Developmental Aspects of Cardiac Adaptation to Increased Workload.

The heart is capable of extensive adaptive growth in response to the demands of the body. When the heart is confronted with an increased workload over a prolonged period, it tends to cope with the situation by increasing its muscle mass. The adaptive growth response of the cardiac muscle changes significantly during phylogenetic and ontogenetic development. Cold-blooded animals maintain the ability for cardiomyocyte proliferation even in adults. On the other hand, the extent of proliferation during ontogenetic development in warm-blooded species shows significant temporal limitations: whereas fetal and neonatal cardiac myocytes express proliferative potential (hyperplasia), after birth proliferation declines and the heart grows almost exclusively by hypertrophy. It is, therefore, understandable that the regulation of the cardiac growth response to the increased workload also differs significantly during development. The pressure overload (aortic constriction) induced in animals before the switch from hyperplastic to hypertrophic growth leads to a specific type of left ventricular hypertrophy which, in contrast with the same stimulus applied in adulthood, is characterized by hyperplasia of cardiomyocytes, capillary angiogenesis and biogenesis of collagenous structures, proportional to the growth of myocytes. These studies suggest that timing may be of crucial importance in neonatal cardiac interventions in humans: early definitive repairs of selected congenital heart disease may be more beneficial for the long-term results of surgical treatment.

Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats.

Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.

Left ventricular function and remodelling in rats exposed stepwise up to extreme chronic intermittent hypoxia.

The main aim was to find out whether long-lasting stepwise exposure to extreme hypoxia affects left ventricular (LV) geometry and systolic function. Adult male rats were exposed to intermittent hypobaric hypoxia (8 h/day) with increasing altitude in steps of 1000 m every 3 weeks up to 8000 m. While the LV cavity diastolic diameter did not change over the whole range of hypoxia, the wall thickness increased significantly at the altitude of 8000 m. LV fractional shortening ranged between 48.1 % and 50.1 % and remained unaffected even at the most severe hypoxia. At the end of experiment, haematocrit reached 83 %, mean systemic arterial pressure 120 % and relative LV weight 154 % of normoxic values while RV systolic pressure and relative RV weight doubled. Myocyte hypertrophy and myocardial fibrosis were more pronounced in RV than in LV. In conclusion, LV systolic function was preserved after chronic stepwise exposure of rats to extreme intermittent hypoxia despite moderate concentric hypertrophy and myocardial remodelling.

Possible role of mitochondrial K-ATP channel and nitric oxide in protection of the neonatal rat heart.

Cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by mitochondrial-K-ATP channels and nitric oxide (NO). During early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury and their resistance cannot be further increased by IPC or IPoC. Therefore, we have speculated, whether mechanisms responsible for high resistance of neonatal heart may be similar to those of IPC and IPoC. To test this hypothesis, rat hearts isolated on days 1, 4, 7, and 10 of postnatal life were perfused according to Langendorff. Developed force (DF) of contraction was measured. Hearts were exposed to 40 min of global ischemia followed by reperfusion up to the maximum recovery of DF. IPoC was induced by 5 cycles of 10-s ischemia. Mito-K-ATP blocker (5-HD) was administered 5 min before ischemia and during first 20 min of reperfusion. Another group of hearts was isolated for biochemical analysis of 3-nitrotyrosine, and serum samples were taken to measure nitrate levels. Tolerance to ischemia did not change from day 1 to day 4 but decreased on days 7 and 10. 5-HD had no effect either on neonatal resistance to I/R injury or on cardioprotective effect of IPoC on day 10. Significant difference was found in serum nitrate levels between days 1 and 10 but not in tissue 3-nitrotyrosine content. It can be concluded that while there appears to be significant difference of NO production, mito-K-ATP and ROS probably do not play role in the high neonatal resistance to I/R injury.

Proteomic analysis of cardiac ventricles: baso-apical differences.

The heart is characterized by a remarkable degree of heterogeneity. Since different cardiac pathologies affect different cardiac regions, it is important to understand molecular mechanisms by which these parts respond to pathological stimuli. In addition to already described left ventricular (LV)/right ventricular (RV) and transmural differences, possible baso-apical heterogeneity has to be taken into consideration. The aim of our study has been, therefore, to compare proteomes in the apical and basal parts of the rat RV and LV. Two-dimensional electrophoresis was used for the proteomic analysis. The major result of this study has revealed for the first time significant baso-apical differences in concentration of several proteins, both in the LV and RV. As far as the LV is concerned, five proteins had higher concentration in the apical compared to basal part of the ventricle. Three of them are mitochondrial and belong to the "metabolism and energy pathways" (myofibrillar creatine kinase M-type, L-lactate dehydrogenase, dihydrolipoamide dehydrogenase). Myosin light chain 3 is a contractile protein and HSP60 belongs to heat shock proteins. In the RV, higher concentration in the apical part was observed in two mitochondrial proteins (creatine kinase S-type and proton pumping NADH:ubiquinone oxidoreductase). The described changes were more pronounced in the LV, which is subjected to higher workload. However, in both chambers was the concentration of proteins markedly higher in the apical than that in basal part, which corresponds to the higher energetic demand and contractile activity of these segments of both ventricles.

Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats.

Mitochondria play an essential role in improved cardiac ischaemic tolerance conferred by adaptation to chronic hypoxia. In the present study, we analysed the effects of continuous normobaric hypoxia (CNH) on mitochondrial functions, including the sensitivity of the mitochondrial permeability transition pore (MPTP) to opening, and infarct size (IS) in hearts of spontaneously hypertensive rats (SHR) and the conplastic SHR-mtBN strain, characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischaemia-resistant brown Norway (BN) strain. Rats were adapted to CNH (10% O2, 3 weeks) or kept at room air as normoxic controls. In the left ventricular mitochondria, respiration and cytochrome c oxidase (COX) activity were measured using an Oxygraph-2k and the sensitivity of MPTP opening was assessed spectrophotometrically as Ca2+-induced swelling. Myocardial infarction was analysed in anaesthetized open-chest rats subjected to 20 min of coronary artery occlusion and 3 h of reperfusion. The IS reached 68±3.0% and 65±5% of the area at risk in normoxic SHR and SHR-mtBN strains, respectively. CNH significantly decreased myocardial infarction to 46±3% in SHR. In hypoxic SHR-mtBN strain, IS reached 33±2% and was significantly smaller compared with hypoxic SHR. Mitochondria isolated from hypoxic hearts of both strains had increased detergent-stimulated COX activity and were less sensitive to MPTP opening. The maximum swelling rate was significantly lower in hypoxic SHR-mtBN strain compared with hypoxic SHR, and positively correlated with myocardial infarction in all experimental groups. In conclusion, the mitochondrial genome of SHR modulates the IS-limiting effect of adaptation to CNH by affecting mitochondrial energetics and MPTP sensitivity to opening.

Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load.

Most of the experimental studies have revealed that female heart is more tolerant to ischemia/reperfusion (I/R) injury as compared with the male myocardium. It is widely accepted that mitochondrial dysfunction, and particularly mitochondrial permeability transition pore (MPTP) opening, plays a major role in determining the extent of cardiac I/R injury. The aim of the present study was, therefore, to analyze (i) whether calcium-induced swelling of cardiac mitochondria is sex-dependent and related to the degree of cardiac tolerance to I/R injury and (ii) whether changes in MPTP components-cyclophilin D (CypD) and ATP synthase-can be involved in this process. We have observed that in mitochondria isolated from rat male and female hearts the MPTP has different sensitivity to the calcium load. Female mitochondria are more resistant both in the extent and in the rate of the mitochondrial swelling at higher calcium concentration (200 µM). At low calcium concentration (50 µM) no differences were observed. Our data further suggest that sex-dependent specificity of the MPTP is not the result of different amounts of ATP synthase and CypD, or their respective ratio in mitochondria isolated from male and female hearts. Our results indicate that male and female rat hearts contain comparable content of MPTP and its regulatory protein CypD; parallel immunodetection revealed also the same contents of adenine nucleotide translocator or voltage-dependent anion channel. Increased resistance of female heart mitochondria thus cannot be explained by changes in putative components of MPTP, and rather reflects regulation of MPTP function.

Gender-Related Differences in Atherosclerosis.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Considerable research has been done over the last several decades to understand the pathophysiology of atherosclerosis. It is widely believed that estrogen is responsible for the protection of women from CVD in the premenopausal age group. However, hormone replacement therapy has failed to decrease CVD events in clinical studies which points to the complexity of the relationship between vascular biology and estrogen hormones. Interestingly, preponderance of vascular and connective tissue disorders in women also points to an inherent role of hormones and tissue factors in maintenance of vascular endothelial function. The differential effect of GPER, lipoprotein A, TLRs, leucocyte-platelet aggregate markers in men and women also suggests inherent gender-related differences in the pathophysiology of atherosclerosis. A better understanding of the pathophysiology is likely to open ways to improve evidence-based treatment of CVD in women.

A mathematical model of the carp heart ventricle during the cardiac cycle.

The poikilothermic heart has been suggested as a model for studying some of the mechanisms of early postnatal mammalian heart adaptations. We assessed morphological parameters of the carp heart (Cyprinus carpio L.) with diastolic dimensions: heart radius (5.73mm), thickness of the compact (0.50mm) and spongy myocardium (4.34mm), in two conditions (systole, diastole): volume fraction of the compact myocardium (20.7% systole, 19.6% diastole), spongy myocardium (58.9% systole, 62.8% diastole), trabeculae (37.8% systole, 28.6% diastole), and cavities (41.5% systole, 51.9% diastole) within the ventricle; volume fraction of the trabeculae (64.1% systole, 45.5% diastole) and sinuses (35.9% systole, 54.5% diastole) within the spongy myocardium; ratio between the volume of compact and spongy myocardium (0.35 systole, 0.31 diastole); ratio between compact myocardium and trabeculae (0.55 systole, 0.69 diastole); and surface density of the trabeculae (0.095µm(-1) systole, 0.147µm(-1) diastole). We created a mathematical model of the carp heart based on actual morphometric data to simulate how the compact/spongy myocardium ratio, the permeability of the spongy myocardium, and sinus-trabeculae volume fractions within the spongy myocardium influence stroke volume, stroke work, ejection fraction and p-V diagram. Increasing permeability led to increasing and then decreasing stroke volume and work, and increasing ejection fraction. An increased amount of spongy myocardium led to an increased stroke volume, work, and ejection fraction. Varying sinus-trabeculae volume fractions within the spongy myocardium showed that an increased sinus volume fraction led to an increased stroke volume and work, and a decreased ejection fraction.

Developmental determinants of cardiac sensitivity to hypoxia.

Cardiac sensitivity to oxygen deprivation changes significantly during ontogenetic development. However, the mechanisms for the higher tolerance of the immature heart, possibilities of protection, and the potential impact of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults have not yet been satisfactorily clarified. The hypoxic tolerance of an isolated rat heart showed a triphasic pattern: significant decrease from postnatal day 1 to 7, followed by increase to the weaning period, and final decline to adulthood. We have observed significant ontogenetic changes in mitochondrial oxidative phosphorylation and mitochondrial membrane potential, as well as in the role of the mitochondrial permeability transition pores in myocardial injury. These results support the hypothesis that cardiac mitochondria are deeply involved in the regulation of cardiac tolerance to oxygen deprivation during ontogenetic development. Ischemic preconditioning failed to increase tolerance to oxygen deprivation in the highly tolerant hearts of newborn rats. Chronic hypoxic exposure during early development may cause in-utero or neonatal programming of several genes that can change the susceptibility of the adult heart to ischemia-reperfusion injury; this effect is sex dependent. These results would have important clinical implications, since cardiac sensitivity in adult patients may be significantly affected by perinatal hypoxia in a sex-dependent manner.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo.

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of ß-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of ß-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

Women and the management of acute coronary syndrome.

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in both men and women in the developed countries. Despite this fact, females are still under-represented in the majority of clinical trials. At the present time, only limited evidence is available with respect to the female-specific aspects of pathogenesis, management, and outcomes in acute coronary syndrome (ACS). Women less frequently undergo coronary intervention, and a lower proportion of women receive evidence-based pharmacotherapy, compared with men. It has been shown that women benefit from an invasive approach and coronary intervention in ACS as much as men, despite their advanced age and higher rate of bleeding complications. Also, administration of beta-blockers, ACE-inhibitors, and intensive statin therapy is associated with a comparable reduction of cardiovascular event rates in women and men. On the other hand, women may profit less than men from fibrinolytic or glycoprotein IIb/IIIa inhibitor therapy. Both sexes benefit equally from aspirin therapy, whereas contradictory data are available on the efficacy of clopidogrel in women. There is an urgent need for intensive research in the development of female-specific therapeutic strategy in ACS, even though the detailed mechanisms of sex differences are still unknown.

Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension.

The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyeicosatrienoic acids), on BP (blood pressure) and myocardial infarct size in male heterozygous TGR (Ren-2 renin transgenic rats) with established hypertension. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. Myocardial ischaemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR (assessed as the ratio of EETs to DHETEs), was accompanied by a significant reduction in BP and a significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist [14,15-epoxyeicosa-5(Z)-enoic acid], supporting the notion that the improved cardiac ischaemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.

Left ventricle shortening fraction: a comparison between euploid and trisomy 21 fetuses in the first trimester.

OBJECTIVES: Measurement of the shortening fraction of the left ventricle (SFLV) is an objective way to assess systolic performance. The aim of the study was to compare first trimester SFLV values in euploid fetuses to those in fetuses with trisomy 21. METHODS: We measured SFLV in 56 fetuses from 11 weeks to 13 weeks 6 days. The left ventricular diastolic diameter (LVDD) and left ventricular systolic diameter (LVSD) were measured offline, and SFLV was calculated. The data were analyzed using Mann-Whitney U test. RESULTS: We found a significant difference in the SFLV measurements between the group of 49 euploid fetuses and the 7 fetuses with trisomy 21 [38.00 (95% CI: 33.72-42.27) vs 49.93 (95% CI: 43.72-56.13)] (p < 0.05). There was also a significant difference in the nuchal translucency measurements between the two groups: 1.78 mm (95% CI: 1.08-2.48 mm) in the euploid population versus 5.06 mm (95% CI: 3.61-6.71 mm) in the fetuses with trisomy 21 (p < 0.05). There were no significant differences between the group of euploid fetuses and the group of trisomy 21 fetuses in the following parameters: CRL (chorionic villus sampling), LVDD and LVSD. CONCLUSIONS: SFLV is a well-defined, simple measurement of systolic function of the fetal myocardium. SFLV values in fetuses with trisomy 21 appear to be significantly higher than in euploid fetuses.

Neonatal cardiac mitochondria and ischemia/reperfusion injury.

Postnatal maturation of the heart is characterized by decreasing tolerance to ischemia/reperfusion (I/R) injury associated with significant changes in mitochondrial function. The aim of this study is to test the hypothesis that the role of the mitochondrial membrane permeability transition pore (MPTP) in the I/R injury differs in the neonatal and in the adult heart. For this purpose, the effect of blockade of MPTP on the degree of I/R injury and the sensitivity of MPTP to swelling-inducing agents was compared in hearts from neonatal (7 days old) and adult (90 days old) Wistar rats. It was found that the release of NAD(+) from the perfused heart induced by I/R can be prevented by sanglifehrin A (SfA) only in the adult myocardium; SfA had no protective effect in the neonatal heart. Furthermore, the extent of Ca-induced swelling of mitochondria from neonatal rats was significantly lower than that from the adult animals; mitochondria from neonatal rats were more resistant at higher concentrations of calcium. In addition, not only the extent but also the rate of calcium-induced swelling was about twice higher in adult than in neonatal mitochondria. The results support the idea that lower sensitivity of the neonatal MPTP to opening may be involved in the mechanism of the higher tolerance of the neonatal heart to I/R injury.

Gender differences in cardiac ischemic injury and protection--experimental aspects.

This review summarizes some available information on gender differences of myocardial injury with particular attention to experimental approach. It has been observed that significant gender differences exist already in normal heart. They involve among others cardiac growth, contractile function, calcium metabolism and function of mitochondria. Differences, characteristic of the normal myocardium, generate the logical presumption of the different reaction of the male and female heart to various pathogenic factors. Most of the experimental studies confirm the clinical observations: increased resistance of the female heart to ischemia/reperfusion injury was shown in dogs, rats, mice and rabbits. Furthermore, gender differences in the ischemic tolerance of the adult myocardium can be influenced by interventions (e.g. hypoxia) imposed during the early phases of ontogenetic development. The already high tolerance of the adult female heart can be increased by adaptation to chronic hypoxia and ischemic preconditioning. It seems that the protective effect depends on age: it was absent in young, highly tolerant heart but it appeared with the decrease of natural resistance during aging. Both experimental and clinical studies have indicated that female gender influences favorably also the remodeling and the adaptive response to myocardial infarction. It follows from the data available that male and female heart differs significantly in many parameters under both physiological and pathological conditions. Detailed molecular and cellular mechanisms of these differences are still unknown; they involve genomic and non-genomic effects of sex steroid hormones, particularly the most frequently studied estrogens. The cardiovascular system is, however, influenced not only by estrogens but also by other sex hormones, e.g. androgens. Moreover, steroid hormone receptors do not act alone but interact with a broad array of co-regulatory proteins to alter transcription. The differences are so important that they deserve serious consideration in clinical practice in search for proper diagnostic and therapeutic procedures.

The past, the present and the future of experimental research on myocardial ischemia and protection.

At present, cardiovascular diseases represent the most important health risks because they are responsible for more than 50% of total mortality. Among them, ischemic heart disease is the leading cause of morbidity and mortality, and according to the World Health Organization, will be the major global cause of death by the year 2020. Major progress in the prognosis, diagnosis and therapy of ischemic heart disease would be impossible without notable achievements of the 20th century that have been critical for further development of cardiology.We are now living in the era of molecular medicine, and the influence of basic research on clinical practice has never been more pronounced. This, however, necessitates a new strategy; future cardiovascular research should include the following general guidelines: 1) to evaluate the role and proportion of already described molecular pathways; descriptive approaches will gradually disappear; 2) to distinguish between acute, chronic and pleiotropic effects of different drugs under in vitro and in vivo conditions, with respect to possible clinical use; 3) to use clinically relevant genetic models; 4) to study possible alterations in intracellular signaling in order to find the decisive steps responsible for abnormal control of cell growth, contractile function, lipid metabolism, cardiac ischemic tolerance, etc.; 5) to study the molecular mechanisms of cardiovascular diseases not only in healthy individuals, but also under different pathological conditions. Such an approach must include developmental and gender differences, which are particularly important for the field of ischemic heart disease; therefore, experimental cardiovascular research can no longer be restricted to males of uncertain age. It is hoped that patients in future decades will profit from the progress of basic cardiovascular research.

ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats.

Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT(1)) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT(1) receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT(1) but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1alpha markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT(1) receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.

Selenium protects the immature rat heart against ischemia/reperfusion injury.

The aim of the study was to find out whether administration of selenium (Se) will protect the immature heart against ischemia/reperfusion.The control pregnant rats were fed laboratory diet (0.237 mg Se/kg diet); experimental rats received 2 ppm Na(2)SeO(3) in the drinking water from the first day of pregnancy until day 10 post partum. The concentration of Se in the serum and heart tissue was determined by activation analysis, the serum concentration of NO by chemiluminescence, cardiac concentration of lipofuscin-like pigment by fluorescence analysis. The 10 day-old hearts were perfused (Langendorff); recovery of developed force (DF) was measured after 40 min of global ischemia. In acute experiments, 10 day-old hearts were perfused with selenium (75 nmol/l) before or after global ischemia. Sensitivity to isoproterenol (ISO, pD(50)) was assessed as a response of DF to increasing cumulative dose.Se supplementation elevated serum concentration of Se by 16%. Se increased ischemic tolerance (recovery of DF, 32.28 +/- 2.37 vs. 41.82 +/- 2.91%, P < 0.05). Similar results were obtained after acute administration of Se during post-ischemic reperfusion (32.28 +/- 2.37 vs. 49.73 +/- 4.40%, P < 0.01). The pre-ischemic treatment, however, attenuated the recovery (23.08 +/- 3.04 vs. 32.28 +/- 2.37%, P < 0.05). Moreover, Se supplementation increased the sensitivity to the inotropic effect of ISO, decreased cardiac concentration of lipofuscin-like pigment and serum concentration of NO. Our results suggest that Se protects the immature heart against ischemia/reperfusion injury. It seems therefore, that ROS may affect the function of the neonatal heart, similarly as in adults.