The production of the pineal hormone melatonin is synchronized with day-night cycle via multisynaptic pathway including suprachiasmatic nucleus linking several physiological functions to diurnal cycle. The recent data indicate that impaired melatonin production is involved in several cardiovascular pathologies including hypertension and ischemic heart disease. However, the mechanisms of melatonin effect on cardiovascular system are still not completely understood. The activation of melatonin receptors on endothelial and vascular smooth muscle cells and antioxidant properties of melatonin could be responsible for the melatonin effects on vascular tone. However, the data from in vitro studies are controversial making the explanation of the melatonin effect on blood pressure in vivo difficult. In vivo, melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. The central and peripheral antiadrenergic action of chronic melatonin treatment might eliminate the mechanisms counter-regulating decreased blood pressure, providing thus additional cardioprotective mechanism. The extraordinary antioxidant activity and antilipidemic effects of melatonin may enhance the modulation of blood pressure by melatonin and probably play the most important role in the amelioration of target organ damage by chronic melatonin treatment. Further investigation of these mechanisms should provide novel knowledge about pathophysiological mechanisms of cardiovascular diseases, additional explanation for their circadian and seasonal variability and potentially generate new impulses for the development of therapeutic arsenal., Ľ. Paulis, F. Šimko., and Obsahuje bibliografii a bibliografické odkazy
In the present paper we describe changes of anatomical parameters in inbred Lewis strain rats, namely their body weight, body weight gain per week, absolute and relative heart, thyroid gland and skeletal muscle weights, that are assumed to reflect experimentally altered thyroid status. The hyperthyroid state was induced by DL-thyroxine or Na 3,3',5-triiodo-L-thyronine, while methimazole was employed for inducing hypothyroidism. We have found that when compared to euthyroid rats, hypothyroidism resulted in a significantly lower body weight gain, absolute and relative heart weight and, in contrast, in a significant increase of absolute and relative thyroid gland weight. On the other hand, hyperthyroidism led to a significant increase of absolute and relative heart weight and to a significant reduction of absolute and relative thyroid gland weight. However, the body mass was not significantly altered in hyperthyroidism as compared with euthyroid rats. We conclude that our protocol leads to chronic hyper- or hypothyroidism as demonstrated by body, heart and thyroid gland weight changes. These anatomical data can thus be utilized as supplemental criteria for the assessment of the thyroid state of experimental rats., T. Soukup, G. Zachařová, V. Smerdu, I. Jirmanová., and Obsahuje bibliografii
The aim of the current study was to clarify the effect of high sucrose diet (HSD) on bile formation (BF) in rats with hereditary hypertriglyceridemia (HHTg). Potentially positive effects were studied for boldine, a natural choleretic agent. Administration of HSD to HHTg rats led to increased triglyceride deposition in the liver. HSD reduced BF as a consequence of decreased biliary secretion of bile acids (BA) and glutathione. Responsible mechanism was down-regulation of hepatic transporters for BA and glutathione, Bsep and Mrp2, respectively. Moreover, gene expressions of transporters for other constituents of bile, namely Abcg5/8 for cholesterol, Abcb4 for phospholipids, and Oatp1a4 for xenobiotics, were also reduced by HSD. Boldine partially attenuated cholestatic effect of HSD by promotion of biliary secretion of BA through up-regulation of Bsep and Ntcp, and by increase in biliary secretion of glutathione as a consequence of its increased hepatic disposition. This study demonstrates mechanisms of impaired BF during nonalcoholic fatty liver disease induced by HSD. Altered function of responsible transporters suggests also potential for changes in kinetics of drugs, which may complicate pharmacotherapy in subjects with high intake of sucrose, and with fatty liver disease. Sucrose induced alterations in BF may be alleviated by administration of boldine., M. Zagorova, A. Prasnicka, Z. Kadova, E. Dolezelova, L. Kazdova, J. Cermanova, L. Rozkydalova, M. Hroch, J. Mokry, S. Micuda., and Obsahuje bibliografii
We investigated the renal response to direct renal nerve stimulation, 2 weeks following reversal of 24-h unilateral (left) ureteric obstruction. Renal nerve stimulation caused a 13-15 % fall in renal blood flow, in 4 groups of anesthetized rats following ureteric obstruction (n=9) or a sham operation (n=7) both with (n=9) and without (n=7) treatment with the mixed ETA/B receptor antagonist, bosentan. In the sham-operated rats, renal nerve stimulation did not change glomerular filtration rate but reduced urine flow rate (37±3 %, P<0.001), and absolute (38±4 %, P<0.001) and fractional (35±5 %, P<0.01) sodium excretion. Following unilateral ureteric obstruction, renal nerve stimulation increased glomerular filtration rate by 22±3 % (P<0.01), but reduced urine flow rate (14±2 %, P<0.001) and fractional sodium excretion (23±5 %, P<0.01). Bosentan treatment had no effect on baseline or renal responses to renal nerve stimulation in the sham group but normalized the renal response to renal nerve stimulation in the unilateral ureteric obstruction group. We conclude that 14 days after a 24-h period of unilateral ureteric obstruction there is an increase in GFR in response to direct renal nerve stimulation, which is due, in part, to the actions of endothelin at the time of obstruction., F. T. Hammad, A. M. Wheatley, G. Davis., and Obsahuje bibliografii
Colonic mucosal protection is provided by the mucus gel, mainly composed of mucins. Several factors can modulate the formation and the secretion of mucins, and among them butyrate, an end-product of carbohydrate fermen tation. However, the specific effect of butyrate on the various colonic mucins, and the consequences in terms of the mucus layer thickness are not known. Our aim was to determine whether butyrate modulates colonic MUC genes expression in vivo and whether this results in changes in mucus synthesis and mucus layer thickness. Mice received daily for 7 days rectal enemas of butyrate (100 mM) versus saline. We demonstrated that butyrate stimulated the gene expression of both secreted (Muc2) and membrane-linked (Muc1, Muc3, Muc4) mucins. Butyrate especially induced a 6-fold increase in Muc2 gene expression in proximal colon. However, butyrate enemas did not modify the number of epithelial cells containing the protein Muc2, and caused a 2-fold decrease in the thickness of adherent mucus layer. Further studies should help understanding whether this last phenomenon, i.e. the decrease in adherent mucus gel thickness, results in a diminished protective function or not., E. Gaudier ... [et al.]., and Obsahuje seznam literatury
Exocytotic machinery in neuronal and endocrine tissues is sensitive to changes in intracellular Ca2+ concentration. Endocrine cell models, that are most frequently used to study the mechanisms of regulated exocytosis, are pancreatic beta cells, adrenal chromaffin cells and pituitary cells. To reliably study the Ca2+ sensitivity in endocrine cells, accurate and fast determination of Ca2+ dependence in each tested cell is required. With slow photo-release it is possible to induce ramp-like increase in intracellular Ca2+ concentration ([Ca2+]i) that leads to a robust exocytotic activity. Slow increases in the [Ca2+] i revealed exocytotic phases with different Ca2+ sensitivities that have been largely masked in step-like flash photo-release experiments. Strikingly, in the cells of the three described model endocrine tissues (beta, chromaffin and melanotroph cells), distinct Ca2+ sensitivity ‘classes’ of secretory vesicles have been observed: a highly Ca2+ -sensitive, a medium Ca2+ -sensitive and a low Ca2+ - sensitive kinetic phase of secretory vesicle exocytosis. We discuss that a physiological modulation of a cellular activity, e.g. by activating cAMP/PKA transduction pathway, can switch the secretory vesicles between Ca2+ sensitivity classes. This significantly alters late steps in the secretory release of hormones even without utilization of an additional Ca2+ sensor protein., J. Dolenšek, M. Skelin, M. S. Rupnik., and Obsahuje bibliografii a bibliografické odkazy
Safranal and crocin are biologically active compounds isolated from Crocus sativus L., commonly known as saffron. Clinical trials confirm that saffron has antidepressant effect, thus being a potential valuable alternative in the treatment of depression. The aim of the present study was to determine, whether systemic administration of safranal and crocin can influence the metabolic activity of CYP3A, CYP2C11, CYP2B, and CYP2A in rat liver microsomes (RLM). The experiments were carried out on male Wistar albino rats intragastrically administered with safranal (4, 20, and 100 mg/kg/day) or with intraperitoneal injections of crocin (4, 20, and 100 mg/kg/day). Our results demonstrate the ability of safranal and crocin to increase the total protein content and to change the metabolic activity of several CYP enzymes assessed as CYP specific hydroxylations of testosterone in RLM. Crocin significantly decreased the metabolic activity of all selected CYP enzymes, while safranal significantly increased the metabolic activity of CYP2B, CYP2C11 and CYP3A enzymes. Therefore, both substances could increase the risk of interactions with co-administered substances metabolized by cytochrome P450 enzymes., G. Dovrtělová, K. Nosková, J. Juřica, M. Turjap, O. Zendulka., and Obsahuje bibliografii
The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ETA and ETB) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ETB endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Dřímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ETB-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors.The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ETB1/B2-selective BQ788 (in mmolar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ETA-selective PD155080 partially protected the rat heart on reperfusion., J. Dřímal, V. Knezl, J. Dřímal Jr , D. Dřímal, K. Bauerová , V. Kettmann, A.M. Doherty , M. Štefek., and Obsahuje bibliografii
The purpose of this study was to assess the endocrine status, thoracic impedance, blood concentration, and hemodynamic dose-responses using different angles of passive head-up tilt (HUT) ranging from 12° to 70° in the same subjects. Measurements were performed during 20 min supine position (pre-HUT), 30 min upright (HUT12, HUT30, HUT53, or HUT70), and 20 min supine (post-HUT); subjects 70 min in the supine position only (HUT0) served as resting controls. Norepinephrine increased above resting control values by 19, 44, 80, and 102 %; epinephrine by 30, 41, 64, and 68 %; aldosterone by 29, 62, 139, and 165 %; plasma renin activity n. s., 41, 91, and 89 %; vasopressin n.s., 27, 47, and 59 %; thoracic bioimpedance n. s., 8, 13, and 16 %; heart rate n. s., 5, 26, and 45 %, and mean arterial pressure n. s., 5, 7, and 10 %; at min 27 of HUT12, HUT30, HUT53, and HUT70, respectively. Pulse pressure decreased with HUT53 and HUT70 by 4 and 10 %. Hematocrit increased by 0.2, 1.7, 6.3, and 7.2 %, respectively. Blood density increased by 2.3 and 3.0 g/l, plasma density by 1.7 and 1.8 g/l with HUT53 and HUT70. After finishing HUT, heart rate fell to values which stayed below pre-HUT, and also below resting control levels for ł 5 min ("post-orthostatic bradycardia") even after the lowest orthostatic load (HUT12). Thoracic impedance and arterial pressure remained increased after terminating HUT30, HUT53, and HUT70. In conclusion, passive orthostatic loading of different extent produces specific dose-responses of different magnitude in the endocrine system, blood composition, thoracic impedance, and hemodynamic variables. The heart rate is depressed even after HUT12, while arterial blood pressure and thoracic impedance exceed pre-stimulus levels after greater head-up tilt, indicating altered cardiovascular response after passive orthostasis., Z. László, A. Rössler, H. G. Hinghofer-Szalkay., and Obsahuje bibliografii