Biomedical subjects

B Ostádal

Publications and source records attributed to B Ostádal.

At least 19 recordsLinked to original sources

PubMed2006

Tolerance to acute ischemia in adult male and female spontaneously hypertensive rats.

Clinical and experimental studies have repeatedly indicated that overloaded hearts have a higher vulnerability to ischemia/reperfusion injury. The aim of the present study was to answer the question whether the degree of tolerance to oxygen deprivation in hearts of spontaneously hypertensive rats (SHR) may be sex-dependent. For this purpose, adult SHR and their normotensive control Wistar Kyoto (WKY) rats were used. The isolated hearts were perfused according to Langendorff at constant pressure (proportionally adjusted to the blood pressure in vivo). Recovery of contractile parameters (left ventricular systolic, diastolic and developed pressure as well as the peak rate of developed pressure) was measured during reperfusion after 20 min of global no-flow ischemia in 5 min intervals. Mean arterial blood pressure was measured by direct puncture of carotid artery under light ether anesthesia in a separate group of animals. The degree of hypertension was comparable in both sexes of SHR. The recovery of contractile functions in SHR males and females was significantly lower than in WKY rats during the whole investigated period. There was no sex difference in the recovery of WKY animals; on the other hand, the recovery was significantly better in SHR females than in SHR males. It may be concluded that the hearts of female SHR are more resistant to ischemia/reperfusion injury as compared with male SHR. This fact could have important clinical implications for the treatment of cardiovascular disease in women.

Animals↗

PubMed2005

MCC-134, a blocker of mitochondrial and opener of sarcolemmal ATP-sensitive K+ channels, abrogates cardioprotective effects of chronic hypoxia.

We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels and activator of sarcolemmal ATP-sensitive K(+) (sarcK(ATP)) channels, on cardioprotection conferred by adaptation to chronic hypoxia. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 5-6 weeks) and susceptibility of their hearts to ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. MCC-134 was administered intravenously 10 min before ischemia and 5 min before reperfusion in a total dose of 0.3 mg/kg or 3 mg/kg divided into two equal boluses. The infarct size (tetrazolium staining) was reduced from 59.2+/-4.4 % of the area at risk in normoxic controls to 43.2+/-3.3 % in the chronically hypoxic group. Chronic hypoxia decreased the reperfusion arrhythmia score from 2.4+/-0.5 in normoxic animals to 0.7+/-0.5. Both doses of MCC-134 completely abolished the antiarrhythmic protection (score 2.4+/-0.7 and 2.5+/-0.5, respectively) but only the high dose blocked the infarct size-limiting effect of chronic hypoxia (54.2+/-3.7 %). MCC-134 had no effect in the normoxic group. These results support the view that the opening of mitoKATP channels but not sarcKATP channels plays a crucial role in the mechanism by which chronic hypoxia improves cardiac tolerance to ischemia/reperfusion injury.

ATP-Binding Cassette Transporters↗

PubMed2004

Low body weight and cardiac tolerance to ischemia in neonatal rats.

Adaptation to intermittent high altitude hypoxia (IHAH) increases tolerance of the isolated neonatal rat heart to ischemia and potentiates protection induced by ischemic preconditioning. In addition to the protective effect, IHAH significantly reduces growth of the animals. The aim of the present study was, therefore, to find out whether low body weight per se might influence cardiac sensitivity to oxygen deprivation. Low body weight was induced either by IHAH (barochamber, 8 h/day, 5000 m) from postnatal day 1 to 10 (HLBW), or by a higher number of sucklings per mother (14 instead of 8), again from postnatal day 1 to 10 (NLBW). Control animals (8 littermates per mother) were kept under normoxic conditions (Controls). The recovery of developed force following 40 min of global ischemia was measured in isolated hearts from 10-day-old rats by perfusing them in the Langendorff mode with Krebs-Henseleit solution at constant pressure, temperature and rate. Ischemic preconditioning was induced by three 3-min periods of global ischemia, each separated by 5-min periods of reperfusion. Low body weight in HLBW and NLBW groups was accompanied by increased hematocrit, and decrease in absolute heart weight (both wet and dry) and developed force. On the other hand, higher hydration, increased cardiac tolerance to ischemia and potentiation of protection by ischemic preconditioning were observed in HLBW rats only. This experimental group also exhibited the highest relative heart weight. It may be concluded that low body weight alone does not influence cardiac tolerance to ischemia in neonatal rats.

Altitude Sickness↗

PubMed2004

Developmental changes of cytochrome c oxidase and citrate synthase in rat heart homogenate.

Activity of cytochrome c oxidase and citrate synthase in rat heart homogenates was determined in 5-, 15-, 28- and 60-day-old rats. The activity of both enzymes increased during postnatal development but their changes followed different kinetics. The membrane-bound cytochrome c oxidase reached its adult values during the early postnatal period, i.e. between days 5 and 15, whereas soluble matrix-localized citrate synthase also continued to increase between days 15 and 60. Our data indicate a relative excess of cytochrome c oxidase in neonatal cardiocytes.

Age Factors↗

PubMed2004

Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia.

Effective protection of the heart against ischemia/reperfusion injury is one of the most important goals of experimental and clinical research in cardiology. Besides ischemic preconditioning as a powerful temporal protective phenomenon, adaptation to chronic hypoxia also increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation such as myocardial infarction, contractile dysfunction and ventricular arrhythmias. Although many factors have been proposed to play a potential role, the detailed mechanism of this long-term protection remains poorly understood. This review summarizes current limited evidence for the involvement of ATP-sensitive potassium channels, reactive oxygen species, nitric oxide and various protein kinases in cardioprotective effects of chronic hypoxia.

Adaptation, Physiological↗

PubMed2004

Myocardial infarct size-limiting effect of chronic hypoxia persists for five weeks of normoxic recovery.

We examined cardioprotective effect of chronic hypoxia and the time course of its recovery under normoxic conditions. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 35 exposures) and susceptibility of their hearts to ischemia-induced ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 30-min coronary artery occlusion and 4-h reperfusion on the day after the last hypoxic exposure and at 7, 35 and 90 days of normoxic recovery. The infarct size was reduced from 69.2+/-1.7 % of the area at risk in normoxic controls to 48.0+/-2.2 % in the chronically hypoxic group and to 61.6+/-2.3 % in the group recovered for 7 days. This residual protection persisted for at least 35 days of normoxic recovery but it was absent after 90 days. In contrast to the infarct size-limitation, the antiarrhythmic protection disappeared already during the first week; the incidence of ventricular fibrillation was even significantly increased 7 and 90 days after the last hypoxic exposure. In conclusion, the duration of cardioprotection induced by chronic hypoxia differs markedly, depending on the end point of ischemia/reperfusion injury examined. Whereas the increased tolerance to lethal myocardial injury persists for at least 5 weeks after the termination of hypoxia, the antiarrhythmic protection rapidly vanishes, being replaced with transient proarrhythmic effect.

Adaptation, Physiological↗

PubMed2003

Effect of intermittent high altitude hypoxia on gene expression in rat heart and lung.

Hypoxia has been identified as an important stimulus for gene expression during embryogenesis and in various pathological situations. Its influence under physiological conditions, however, has only been studied occasionally. We therefore investigated the effect of intermittent high altitude hypoxia on the mRNA expression of different cytokines and protooncogenes, but also of other genes described to be regulated by hypoxia, in the left ventricle (LV), the right ventricle (RV), atria and the lung of adult rats after simulation of hypoxia in a barochamber (5000 m, 4 hours to 10 days). Heme oxygenase-1 as well as transforming growth factor-beta1 showed an increased expression in all regions of the heart and the lung at different periods of hypoxia. For lactate dehydrogenase-A, we found a significant up-regulation in the RV and the lung, for lactate dehydrogenase-B up-regulation in the RV, but down-regulation in the LV and the atria. Vascular endothelial growth factor was up-regulated in the RV, the LV and the lung, but down-regulated in the atria. Its receptor Flk-1 mRNA was significantly increased in the atria and RV only. Expression of c-fos was found in the LV and RV only after 4 hours of hypoxia. The level of c-jun was significantly increased in the LV but decreased in the atria. Our data clearly demonstrate that intermittent hypoxia is a modulator of gene expression under physiological conditions. It differently regulates the expression of distinct genes not only in individual organs but even within one organ, i.e. in the heart.

Adaptation, Physiological↗

PubMed2003

Cardioprotective effect of chronic hypoxia is blunted by concomitant hypercapnia.

The effect of chronic hypercapnia on cardioprotection induced by chronic hypoxia was investigated in adult male Wistar rats exposed to isobaric hypoxia (10 % O(2)) for three weeks. In the first experimental group, CO(2) in the chamber was fully absorbed; in the second group, its level was increased to 4.1 %. Normoxic controls were kept in atmospheric air. Anesthetized open-chest animals were subjected to 20-min LAD coronary artery occlusion and 3-h reperfusion for infarct size determination (TTC staining). Chronic hypoxia alone reduced body weight and increased hematocrit; these effects were significantly attenuated by hypercapnia. The infarct size was reduced from 61.9+/-2.2 % of the area at risk in the normoxic controls to 44.5+/-3.3 % in the hypoxic group (P<0.05). Hypercapnia blunted the infarct size-limiting effect of hypoxia (54.8+/-2.4 %; P<0.05). It is concluded that increased CO(2) levels in the inspired air suppress the development of the chronic hypoxia-induced cardioprotective mechanism, possibly by interacting with ROS signalling pathways.

Animals↗

PubMed2002

Mitochondrial membrane potential in cardiac myocytes.

Mitochondria are involved in cellular functions that transcend the traditional role of these organelles as the energy factory of the cell. Their relative inaccessibility and the difficulties involved in attempts to study them in their natural environment -- the cytosol -- has delayed much of this understanding and they still have many secrets to yield. One of the relatively new fields in this respect is undoubtedly the analysis of mitochondrial membrane potential. The realization that its alteration may have important pathophysiological consequences has led to an increased interest in measuring this variable in a variety of biological settings, including cardiovascular diseases. Measurements of mitochondrial membrane potential tell us much about the role of mitochondria in normal cell function and in processes leading to cell death. However, we must be aware of the limitations of using isolated mitochondria, single cells and different fluorescent indicators.

Animals↗

PubMed2001

Ontogenetic development of energy-supplying enzymes in rat and guinea-pig heart.

The purpose of the present study was to compare the ontogenetic development of the activity of myocardial energy-supplying enzymes in two mammalian species, differing significantly in their level of maturation at birth. The animals were investigated during the late prenatal period and 2, 7, 14, 21, 25, 30, 63, 120 and 730 days after birth in the rat and 2, 21, 84 and 175 days in the guinea-pig. The following enzymes were assayed in the right and left ventricular myocardium: lactate dehydrogenase (LDH, lactate uptake and/or formation), triose phosphate dehydrogenase (TPDH, carbohydrate metabolism), glycerol phosphate dehydrogenase (GPDH, glycerol-P shuttle)), hexokinase (HK, glucose phosphorylation), malate dehydrogenase (MDH, tricarboxylic cycle), citrate synthase (CS, tricarboxylic cycle) and hydroxyacyl-CoA dehydrogenase (HOADH, fatty acid breakdown). The rat heart, highly immature at birth, exhibits three different developmental patterns of energy-supplying enzymes, identical in both ventricles: (i) two mitochondrial enzymes of aerobic metabolism (CS, HOADH) and GPDH have a relatively low activity at the end of prenatal life; thereafter their activity steadily increases, approaching the adult levels between the 3rd and 4th postnatal weeks. A significant decrease was observed between the 4th and 24th months. (ii) MDH and LDH: prenatal values were significantly higher as compared with the 2nd postnatal day; after this period the activities increased up to adulthood (4 months) and decreased during senescence. (iii) The activities of HK and TPDH are characterized by only moderate changes during development. HK differs from all other enzymes by the highest prenatal values, which exceed even adult values. In contradiction to the rat heart, the developmental differences in more mature guinea-pig heart were significantly less pronounced. The only ontogenetic differences observed were the lower activities of enzymes connected with aerobic metabolism at the end of the prenatal period. Our results point to possible differences in the development of adaptive metabolic pathways in animals with different levels of maturation at birth.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2000

Optimal conditions for determination of cytochrome c oxidase activity in the rat heart.

The determination of cytochrome c oxidase (COX) activity represents an important indicator for the evaluation of cell oxidative capacity. However, it has been shown repeatedly that different factors modify the rate of COX activity under various experimental conditions. The most important concern the ionic concentrations of the medium and the application of various detergents for the solubilization of mitochondrial membranes. We found the highest activity of COX in rat heart homogenates and mitochondria at 40-60 mM potassium phosphate. The rate of COX activity is dependent on the detergent/protein (P) ratio. Using n-dodecyl-beta-D-maltoside (lauryl maltoside, LM) as the detergent, we obtained the highest activity at LM/P ratios of (50:100):1. By kinetic measurements of low-affinity binding sites in heart mitochondria, we found Vlim values of 4.3 and 22.2 micromol cytochrome c per min per mg P in the presence or absence of lauryl maltoside, respectively. The Km values were 16.7 micromol in the presence or absence of lauryl maltoside. Our results thus indicate that 1) the exact assessment of COX activity in heart homogenates and mitochondria requires the determination of optimum phosphate concentrations in the medium used, and 2) even small modifications of the experimental procedure may induce significant differences in the maximum values of COX activity.

Animals↗

PubMed2000

Effects of adaptation to intermittent high altitude hypoxia on ischemic ventricular arrhythmias in rats.

We compared the effects of adaptation to intermittent high altitude (IHA) hypoxia of various degree and duration on ischemia-induced ventricular arrhythmias in rats. The animals were exposed to either relatively moderate hypoxia of 5000 m (4 or 8 h/day, 2-3 or 5-6 weeks) or severe hypoxia of 7000 m (8 h/day, 5-6 weeks). Ventricular arrhythmias induced by coronary artery occlusion were assessed in isolated buffer-perfused hearts or open-chest animals. In the isolated hearts, both antiarrhythmic and proarrhythmic effects were demonstrated depending on the degree and duration of hypoxic exposure. Whereas the adaptation to 5000 m for 4 h/day decreased the total number of premature ventricular complexes (PVCs), extending the daily exposure to 8 h and/or increasing the altitude to 7000 m led to opposite effects. On the contrary, the open-chest rats adapted to IHA hypoxia exhibited an increased tolerance to arrhythmias that was even more pronounced at the higher altitude. The distribution of PVCs over the ischemic period was not altered by any protocol of adaptation. It may be concluded that adaptation to IHA hypoxia is associated with enhanced tolerance of the rat heart to ischemic arrhythmias unless its severity exceeds a certain upper limit. The opposite effects of moderate and severe hypoxia on the isolated hearts cannot be explained by differences in the occluded zone size, heart rate or degree of myocardial fibrosis. The proarrhythmic effect of severe hypoxia may be related to a moderate left ventricular hypertrophy (27 %), which was present in rats adapted to 7000 m but not in those adapted to 5000 m. This adverse effect can be overcome by an unknown protective mechanism(s) that is absent in the isolated hearts.

Adaptation, Physiological↗

PubMed1999

Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial K(ATP) channel.

The aim was to determine whether adaptation to chronic hypoxia protects the heart against ischemic arrhythmias and whether ATP-dependent potassium channels (K(ATP)) play a role in the antiarrhythmic mechanism. Adult male rats were adapted to intermittent high altitude hypoxia (5000 m, 4 h/day) and susceptibility to ischemia-induced ventricular arrhythmias was evaluated in the Langendorff-perfused hearts subjected to either an occlusion of the coronary artery for 30 min or pre-conditioning by brief occlusion of the same artery prior to 30-min reocclusion. In separate groups, either a K(ATP) blocker, glibenclamide (10 micromol/l), or a mitochondrial K(ATP) opener, diazoxide (50 micromol/l), were added to a perfusion medium 20 min before the occlusion. Adaptation to hypoxia reduced the total number of ventricular arrhythmias by 64% as compared with normoxic controls. Preconditioning by a single 3-min coronary artery occlusion was antiarrhythmic only in the normoxic group, while two occlusion periods of 5 min each were needed to pre-condition the hypoxic hearts. Glibenclamide increased the number of arrhythmias in the normoxic hearts from 1316+/-215 to 2091+/-187 (by 59%) and in the hypoxic group from 636+/-103 to 1777+/-186 (by 179%). In contrast, diazoxide decreased the number of arrhythmias only in the normoxic group from 1374+/-96 to 582+/-149 (by 58%), while its effect in the hypoxic group was not significant. It is concluded that long-term adaptation of rats to high altitude hypoxia decreases the susceptibility of their hearts to ischemic arrhythmias and increases an antiarrhythmic threshold of pre-conditioning. The mitochondrial K(ATP) channel, rather than the sarcolemmal K(ATP) channel, appears to be involved in the protective mechanism afforded by adaptation.

Acclimatization↗

PubMed1998

Pressure overload induced in newborn rats: effects on left ventricular growth, morphology, and function.

Gradual pressure overload was induced by abdominal aortic constriction in male rats on postnatal d 6 (AC6) or 2 (AC2). At the age of 8 wk, the systemic blood pressure was measured, and the contractile performance of the left ventricle (LV) was assessed after acute ligation of the ascending aorta in open chest anesthetized animals. The LV free wall was used for the determination of collagen concentration and morphometric analysis of cardiac myocytes and capillaries. Aortic constriction resulted in LV hypertrophy, which was more pronounced in AC2 (by 71%) as compared with AC6 (by 34%) groups and correlated closely with the degree of pressure overload (r = 0.88 and 0.80, respectively). The right ventricular weight was increased by 13% in the AC2 group only. Contractile performance of the LV of aortic constricted rats was significantly higher before as well as after the acute load, but the average functional reserve was unchanged in both experimental groups. Although the maximum value of the rate of pressure development increased linearly with the degree of ventricular hypertrophy in the AC6 group (r = 0.82), a negative correlation was observed in the AC2 animals (r = -0.61). The density of myocytes was decreased, and the calculated average myocyte cross-sectional area was increased in aortic constricted rats, but the coronary capillary density and myocardial concentration of collagen remained constant. Thus, in spite of the larger cardiac growth response in the younger age group, the capillary proliferation and collagen formation were proportional to the ventricular hypertrophy. Therefore, the degrees of overload and hypertrophy do not seem to be limiting factors. Pressure overload induced in newborn rats can be a useful model for the study of mechanisms that control either the growth and differentiation of myocardium soon after birth, as well as the transition from compensated to decompensated hypertrophy at later stages.

Animals↗

PubMed1997

Effect of the preweaning nutritional state on the cardiac protein profile and functional performance of the rat heart.

The aim of the study was to find out whether the changes in nutritional status induced by different litter size during early postnatal development can influence quantitative and qualitative protein remodeling and contractile performance of the myocardium. Male Wistar rats born at the same day were pooled together at 2 days postbirth and assigned by random selection to dams in groups of 4, 8 or 16 rats/litter. The animals were investigated at the age of 4 and 16 weeks. The results revealed that the early postnatal nutritional modification altered weight parameters: whereas lower heart weight persisted in slow-growing rats until 16 weeks, higher body weight of fast-growing rats returned to the control level at the age of 16 weeks. Altered nutritional status influenced also protein remodeling of the myocardium: the concentration of all noncollagenous proteins (fractions of metabolic and contractile proteins) significantly increased in slow-growing rats, on the other hand, the concentration of collagenous proteins (pepsin-soluble and -insoluble fractions) was higher in fast-growing animals. The changes were, however, only transitional: three months after the end of the weaning period most protein changes returned to the control level. However, higher concentration of total blood lipids and triglycerides in fast-growing rats persisted until adulthood. Nutritional changes had, however, only minor effect on ventricular performance. No differences among groups were observed in basal values of the left ventricular pressure, while the maximum pressure attained after an acute ventricular loading and the contractile reserve were significantly decreased in slow-growing 4 week old rats. The functional consequence of altered nutritional status during weaning was only transitional, in agreement with the transient character of most structural and biochemical markers of myocardial remodeling.

Animal Nutritional Physiological Phenomena↗

PubMed1996

The inhibition of angiotensin converting enzyme attenuates the effects of chronic hypoxia on pulmonary blood vessels in the rat.

The effect of chronic administration of angiotensin converting enzyme inhibitor on the development of hypoxic pulmonary hypertension was studied in rats. Male Wistar rats were-exposed for 3 weeks to isobaric hypoxia (10% O2) and treated with 10 mg/kg b.w. of Ramipril daily. The haemodynamic properties of the pulmonary vasculature were then measured in isolated blood-perfused lung preparation. Ramipril administration during the sojourn in hypoxia resulted in lower baseline perfusion pressure and lower slope of perfusion pressure-flow relationship compared to non-treated hypoxic rats. Partitioning of the distribution of pulmonary vascular resistance across the vascular bed by the occlusion technique showed that it was mainly due to a decrease of arterial and venous vascular resistances to blood flow. It is suggested that Ramipril attenuates the process of morphological reconstruction of pulmonary vasculature by chronic hypoxia rather than the level of vascular smooth muscle tone.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Inotropic effect of increasing concentration of Ca2+ in the fetal rat heart with retinoic acid-induced malformations.

Cardiac malformations (pulmonary trunk stenosis, ventricular septal defect, and double outlet right ventricle) were induced by the administration of two doses of retinoic acid (RA) to Wistar rats on d 13 of pregnancy. Contractile performance of the isolated perfused rat heart and its inotropic response to Ca2+ (0.6-10.0 mmol.L-1) was studied in 20-d-old fetuses. The body weight of RA-exposed fetuses was significantly lower compared with controls. RA negatively influenced the contractile parameters of the fetal rat heart. The most pronounced effect was, except at a Ca2+ concentration of 2.5 mmol.L-1, observed at developed force at all other concentrations. Simultaneously, the sensitivity to Ca2+, expressed as the Ca2+ concentration at which 30% of maximum was attained, ws significantly lower in RA-exposed hearts. This implies that the malformed heart is more dependent on the extracellular sources of Ca2+.

Animals↗

PubMed1995

Ontogenetic differences in cardiopulmonary adaptation to chronic hypoxia.

Cardiopulmonary adaptation to chronic hypoxia was compared in rats exposed to simulated high altitude (barochamber, 8 h per day, 5 days a week, stepwise up to 7000 m, a total of 24 exposures) either from the 4th day or the 12th week of postnatal life. Pulmonary hypertension and right ventricular (RV) enlargement were comparable in both age groups. Whereas in young hypoxic animals the individual values of RV weight increased linearly with a rise of RV pressure (r = 0.72), no significant correlation was found in adult rats. Chronic hypoxia increased the concentration of cardiac collagenous proteins; this effect was more pronounced in adult animals. On the other hand, the collagen VIII ratio was markedly lower in young rats suggesting increased synthesis of collagen III in this age group. A protective effect of adaptation, i.e. increased cardiac resistance to acute hypoxic injury, was similar in both age groups and persisted even 4 months after removal of animals from the hypoxic atmosphere.

Adaptation, Physiological↗