We assessed the effect of the previously uncovered gap junctio n protein alpha 8 (Gja8) mutation present in spontaneously hypertensive rat - dominant cataract (SHR - Dca ) strain on blood pressure, metabolic profile, and heart and renal transcriptomes. Adult, standard chow-fed male rats of SHR and SHR - Dca strains were used. We found a significant, consistent 10-15 mmHg decrease in both systolic and diastolic blood pressures in SHR - Dca compared with SHR (P<0.01 and P<0.05 , respectively; repeated measures analysis of variance (ANOVA)). With immunohistochemistry, we were able to localize Gja8 in heart, kidney, aorta, liver, and lungs, mostly in endothelium; with no differences in expression between strains. SHR - Dca rats showed decreased body weight, high-density lipoprotein cholesterol concentrations and basa l insulin sensitivity in muscle. There were 21 transc ripts common to the sets of 303 transcripts in kidney and 487 in heart showing >1.2-fold difference in expression between SHR and SHR - Dca. Tumor necrosis factor was the most significant upstream regulato r and glial cell-derived neurotrophic factor family ligand-receptor interactions was the common enriched and downregulated canonical pathway both in heart and kidney of SHR - Dca. The connexin 50 mutation L7Q lowers blood pressure in the SHR - Dca strain, decr eases high-density lipoprotein cholesterol, and leads to substantial transcriptome changes in heart and kidney., O. Šeda, F. Liška, M. Pravenec, Z. Vernerová, L. Kazdová, D. Křenová, V. Zídek, L. Šedová, M. Krupková, V. Křen., and Obsahuje bibliografii
Muscarinic acetylcholine receptors in the heart have been shown to display agonist-independent spontaneous (constitutive) activity which causes changes in the opening of cardiac ion channels and in the activity of G proteins. We investigated whether an inhibition of the constitutive activity of muscarinic receptors induced by the binding of antagonist brings about a change in the synthesis of cyclic AMP in rat cardiac membranes, and whether the action of the antagonist is stereospecific. Atropine and S-(-)-hyoscyamine were indeed found to enhance the forskolin-stimulated synthesis of cyclic AMP in rat cardiac (both atrial and ventricular) membranes by up to 24%. The effect was stereospecific and the potency of R-(+)-hyoscyamine was 30 fold lower than that of the S-(-) enantiomer, confirming that the action of hyoscyamine is receptor-mediated. The effect did not depend on the presence of endogenous acetylcholine in the system used. The results strongly suggest that the adenylyl cyclase in the heart is exposed to continuous mild inhibition by constitutively active muscarinic receptors in the membranes of cardiomyocytes., J. Říčný, F. Gualtieri, S. Tuček., and Obsahuje bibliografii
The aim of this study was to investigate whether the inhibition of one of the endothelial receptor sites in the rat pulmonary artery (muscarinic, histaminergic, purinergic, a 2-adrenergic) affects the NO-mediated relaxation induced by the activation of the other type of receptors. Acetylcholine (ACh)-, histamine (Hist)-, adenosine (Ade)- , and clonidine (Clon)-induced endothelium-dependent relaxations were reduced by the administration of specific antagonists of muscarinic, H1-histaminergic, purinergic or a 2-adrenergic receptors, respectively. The inhibition of H1-histaminergic receptors by chlorphenyramine did not prevent ACh-induced relaxation. Similarly, the inhibition of muscarinic receptors by atropine did not prevent the relaxations to histamine, adenosine and clonidine. On the other hand, the relaxations induced by acetylcholine, histamine, adenosine or clonidine were regularly reduced by NO-synthase inhibitor NG-nitro-L-arginine methyl ester (10-4 mol/l). These results suggest that the inhibition of NO-synthase abolished arterial relaxations induced by all agonists. After inhibition of one type of the endothelial receptors, the NO-dependent relaxation could still be evoked by activation of one of the others., S. Kyselá, J. Török., and Obsahuje bibliografii
The aim of our study was to inve stigate mechanism of action of endothelins 1, 2 and 3 on spontaneous activity, tone and intraluminal pressure of human ureter. Both longitudinal tension and intraluminal pressure were recorded from the isolated segments of proximal human ureter. Endothelins 1, 2 and 3 (5.35x10 -11 M- 5.05x10-8M) produced concentration-dependent tonic contraction and sustained increase in intraluminal pressure of isolated preparations of hum an ureter. Endo thelins 1 and 3 produced also concentration-dependent inhibition of spontaneous, phasic contractions of the isolated preparations. Selective antagonist of ETA receptors BQ123 and selective antagonist of ET B receptors BQ788 produced significant inhibition of endothelin-1-induced tonic contraction (pA2=8.80 and 6.55, respectively) and increase in intraluminal pressure (pA2=8.68 and 7.02, respectively), while they did not affect endothelin-1-induced inhibition of spontaneous activity. Endothelin 1 produces increase in tone and intraluminal pressure of isolated human ureter acting on both ETA and ETB receptors, the first one being functionally more important. On ly endothelins 1 and 3 inhibit spontaneous, phasic activity of human ureter, but this effect was not blocked by selective antagonists of ETA and ETB receptors., S. M. Jankovic ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein. The aim of our study was to evaluate, if the polymoprhisms within ABCB1 gene alter tamoxifen adjuvant treatment efficacy in premenopausal women. Totally 71 premenopausal women with estrogen receptor positive breast cancer indicated for tamoxifen adjuvant treatment were followed retrospectively for median period of 56 months. The gentic polymorphisms of CYP2D6 and ABCB1 were analyzed and potential covariates as tumor grading, staging, age at the diagnosis, comedication, quantitative positivity of ER or PR were also evaluated. Cox proportional-hazards regression model indicated that patients carrying at least one variant allele in ABCB1 rs1045642 had significantly longer time to event survival compared to wild type subjects. Non-significant trend was noted for better treatment outcome of patients carrying at least one variant allele in the SNP rs2032582, while for the CYP2D6 polymorphism poor metabolizer phenotype resulted in worse outcome in comparison to extensive metabolizers subjects with HR of 4.04 (95 % CI 0.31-52.19). Similarly, patients using CYP2D6 inhibitors had non-significantly shorter time-to-event as compared to never users resulting in hazard ratio of 2.06 (95 % CI 0.40-10.63). ABCB1 polymorphisms may affect outcome of tamoxifen adjuvant treatment in premenopausal breast cancer patiens. This factor should be taken into account in addition to the CYP2D6 polymorphism or phenotypic inhibition of CYP2D6 activity., S. Argalácsová, O. Slanař, P. Vítek, P. Tesařová, H. Bakhouche, M. Dražďáková, O. Bartošová, T. Zima, L. Pertuželka., and Obsahuje bibliografii
We aimed to compare the effect of angiotensin converting enzyme (ACE) inhibitors captopril (containing thiol group) and enalapril (without thiol group) on the development of spontaneous hypertension and to analyze mechanisms of their actions, particularly effects on oxidative stress and NO production. Six-week-old SHR were divided into three groups: control, group receiving captopril (50 mg/kg/day) or enalapril (50 mg/kg/day) for 6 weeks. At the end of experiment, systolic blood pressure (SBP) increased by 41 % in controls. Both captopril and enalapril prevented blood pressure increase, however, SBP in the captopril group (121±5 mmHg) was significantly lower than that in the enalapril group (140±5 mmHg). Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group. Captopril and enalapril increased NO synthase activity in the heart and aorta to the similar level. Neither captopril nor enalapril was, however, able to increase the expression of eNOS. Both ACE inhibitors increased the level of cGMP. However, cGMP level was significantly higher in the aorta of captopril group. We conclude that captopril, beside inhibition of ACE, prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration., O. Pecháňová., and Obsahuje bibliografii
The present study proposed procedure for predicting an optimal left and right ventricular pacing interval delay (V-V interval). In 16 patients (heart failure, left bundle branch block, biventricular pacing) two methods (A and B) identifying optimal V-V interval were tested. Method A: predicted optimal V-V interval A (POVV-A) = electromechanical delay of the segment paced by left ventricle lead minus electromechanical delay of the segment paced by right ventricle lead. Method B: predicted optimal V-V interval B (POVV-B) = difference in the onset of aortic and pulmonary flows. Both methods were validated using echocardiography and right-sided heart catheterization. Cardiac output during POVV-A (4.6 l.min-1 ) was significantly better than that during POVV-A minus 20 ms (4.3 l.min-1, p<0.01) and POVV-A plus 20 ms (4.3 l.min-1 , p<0.01), and than that during POVV-B (4.4 l.min-1, p<0.05). LV dP/dt during POVV-A (818 mm Hg.s-1 ) exceeded that during POVV-A plus 20 ms (717 mm Hg.s-1 , p<0.05) and POVV-A minus 20 ms (681 mm Hg.s-1, p<0.05), and that during POVV-B (727 mm Hg.s-1 , p<0.01). The time difference in onsets of myocardial deformation of left ventricle segment paced by the left ventricle and right ventricle lead allows identifying the optimal V-V interval and improves left ventricle performance., M. Novák, J. Lipoldová, J. Meluzín, J. Krejčí, P. Hude, V. Feitová, L. Dušek, P. Kamarýt, J. Vítovec., and Obsahuje bibliografii a bibliografické odkazy
Functional magnetic resonance imaging (fMRI) was used to demonstrate the brain activation during transition from unconscious to conscious breathing in seven healthy human subjects. In right-handed volunteers, the activated areas were found in both hemispheres. The medial part of the precentral gyrus (area 4) was constantly activated in the left hemisphere. Additional activated areas were demonstrated in the premotor cortex and in the posterior parietal cortex. The activated cortical sites exhibited analogous distribution in the right hemisphere. In two out of the seven subjects, activated sites were also observed in the cerebellar hemispheres, and in the lentiform and caudate nuclei., V. Šmejkal, R. Druga, J. Tintěra., and Obsahuje bibliografii
This study extends our previous work by examining the effects of alpha2 -adrenoceptors under cold stimulation involving the increase of myogenic vascular oscillations as increases of very-low-frequency and low-frequency of the blood pressure variab ility. Forty-eight adult male Sprague-Dawley rats were randomly divided into four groups: vehicle; yohimbine; hexamethonium+yohimbine; guanethidine+yohimbine. Systolic blood pressure, heart rate, power spectral analysis of spontaneous blood pressure and he art rate variability and spectral coherence at very-low-frequency (0.02 to 0.2 Hz), low-frequency (0.2 to 0.6 Hz), and high-frequency (0.6 to 3.0 Hz) regions were monitored using telemetry. Key findings are as follows: 1) Cooling-induced pressor response was attenuated by yohimbine and further attenuated by hexamethonium+yohimbine and guanethidine+yohimbine, 2) Cooling-induced tachycardia response of yohimbine was attenuated by hexame - thonium+yohimbine and guanethidine+yohimbine, 3) Different patterns of p ower spectrum reaction and coherence value compared hexamethonium+yohimbine and guanethi-dine+yohimbine to yohimbine alone under cold stimulation. The results suggest that sympathetic activation of the postsynaptic alpha2-adrenoceptors causes vasoconstriction and heightening myogenic vascular oscillations, in turn, may increase blood flow to prevent tissue damage under stressful cooling challenge., Y.-H. Lin, Y.-P. Liu, Y.-C. Lin, P.-L. Lee, C.-S. Tung., and Obsahuje bibliografii
The goal of this study is to summarize the current knowledge on the effects of one of the essential metals, copper (Cu) on the reproductive system. The development of past four decades addressing effects of Cu on reproductive organs is reviewed. The most relevant data obtained from in vivo and in vitro experiments performed on humans and other mammals, including effects of copper nanoparticles (CuNPs) on the reproductive functions are presented. Short term Cu admi nistration has been found to exert deleterious effect on intracellular organelles of rat ovarian cells in vivo . In vitro administration in porcine ovarian granulosa cells releases insulin-like growth factor (IGF-I), steroid hormone progesterone (P4), and induces expression of peptides related to proliferation and apoptosis. Adverse effect of Cu on male reproductive functions has been indicated by the decrease in spermatozoa parameters such as concentration, viability and motility. Copper nanoparticles are capable of generating oxidative stress in vitro thereby leading to reproductive toxicity. Toxic effect of CuNPs has been evident more in male mice than in females. Even though further investigations are necessary to arrive at a definitive conclusion, Cu notably influences the reproductive functions by interfering with both male and female reproductive systems and also hampers embryo development in dose-dependent manner., S. Roychoudhury, S. Nath, P. Massanyi, R. Stawarz, M. Kacaniova, A. Kolesarova., and Obsahuje bibliografii