase in the first period, while a substantial part of the decrease in the second period was explained by the presence of shorter pregnancies. The increasing birthweights in 1999­2008 may forecast an increased risk of cardiometabolic diseases in offsprings born in this period. In contrast, the decreasing birthweight trends after 2008 may reflect some beneficial effects on perinatal morbidity. However, its long-term consequences cannot be predicted, as the trend is mostly explained by the shorter pregnancies.

Spherical Closo Deltahedra with Surface Metal-Metal Multiple Bonding versus Oblate Deltahedra with Internal Metal-Metal Bonding in Dichromadicarbaborane Structures: The Nature of Stone's Icosahedral Dichromadicarbaborane.

The dichromadicarbaboranes Cp2Cr2C2B n-4H n-2 ( n = 8-12) related to the icosahedral structure reported in 1983 by Stone and co-workers and formulated by them as Cp2Cr2C2B8H10 have been investigated using density functional theory. In most cases, the lowest-energy structures are flattened oblatocloso structures with degree 6 and 7 chromium vertices similar to the lowest-energy and experimental structures of the isoelectronic dirhenaboranes Cp2Re2B n-2H n-2. However, most isomeric spherical closo deltahedral structures with surface Cr≣Cr quadruple bonds as well as isocloso structures with surface metal-metal Cr≡Cr triple bonds lie at accessible energies, typically lower than those in the corresponding dirhenaborane systems. However, for the 11-vertex Cp2Cr2C2B7H9 system, the most spherical closo/ isocloso deltahedral structure with a degree 6 metal vertex and degree 4 carbon vertices as well as a surface M≡M triple bond lies energetically below the lowest-energy oblatocloso structure. Calculations of the Cr-Cr distances in an icosahedral Cp2Cr2C2B8H10 structure and in a dihydrogenated icosahedral Cp2Cr2(µ-H)2C2B8H10 structure suggest the latter structure for "Cp2Cr2C2B8H10" reported by Stone and co-workers.

Paramagnetism in Metallacarboranes: The Polyhedral Chromadicarbaborane Systems.

The chromadicarbaboranes CpCrC2Bn-3Hn-1 (8 ≤ n ≤ 12) are of interest in providing stable paramagnetic deltahedral metallaboranes among which the 12-vertex CpCrC2B9H11 has been synthesized by Hawthorne and co-workers. Density functional theory shows that the lowest-energy such structures are quartet spin-state Cr(III) structures in which the central CrC2Bn-3 units exhibit most spherical closo deltahedral geometries similar to those found in the borane dianions BnHn2-. Higher-energy doublet CpCrC2Bn-3Hn-1 (8 ≤ n ≤ 11) structures are found exhibiting central CrC2Bn-3 isocloso deltahedral geometries, thereby providing a degree 6 vertex for the chromium atom. The lowest-energy CpCrC2Bn-3Hn-1 (8 ≤ n ≤ 11) structures all have both carbon atoms at degree 4 vertices. However, the lowest-energy CpCrC2B9H11 structures all have central CrC2B9 icosahedra and thus lack degree 4 vertices for the carbon atoms. For all of the CpCrC2Bn-3Hn-1 (8 ≤ n ≤ 12) systems the lowest-energy isomers are those with the maximum number of Cr-C edges in contrast to the related CpCoC2Bn-3Hn-1 systems.

Hypoelectronicity and Chirality in Dimetallaboranes of Group 9 Metals.

The structures and energetics of the dimetallaboranes Cp2M2Bn-2Hn-2 (n = 8, 9, 10, 11, 12; M = Co, Rh, Ir; Cp = η5-C5H5) were studied using density functional theory. The lowest energy Cp2M2B6H6 and Cp2M2B7H7 structures are chiral C2 structures based on the corresponding closo deltahedra, namely the bisdisphenoid and the tricapped trigonal prism. The permethylated iridaboranes Cp*2Ir2B6H6 and Cp*2Ir2B7H7 (Cp* = η5-Me5C5) were synthesized by Ghosh and co-workers. However, they were found by X-ray crystallography to have nondeltahedral structures containing a quadrilateral face, namely a bicapped trigonal prism and a capped square antiprism for the 8- and 9-vertex systems, respectively. These structures correspond to a mean of the two opposite enantiomers and can also represent the "square" intermediate in the interconversion of the two enantiomers. The lowest energy structures for the 10-vertex Cp2M2B8H8 systems are two isocloso deltahedra with one metal atom at a degree 6 vertex and the other metal atom at a degree 5 vertex. Both isomers have been realized experimentally for Cp2Ir2B8H8. The lowest energy structures for the 11-vertex Cp2M2B9H9 systems have central closo/isocloso deltahedra with one metal atom at a degree 6 vertex and the other metal atom at a nonadjacent degree 5 vertex. This structure type has been found experimentally in both the rhodaboranes and iridaboranes Cp*2M2B9H9 (M = Rh, Ir). The lowest energy structures for the 12-vertex systems Cp2M2B10H10 (M = Co, Rh, Ir) are deltahedra with two adjacent degree 6 vertices for the metal atoms. This type of structure is found experimentally in the rhodium complexes Cp*2Rh2B10H10-n(OH)n (n = 1, 2).

[The myo-inositol is beneficial in the therapy of pregnancy with insulin-dependent type 2 diabetes and polycystic ovary syndrome]. / A mio-inozitol jótékony hatása inzulint igénylo 2-es típusú cukorbetegséghez társuló polycystás ovarium szindrómás várandós terápiájában.

Authors would like to demonstrate the beneficial effect of myo-inositol supplementation in a pregnant woman with insulin-dependent type 2 diabetes mellitus and polycystic ovary syndrome. Insulin and metformin treatment could not achieve normalization of glucose homeostasis for 3 years, and hypoglycemic episodes were frequent. Myo-inositol and folic acid supplementation added to the basic treatment resulted in improved glucose levels in 2 months. At this time she became pregnant. During pregnancy serum glucose levels still improved in the next 2 months. The amniotic membrane ruptured at the 19th gestational week, and pregnancy had to be finished. Developmental disturbances were excluded by the pathologist. She became pregnant again and gave birth to a premature male neonate at the 29th gestational week. The aim of the report was to demonstrate that myo-inositol supplementation may improve the efficacy of the therapy in type 2 diabetes mellitus. Orv. Hetil., 2017, 158(14), 541-545.

A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release.

BACKGROUND AND PURPOSE: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. EXPERIMENTAL APPROACH: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. KEY RESULTS: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2-like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG-nitro-l-arginine and a D1-like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. CONCLUSION AND IMPLICATIONS: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction.

Dynamics of Dental Enamel Surface Remineralization under the Action of Toothpastes with Substituted Hydroxyapatite and Birch Extract.

To address tooth enamel demineralization resulting from factors such as acid erosion, abrasion, and chronic illness treatments, it is important to develop effective daily dental care products promoting enamel preservation and surface remineralization. This study focused on formulating four toothpastes, each containing calcined synthetic hydroxyapatite (HAP) in distinct compositions, each at 4%, along with 1.3% birch extract. Substitution elements were introduced within the HAP structure to enhance enamel remineralization. The efficacy of each toothpaste formulation was evaluated for repairing enamel and for establishing the dynamic of the remineralization. This was performed by using an in vitro assessment of artificially demineralized enamel slices. The structural HAP features explored by XRD and enamel surface quality by AFM revealed notable restorative properties of these toothpastes. Topographic images and the self-assembly of HAP nanoparticles into thin films on enamel surfaces showcased the formulations' effectiveness. Surface roughness was evaluated through statistical analysis using one-way ANOVA followed by post-test Bonferroni's multiple comparison test with a p value < 0.05 significance setting. Remarkably, enamel nanostructure normalization was observed within a short 10-day period of toothpaste treatment. Optimal remineralization for all toothpastes was reached after about 30 days of treatment. These toothpastes containing birch extract also have a dual function of mineralizing enamel while simultaneously promoting enamel health and restoration.

Pregnancy outcomes of women with untreated 'mild' gestational diabetes (gestational diabetes by the WHO 2013 but not by the WHO-1999 diagnostic criteria) - A population-based cohort study.

AIMS: We compared pregnancy outcomes of untreated 'mild' GDM (GDM by WHO 2013 but not by WHO-1999) to normal glucose tolerant women (NGT). METHODS: In a universal screening program 4333 pregnant women had a 3-point 75 g OGTT in Hungary in 2009-2013. By WHO-2013 untreated NGT was diagnosed in n = 3303, 'mild' GDM in n = 336 cases. RESULTS: 'Mild' GDM women were older (mean difference, SE: 1.4, 0.3 yrs), had higher fasting (1.0, 0.02), 60-minute (1.0, 0.09), and 120-minute (0.4, 0.06 mmol/l) blood glucose, and blood pressure (2.6, 0.5/2.0, 0.5 mmHg). Weight gain was similar in both groups (-0.3, 0.3 kg). GDM newborns were heavier (142, 50 g) and were more frequently macrosomic (>4000 g, OR 1.85, 95 %CI 1.35-2.54). Hypertension during pregnancy was more prevalent in the GDM group (OR 1.55, 95 %CI 1.05-2.28), as well as induced (OR 1.38, 95 %CI 1.10-1.74) and instrumental delivery (OR 1.34, 95 %CI 1.07-1.68), and acute caesarean section (OR 1.32, 95 %CI 1.04-1.64). Most of these differences substantially attenuated or became non-significant after adjustment for pre-pregnancy BMI. CONCLUSIONS: Pregnancy outcomes of 'mild' GDM were worse compared to normal glucose tolerant women however these differences were explained by the pre-pregnancy BMI difference between groups.

Flow-evoked vasodilation is blunted in penile arteries from Zucker diabetic fatty rats.

INTRODUCTION: Endothelium-derived relaxing factors such as nitric oxide (NO), prostanoids, and endothelium-derived hyperpolarizing factor (EDHF) are thought to play an important role in vasodilation of penile arteries. AIM: The present study investigated the mechanisms involved in flow- and acetylcholine-induced vasodilation in penile arteries, and whether acetylcholine- and flow-mediated vasodilation is altered in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Moreover, it was addressed whether enhanced myogenic tone may explain impaired flow-evoked vasodilation in arteries from ZDF rats. METHODS: Penile dorsal arteries obtained from lean control and ZDF rats were suspended in a pressure myograph, and flow- and acetylcholine-evoked vasodilation was measured as changes in arterial diameter. MAIN OUTCOME MEASURE: Changes in penile arterial diameter. RESULTS: Incubation with an inhibitor of NO synthase, asymmetric dimethyl-L-arginine (ADMA), and of cyclooxygenase, indomethacin, reduced acetylcholine but not flow-evoked vasodilation in penile arteries, while both responses were abolished by endothelial cell removal. Iberiotoxin, a blocker of large-conductance calcium-activated K+ (BK(Ca) ) channels, inhibited flow-evoked vasodilation. Flow-evoked vasodilation was reduced in arteries from ZDF rats in the absence, but not in the presence, of indomethacin plus ADMA. Elevation of intraluminal pressure increased myogenic tone, which was reduced in arteries from ZDF rats. CONCLUSION: The present findings show that flow evokes endothelium-dependent EDHF-type vasodilation involving BK(Ca) channels in penile arteries. Flow-evoked vasodilation is reduced and only of EDHF-type in penile arteries from type 2 diabetic rats suggesting modulation of this pathway may restore endothelial function and preserve erection in diabetes.

Insulin resistance is associated with gestational hypertension and not with preeclampsia: a population-based screening study.

AIMS: To investigate the relationship between insulin resistance (IR) and subsequent gestational hypertension (GH) or preeclampsia (PE) in normoglycemic and in gestational diabetic pregnant women. Furthermore, we tested whether this association was independent of the prepregnancy body mass index (BMI). METHODS: Each participant underwent a 75-gram oral glucose tolerance test (OGTT) according to World Health Organization recommendation criteria with determination of serum glucose and C-peptide concentrations. IR was determined as a C-peptide-to-glucose ratio at the fasting (FCGR) state and at 2 h (2CGR) after load. RESULTS: A total of 2,954 women were included with a singleton pregnancy, delivery at term, no chronic hypertension, and data on both glucose and C-peptide. Of these women, 183 (6.2%) developed GH and 49 (1.7%) PE. Gestational diabetes mellitus (GDM) was diagnosed in 6.0% of the participants. The FCGR and 2CGR were significantly higher in all women with GH, irrespective of their BMI, compared to the normotensive group; however, the PE and the normotensive groups had similar FCGR and 2CGR values. CONCLUSIONS: The present study suggests that IR at the OGTT is associated with the later development of GH; on the other hand, it is not associated with PE. These relationships are independent of the maternal BMI.

Comparison of clinical characteristics of patients with pandemic SARS-CoV-2-related and community-acquired pneumonias in Hungary - a pilot historical case-control study.

The distinction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related and community-acquired pneumonias poses significant difficulties, as both frequently involve the elderly. This study aimed to predict the risk of SARS-CoV-2-related pneumonia based on clinical characteristics at hospital presentation. Case-control study of all patients admitted for pneumonia at Semmelweis University Emergency Department. Cases (n = 30) were patients diagnosed with SARS-CoV-2-related pneumonia (based on polymerase chain reaction test) between 26 March 2020 and 30 April 2020; controls (n = 82) were historical pneumonia cases between 1 January 2019 and 30 April 2019. Logistic models were built with SARS-CoV-2 infection as outcome using clinical characteristics at presentation. Patients with SARS-CoV-2-related pneumonia were younger (mean difference, 95% CI: 9.3, 3.2-15.5 years) and had a higher lymphocyte count, lower C-reactive protein, presented more frequently with bilateral infiltrate, less frequently with abdominal pain, diarrhoea, and nausea in age- and sex-adjusted models. A logistic model using age, sex, abdominal pain, C-reactive protein, and the presence of bilateral infiltrate as predictors had an excellent discrimination (AUC 0.88, 95% CI: 0.81-0.96) and calibration (p = 0.27-Hosmer-Lemeshow test). The clinical use of our screening prediction model could improve the discrimination of SARS-CoV-2 related from other community-acquired pneumonias and thus help patient triage based on commonly used diagnostic approaches. However, external validation in independent datasets is required before its clinical use.

Role for tyrosine kinases in contraction of rat penile small arteries.

INTRODUCTION: The devasting effect of cancer and treatment thereof contribute to sexual dysfunction. Recently, a series of tyrosine kinase inhibitors have been approved either as add-on or for targeted treatment of cancer. However, tyrosine kinases are not only important for cell growth and proliferation, but also in regulation of vascular tone. AIM: The present study investigated whether tyrosine kinases contribute to contractility in rat penile arteries, and addressed whether they are involved in calcium entry and/or related to the RhoA/Rho-kinase pathway. METHODS: Segments of the rat dorsal penile artery were mounted in microvascular myographs for simultaneous measurements of intracellular calcium concentration ([Ca(2+)](i)) and tension, and tyrosine kinase activity, and phosphorylation of 20-kDa myosin light chain (MLC(20)) was measured in dorsal penile artery homogenates. MAIN OUTCOME MEASURES: In vitro evidence for contractility and changes in intracellular Ca(2+) in small penile arteries. RESULTS: Sodium vanadate (Na(3)VO(4), 1 mM), a tyrosine phosphatase inhibitor, increased [Ca(2+)](i) and tension. A l-type calcium channel blocker, nifedipine (1 µM), markedly reduced Na(3)VO(4)-evoked increases in [Ca(2+)](i) and tension. A thromboxane analog, U46619, increased TK activity. In contrast to the inactive analogue, genistein, a general TK inhibitor, concentration-dependently reduced both U46619-evoked contraction, and [Ca(2+)](i). U46619-induced contraction was markedly inhibited by tyrphostin A23 and bis-tyrphostin, whereas there was no effect of the tyrosine kinase c-Src inhibitor, herbimycin A. Tyrphostin A23 suppressed U46619-mediated phosphorylation of MLC(20). CONCLUSIONS: This study suggests that activation of tyrosine kinases is involved in contraction of rat penile smooth muscle probably by regulation of calcium entry through l-type calcium channels. These findings may have implications for the selections of novel add on anticancer treatments, e.g., inhibitors of tyrosine kinases, and for novel approaches to treat erectile dysfunction.

Does small-conductance calcium-activated potassium channel contribute to cardiac repolarization?

Small-conductance calcium-activated potassium channels (SK channels) have a significant role in neurons. Since they directly integrate calcium handling with repolarization, in heart their role would be particularly important. However, their contribution to cardiac repolarization is still unclear. A previous study reported a significant lengthening effect of apamin, a selective SK channel inhibitor, on the action potential duration in atrial and ventricular mouse cardiomyocytes and human atrial cells. They concluded that these channels provide an important functional link between intracellular calcium handling and action potential kinetics. These findings seriously contradict our studies on cardiac "repolarization reserve", where we demonstrated that inhibition of a potassium current is not likely to cause excessive APD lengthening, since its decrease is mostly compensated by a secondary increase in other, unblocked potassium currents. To clarify this contradiction, we reinvestigated the role of the SK current in cardiac repolarization, using conventional microelectrode and voltage-clamp techniques in rat and dog atrial and ventricular multicellular preparations, and in isolated cardiomyocytes. SK2 channel expression was confirmed with immunoblot technique and confocal microscopy. We found, that while SK2 channels are expressed in the myocardium, a full blockade of these channels by 100 nM apamin--in contrast to the previous report--did not cause measurable electrophysiological changes in mammalian myocardium, even when the repolarization reserve was blunted. These results clearly demonstrate that in rat, dog and human ventricular cells under normal physiological conditions--though present--SK2 channels are not active and do not contribute to action potential repolarization.

(Diethyl-enetriamine)bis-(theophyllinato)zinc(II) dihydrate.

In the title compound, [Zn(C(7)H(7)N(4)O(2))(2)(C(4)H(13)N(3))]·2H(2)O, the Zn(II) ion is penta-coordinated by three N atoms of the diethyl-enetriamine ligand and one N atom of each of the two theophyllinate anions in a distorted trigonal-bipyramidal geometry. The Zn-N distances range from 2.076 (3) to 2.221 (3) Å. The crystal packing is stabilized by O-H⋯O, O-H⋯N and N-H⋯O hydrogen bonds involving the theophylline and diethyl-enetriamine ligands and uncoordinated water mol-ecules.

C-type natriuretic peptide hyperpolarizes and relaxes human penile resistance arteries.

INTRODUCTION: In addition to nitric oxide (NO), it is thought that an endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the relaxation of penile arteries. Recently, it has been shown that C-type natriuretic peptide (CNP) shows the characteristics of EDHF in systemic small arteries. AIM: To investigate the mechanism involved in CNP-evoked vasodilatation and to address whether CNP is an EDHF in human penile resistance arteries. METHODS: Erectile tissue was obtained in connection with transsexual operations. Intracavernous penile resistance arteries were isolated and mounted in microvascular myographs for recording of isometric tension. Membrane potential was recorded by the use of a small glass electrode inserted in the smooth muscle layer. MAIN OUTCOME MEASURE: In vitro evidence for hyperpolarization and vasorelaxation induced by CNP. RESULTS: Acetylcholine (ACh) and CNP hyperpolarized smooth muscle membrane potential in resting penile resistance arteries. In penile small arteries incubated with inhibitors of NO synthase and cyclooxygenase and contracted with phenylephrine, ACh and CNP evoked concentration-dependent relaxations with maximum of 56 +/- 6% and 71 +/- 6%, respectively. Addition of a combination of blockers of small- and intermediate-conductance calcium-activated K(+) channels, apamin plus charybdotoxin, respectively, and a combination thought to block the smooth muscle response of EDHF-type relaxation, barium plus ouabain, markedly reduced ACh- and CNP-evoked relaxation. Iberiotoxin, a blocker of big-conductance calcium-activated K(+) channels inhibited the vasorelaxant responses evoked by ACh and CNP. A selective natriuretic peptide receptor type C (NPR-C) agonist, C-atrial natriuretic factor(4-23) (cANF(4-23)), induced relaxations with less maximum response compared to CNP. CONCLUSION: The present findings suggest that CNP possesses the characteristics of an EDHF in human penile resistance arteries. By activation of natriuretic peptide receptor type B and NPR-C receptors, CNP causes relaxation by activation, respectively, of large-conductance calcium-activated K(+) channels and Na(+)/K(+)-adenosine triphosphatase (ATPase), and barium-sensitive inward rectifier K(+) channels. Modulation of the CNP pathway opens for new treatment modalities of erectile dysfunction.

Effect of partial blockade of the Na(+)/Ca(2+)-exchanger on Ca(2+) handling in isolated rat ventricular myocytes.

SEA0400 is a selective inhibitor of the Na(+)/Ca(2+) exchanger having equal potencies to suppress both the forward and reverse mode operation of the Na(+)/Ca(2+) exchanger. Present experiments were designed to study the effect of partial blockade of Na(+)/Ca(2+) exchanger on Ca(2+) handling in isolated rat ventricular myocytes. Intracellular Ca(2+) transient and cell shortening were measured in ventricular myocytes loaded with Fura-2-AM fluorescent dye. Partial blockade of Na(+)/Ca(2+) exchanger was induced by superfusion of the cells with SEA0400 at a concentration of 0.3 microM. Amplitude of the intracellular Ca(2+) transient and cell shortening was significantly increased by SEA0400 in both field stimulated and voltage clamped myocytes, without significant elevation of diastolic Ca(2+) level and the decay time constant of the Ca(2+) transient. In patch clamped myocytes the SEA0400 induced increase in the Ca(2+) transient and cell shortening was accompanied by significant reduction of peak L-type Ca(2+) current. These effects can be explained by the autoregulative nature of cardiac Ca(2+) handling, as the reduced Ca(2+) efflux from the cell results in an increased Ca(2+) load to the sarcoplasmic reticulum leading to increased Ca(2+) release, which in turn may decrease the L-type Ca(2+) current by accelaration of Ca(2+) dependent inactivation of L-type Ca(2+) current. Our results suggest that complex changes in the Ca(2+) cycling can occur after selective pharmacological inhibition of the Na(+)/Ca(2+) exchanger.

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice.

Modulation of endothelial calcium-activated K+ channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K+ channels (KCa2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (KCa2.3 T/T(-Dox)) or down-regulation (KCa2.3 T/T(+Dox)) of the KCa2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that KCa2.3 and KCa1.1 channels were the most abundant in mouse corpus cavernosum. KCa2.3 channels were found by immunoreactivity and electron microscopy in the apical-lateral membrane of endothelial cells in the corpus cavernosum. Norepinephrine contraction was enhanced in the corpus cavernosum of KCa2.3 T/T(+Dox) versus KCa2.3 T/T(-Dox) mice, while acetylcholine relaxation was only reduced at 0.3 µM and relaxations in response to the nitric oxide donor sodium nitroprusside were unaltered. An opener of KCa2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in KCa2.3 T/T(-Dox) mice compared with WT and KCa2.3 T/T(+Dox) mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in KCa2.3 T/T(+Dox) mice at low frequencies. Our findings suggest that down-regulation of KCa2.3 channels contributes to erectile dysfunction, and that pharmacological activation of KCa2.3 channels may have the potential to restore erectile function.

Vasorelaxing effect of levosimendan against 5-hydroxytryptamine-induced contractions in isolated human conduit bypass grafts.

Levosimendan is a novel inodilator drug developed for the treatment of heart failure. The possible vasodilating property of the drug in human coronary artery bypass grafts was investigated. Isometric tensions of the left internal thoracic artery (LITA, n = 8) as well as the proximal and distal segments of the radial artery (RA, n = 8 and 8) were measured in isolated organ baths. Concentration-relaxation curves for levosimendan (0.009-1.14 micromol L(-1)) were obtained against 5-hydroxytryptamine (5-HT; serotonin, 0.002-9.3 micromol L(-1))-induced contractions. 5-HT-induced contraction of LITA was considerably smaller than that of the proximal and distal RAs. Levosimendan relaxed the grafts in the following order of calculated maximum efficacies (E(max)): LITA > proximal RA > distal RA (LITA 100.3+/-16.2% of 5-HT-induced maximum tension, proximal RA 86.9+/-8.6%, distal RA 59.4+/-17.5%, P < 0.05 LITA vs distal RA). The potency values of levosimendan, expressed as the negative logarithm of 50% effective concentrations (pD(2)), were comparable in the three bypass grafts (LITA -6.52+/-0.44 log mol L(-1), proximal RA -6.60+/-0.49 log mol L(-1), distal RA -6.85+/-0.45 log mol L(-1)). The results suggest that levosimendan is an effective vasorelaxant of conduit bypass grafts and may serve as a new therapeutic tool, especially in the case of LITA and proximal RA grafts, for relieving perioperative spasm and subsequent graft failure.

On the roles of the alanine and serine in the ß-sheet structure of fibroin.

In its silk II form, fibroin is almost exclusively formed from layers of ß-sheets, rich in glycine, alanine and serine. Reported here are computational results on fibroin models at semi-empirical, DFT levels of theory and molecular dynamics (MD) for (Gly)10, (Gly-Ala)5 and (Gly-Ser)5 decapeptides. While alanine and serine introduce steric repulsions, the alanine side-chain adds to the rigidity of the sheet, allowing it to maintain a properly pleated structure even in a single ß-sheet, and thus avoiding two alternative conformations which would interfere with the formation of the multi-layer pleated-sheet structure. The role of the serine is proposed to involve modulation of the hydrophobicity in order to construct the supramolecular assembly as opposed to random precipitation due to hydrophobicity.

Ca2+-activated K+ channels in the endothelial cell layer involved in modulation of neurogenic contractions in rat penile arteries.

The present study was designed to investigate the functional K+ channels involved in contractions induced by electrical field stimulation in isolated rat penile arteries. Blockers of Ca2+-activated K+ channels (KCa), tetraethylammonium, and of large-conductance KCa channels, charybdotoxin and iberiotoxin, as well as a blocker of voltage-dependent K+ channels (KV), 4-aminopyridine, increased resting tension in penile small arteries. In the presence of propranolol and NG-nitro-L-arginine (L-NOARG), electrical field stimulation evoked prazosin-sensitive contractions. In endothelium-intact preparations, these latter contractions were enhanced in the presence of tetraethylammonium and charybdotoxin. However, these blockers did not enhance contractions evoked by exogenously added noradrenaline. Endothelial cell removal increased the neurogenic contractions but tetraethylammonium had no further potentiating effect in these preparations. In the presence of an inhibitor of cyclooxygenase, indomethacin, and inhibitor of nitric oxide (NO) synthase, L-NOARG, acetylcholine evoked relaxations, which were abolished in the presence of either tetraethylammonium or charybdotoxin. In phenylephrine-contracted arteries treated with guanethidine and atropine, electrical field stimulation evoked relaxations, which were partially inhibited by L-NOARG and tetraethylammonium, without any additive effect of these drugs. These observations suggest that both large-conductance KCa channels and KV channels sensitive to iberiotoxin/tetraethylammonium and 4-aminopyridine, respectively, are directly involved in the modulation of myogenic tone of rat penile arteries. Furthermore, activation of endothelial intermediate-conductance KCa channels sensitive to tetraethylammonium and charybdotoxin leads to release of a non-NO nonprostanoid factor, which inhibits release of the neurotransmitter, noradrenaline, but these channels do not appear to be involved in inhibition of contraction evoked by exogenously applied noradrenaline in rat penile arteries.