We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the followup period was 50 weeks. RAS was blocked using angiotensinconverting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF., P. Kala, L. Sedláková, P. Škaroupková, L. Kopkan, Z. Vaňourková, M. Táborský, A. Nishiyama, S. H. Hwang, B. D. Hammock, J. Sadowski, V. Melenovský, J. D. Imig, L. Červenka., and Obsahuje bibliografii
This study was designed to validate the measures of heart period variability for assessing of autonomic nervous system control in calves. Eight calves received an injection of either 0.5 mg/kg atenolol (sympathetic tone blockade), 0.2 mg/kg atropine sulfate (parasympathetic tone blockade), 0.5 mg/kg atenolol + 0.2 mg/kg atropine sulfate (double autonomic blockade) or saline. In the time-domain, we calculated the mean instantaneous heart rate (HR), mean of RR intervals (MeanRR), standard deviation of RR intervals (SDRR) and that of the difference between adjacent intervals (RMSSD). In the frequency-domain, the power of the spectral band 0-1 Hz (TPW), the power of the 0-0.15 Hz band (LF), that of the 0.15-1 Hz band (HF), and the LF/HF ratio were considered. The net vago-sympathetic effect (VSE) was calculated as the ratio of MeanRR in a defined situation to MeanRR during the double blockade. Atenolol injection had no effect on cardiac activity, whereas atropine induced large modifications which were moderated when atenolol was administered at the same time. VSE, HR, MeanRR and RMSSD were found to be valid indicators of the parasympathetic tone of calves because of large variations due to the drug and low individual variations. No measure reflected the sympathetic tone., G. Després, I. Veissier, A. Boissy., and Obsahuje bibliografii
The aim of this study was to investigate nitric oxide (NO) production and L-NAME-sensitive component of endothelium-dependent vasorelaxation in adult normotensive Wistar-Kyoto rats (WKY), borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR). Blood pressure (BP) of WKY, BHR and SHR (determined by tailcuff) was 111±3, 140±4 and 184±6 mm Hg, respectively. NO synthase activity (determined by conversion of [3H]-Larginine) was significantly higher in the aorta of BHR and SHR vs. WKY and in the left ventricle of SHR vs. both BHR and WKY. L-NAME-sensitive component of endothelium-dependent relaxation was investigated in the preconstricted femoral arteries using the wire myograph during isometric conditions as a difference between acetylcholine-induced relaxation before and after acute NG-nitro-L-arginine methyl ester pre-treatment (L-NAME, 10-5 mol/l). Acetylcholineinduced vasorelaxation of SHR was significantly greater than that in WKY. L-NAME-sensitive component of vasorelaxation in WKY, BHR and SHR was 20±3 %, 29±4 % (p<0.05 vs. WKY) and 37±3 % (p<0.05 vs. BHR), respectively. There was a significant positive correlation between BP and L-NAME-sensitive component of relaxation of the femoral artery. In conclusion, results suggest the absence of endothelial dysfunction in the femoral artery of adult borderline and spontaneously hypertensive rats and gradual elevation of L-NAME-sensitive component of vasorelaxation with increasing blood pressure., A. Púzserová, Z. Csizmadiová, I. Bernátová., and Obsahuje bibliografii
Chronic continuous light exposure leads to melatonin deficiency along with complex neurohumoral activation resulting in hypertension development in rats. The aim of this study was to show, whether continuous light in duces fibrotic rebuilding of the aorta and whether the treatment with melatonin or angiotensin converting enzyme inhibitor captopril can prevent these potential alterations. In a six-week experiment, 3-month-old Wistar rats were divided into 4 groups (t en per group): controls, rats exposed to continuous light, exposed to continuous light plus treated with captopril (100 mg/kg/24 h) and exposed to continuous light plus treated with melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP) and collagen type I and III in the media of thoracic aorta were me asured. Continuous light induced hypertension and fibrotic rebuilding of the aorta in terms of enhancement of collagen I and III concentration in the aortic media. Both captopril and melatonin prevented SBP rise and reduced collagen III concentration in the aorta. However, only melatonin reduced collagen I and the sum of collagen I and III in the aortic tissue. We conclude that in continuous light-induced hypertension, administration of melatonin, along with SBP reduction, decreases collagen I and III concentration in the aorta. It is suggested that antifibrotic effect of melatonin may reduce the stiffness of the aorta and small arteries and beneficially influence the nature of the pulse wave and peripheral vascular resistance., K. Repová-Bednárová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibitor captopril on cGMP and cAMP concentration in the left ventricle and aorta after NO synthase inhibition by 4-week-lasting NG-nitro-L-arginine-methyl ester (L-NAME) treatment. Five groups of rats were investigated: controls, L-NAME in the dose 20 mg/kg/day (L-NAME 20), L-NAME in the dose 40 mg/kg/day (L-NAME 40), captopril in the dose 100 mg/kg/day, L-NAME 40 mg/kg/day together with captopril 100 mg/kg/day. Captopril completely prevented L-NAME-induced hypertension and LV hypertrophy development. Compared to the controls, cGMP concentration in the L-NAME 20 and L-NAME 40 groups was decreased by 13 % and 22 %, respectively, in the left ventricle and by 27 % and 56 % in the aorta, respectively. Captopril did not influence this decrease of cGMP concentration. Cyclic AMP concentration in the aorta of L-NAME 20 group increased by 17 %. In the L-NAME 40 group, cAMP concentration increased by 17 % in the left ventricle and by 34 % in the aorta compared to controls. This increase was enhanced in rats given L-NAME together with captopril. Captopril alone had no effect on cAMP concentration. We conclude that captopril does not affect the concentration of cGMP, however, it has more than the additive effect on the cAMP concentration increase in the cardiovascular system during long-term NO synthase inhibition., O. Pecháňová, I. Bernátová., and Obsahuje bibliografii
Angiotensin converting enzyme inhibitors are widely used in therapy of cardiovascular diseas es. However, the consensus on effects of these inhibitors in control of myocardial oxygen consumption during the process of experimental hypercholesterolemia and under the condition of endothelial dysfunction has not been reached. Here we examined effects of captopril, an angiotensin converting enzyme inhibitor, on serum lipid levels and oxygen consumption rate in mitochondria isolated from heart of rabbits treated by hypercholesterolemic diet. During the twelve-week period, th e Chinchilla male rabbits were daily treated by saline (controls); 1 % cholesterol diet; 5 mg/kg/day captopril or 1 % cholesterol + 5 mg/kg/day captopril. Total- and high-densi ty lipoprotein cholesterol and triglyceride in serum were measured spectrophotometricly. The left ventricle mitochondrial fraction was isolated and myocardial oxygen consumption was measur ed by Biological Oxygen Monitor. Mitochondria isolated from hearts of rabbits exposed to hypercholesterolemic diet sh owed significantly reduced respiration rates (state 3 and state 4) with altering adenosine diphosphate/oxygen ratio, whereas the respiratory control ratio was not affected when compared to controls. Mitochondria from cholesterol/captopril-treated animals showed significantly reduced respiration rates without altering adenosine diphosphate/oxygen ratio index or respiratory control ratio. Although captopril did not exert the favorable effect on serum lipid levels in cholesterol-treated animals, it restored the mitochondrial oxygen consumption. Further studies should be performed to define the under lying physiological and/or pathophysiological mechanisms and clinical implications., Z. Kojic ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The aim of our study was to evaluate the efficacy of FK506, mycophenolate mofetil (MM) and aminoguanidine (AMG) on infiltration of macrophages (MPHs), neutrophils (NPHs) and dendritic cells (DC) into corneal grafts during the early phases after transplantation (Tx). Tx was performed in mice (C57BL/10 to BALB/c). Therapy included FK506 (0.2 mg/kg), MM (30 mg/kg) or AMG (0.1 g/kg), started at the day of Tx and was injected i.p. daily. Corneas were excised on the 3rd and 7th day after Tx. Immunohistological evaluation using antibodies against MPHs, NPHs and DC was performed and corneal grafts were assessed in the periphery and in central part of the cornea separately. On the 3rd day after Tx, a massive infiltration of MPHs and NPHs into corneal grafts was revealed; the DC in filtration was lower in all treated groups. Treatment with FK506 and MM led to a significant reduction of NPHs in the centers of the grafts, but not of MPHs. In contrast, AMG significantly reduced MPHs migration into allografts on the third day after Tx, whereas NPHs infiltration has not been attenuated. However, immunosuppressants had no influence on the infiltration of DC during early phases after Tx., P. Bysterská, P. Svozílková, H. Farghali., and Obsahuje bibliografii a bibliografické odkazy
Stellate ganglion blockade (SGB) with a local anesthetic increases muscle sympathetic nerve activity in the tibial nerve in humans. However, whether this sympathetic excitation in the tibial nerve is due to a sympathetic blockade in the neck itself, or due to infiltration of a local anesthetic to adjacent nerves including the vagus nerve remains unknown. To rule out one mechanism, we examined the effects of cervical sympathetic trunk transection on renal sympathetic nerve activity (RSNA) in anesthetized rats. Seven rats were anesthetized with intraperitoneal urethane. RSNA together with arterial blood pressure and heart rate were recorded for 15 min before and 30 min after left cervical sympathetic trunk transection. The baroreceptor unloading RSNA obtained by decreasing arterial blood pressure with administration of sodium nitroprusside was also measured. Left cervical sympathetic trunk transection did not have any significant effects on RSNA, baroreceptor unloading RSNA, arterial blood pressure, and heart rate. These data suggest that there was no compensatory increase in RSNA when cervical sympathetic trunk was transected and that the increase in sympathetic nerve activity in the tibial nerve during SGB in humans may result from infiltration of a local anesthetic to adjacent nerves rather than a sympathetic blockade in the neck itself., T. Ikeda ... [et al.]., and Obsahuje seznam literatury
Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings., M. Šíma, P. Pokorná, K. Hronová, O. Slanař., and Obsahuje bibliografii