Cardiac tolerance to ischemia in neonatal spontaneously hypertensive rats.

Hypertension is the risk factor of serious cardiovascular diseases, such as ischemic heart disease and atherosclerosis. The aim of the present study was to analyze the development of cardiac tolerance to ischemia in neonatal spontaneously hypertensive rats (SHR) and possible protective effect of ischemic preconditioning (IP) or adaptation to intermittent high-altitude hypoxia (IHAH). For this purpose we used 1- and 10-day-old pups of SHR and their normotensive control Wistar Kyoto rats (WKY). Isolated hearts were perfused in the Langendorff mode with Krebs-Henseleit solution at constant pressure, temperature and rate. Cardiac tolerance to ischemia was expressed as a percentage of baseline values of developed force (DF) after global ischemia. IP was induced by three 3-min periods of global ischemia, each separated by 5-min periods of reperfusion. IHAH was simulated in barochamber (8 h/day, 5000 m) from postnatal day 1 to 10. Cardiac tolerance to ischemia in 1-day-old SHR was higher than in WKY. In both strains tolerance decreased after birth, and the difference disappeared. The high cardiac resistance in 1- and 10-day-old SHR and WKY could not be further increased by both IP and adaptation to IHAH. It may be concluded that hearts from newborn SHR are more tolerant to ischemia/reperfusion injury as compared to age-matched WKY; cardiac resistance decreased in both strains during the first ten days, similarly as in Wistar rats.

Developmental changes of the sensitivity of cardiac and liver mitochondrial permeability transition pore to calcium load and oxidative stress.

Opening of the mitochondrial membrane permeability transition pore (MPTP) is an important factor in the activation of apoptotic and necrotic processes in mammalian cells. In a previous paper we have shown that cardiac mitochondria from neonatal rats are more resistant to calcium load than mitochondria from adult animals. In this study we have analyzed the ontogenetic development of this parameter both in heart and in liver mitochondria. We found that the high resistance of heart mitochondria decreases from day 14 to adulthood. On the other hand, we did not observe a similar age-dependent sensitivity in liver mitochondria, particularly in the neonatal period. Some significant but relatively smaller increase could be observed only after day 30. When compared with liver mitochondria cardiac mitochondria were more resistant also to the peroxide activating effect on calcium-induced mitochondrial swelling. These data thus indicate that the MPTP of heart mitochondria is better protected against damaging effects of the calcium load and oxidative stress. We can only speculate that the lower sensitivity to calcium-induced swelling may be related to the higher ischemic tolerance of the neonatal heart.

[Significance of mitochondria in the heart muscle]. / Význam mitochondrií v srdecním svalu.

Besides their traditional role as the energy factory of the cell, mitochondria play an important role in other aspects of cardiac cell functioning under physiological and pathological conditions. They are involved in the regulation of calcium homeostasis, production of reactive oxygen species as well as in the process of cardiac cell death. Recently, the interest in their participation in ischemia-reperfusion injury and potential role in cardioprotective mechanisms, with particular attention to developmental aspects has markedly increased.

Exposure to intermittent high altitude induces different changes in adenylyl cyclase activity in hearts of young and adult Wistar rats.

This study investigates changes of adenylyl cyclase activity in the heart of young and adult Wistar rats exposed to experimental conditions simulating high altitude hypoxia as a model for interpretation of some adaptive changes of adenylyl cyclase observed in human. The exposure of rats to intermittent high altitude (IHA) hypoxia (5000 m) showed significant adaptive changes. The right ventricular weight and the ratio of right/left ventricular weights of adult rats exposed to IHA were significantly increased when compared to appropriate controls; adaptive changes of cardiac adenylyl cyclase being dependent on the age of the animals. The isoprenaline-stimulated activity was higher in the left than in the right ventricle, and in both ventricles it was higher in young rats than in adult rats. When compared to controls, isoprenaline stimulation was decreased in the right ventricles of adapted young rats and, by contrast, it was increased in the left ventricles of adapted adult rats. This decrease and increase of adenylyl cyclase activity evoked by isoprenaline was paralleled by forskolin-induced adenylyl cyclase activity in these experimental groups. It seems therefore that the changes in the pattern of total adenylyl cyclase activity observed under IHA hypoxia may at least be partially explained by the changes of beta-adrenergic receptor susceptibility following IHA hypoxia.

Effects of melatonin on ischemia and reperfusion injury of the rat heart.

Effects of melatonin on various manifestations of ischemia/reperfusion injury of the isolated perfused rat heart were examined. Ischemia- and reperfusion-induced ventricular arrhythmias were studied under constant flow in hearts subjected to 10, 15 or 25 min of regional ischemia (induced by LAD coronary artery occlusion) and 10-min reperfusion. Melatonin was added to the perfusion medium 5 min before ischemia at concentrations of 10 micromol/l or 10 nmol/l and was present throughout the experiment. Recovery of the contractile function was evaluated under constant perfusion pressure after 20-min global ischemia followed by 40-min reperfusion. Hearts were treated with melatonin at a high concentration (10 micromol/l) either 5 min before ischemia only (M1) or 5 min before ischemia and during reperfusion (M2) or only during reperfusion (M3). At the high concentration, melatonin significantly reduced the incidence of reperfusion-induced ventricular fibrillation and decreased arrhythmia score (10% and 2.2+/-0.3, respectively) as compared with the corresponding untreated group (62% and 4.1+/-0.3, respectively); the low concentration had no effect. This substance did not affect the incidence and severity of ischemic arrhythmias. Melatonin (M2, M3) significantly improved the recovery of the contractile function as compared with the untreated group; this protection did not appear if melatonin was absent in the medium during reperfusion (Ml). Our results show that melatonin, in accordance with its potent antioxidant properties, effectively protects the rat heart against injury associated with reperfusion. It appears unlikely that melatonin is cardioprotective at physiological concentrations.

The effect of the ultrashort beta-blocker esmolol on cardiac function recovery: an experimental study.

OBJECTIVE: This is an experimental work designed to determine, using the isolated perfused rat heart, the effect of the ultra-short acting beta-blocker esmolol on cardiac arrest and cardiac function recovery following esmolol withdrawal. METHODS: Changes in heart rate, coronary flow, diastolic pressure and the rate pressure product were evaluated on the isolated heart (Langendorff model). Esmolol concentrations of 125, 250, and 500 mg/l were tested. In another experiment using esmolol concentration of 250 mg/l, cardiac function recovery was assessed after 20- and 45-min arrest. RESULTS: While concentrations of 250 and 500 mg/l are necessary to produce cardiac arrest, the concentration of 500 mg/l does not result in full cardiac function recovery following esmolol withdrawal. After the highest concentration of esmolol, coronary flow, heart rate and the rate-pressure product recovered to about 80, 70 and 60% of the initial control values, respectively. When comparing 20- and 45-min arrests we found cardiac function normalization occurs later after 45-min arrest. CONCLUSION: The induction of cardiac arrest by esmolol is optimal at a concentration of 250 mg/l. A concentration of 125 mg/l does not result in cardiac arrest and produces bradycardia only, a concentration of 500 mg/l may be dangerous on account of persisting undesirable effects on the rat heart.

Regression of chronic hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and fibrosis: effect of enalapril.

Chronic hypoxia induces pulmonary hypertension and right ventricular hypertrophy. These changes are completely reversible, except for persistent myocardial fibrosis. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can reduce the ventricular collagen content in animals recovering from chronic hypoxia. Adult male Wistar rats were exposed to intermittent high-altitude hypoxia simulated in a barochamber (7000 m, 8 hr/day, 5 days a week, 24 exposures), then transferred to normoxia and divided into two groups: (a) treated with enalapril (0.1 g/kg/day for 60 days) and (b) without treatment. The corresponding control groups were kept under normoxic conditions. Enalapril significantly decreased the heart rate, systemic arterial pressure, and absolute left and right ventricular weights in both hypoxic and control rats; on the other hand, the pulmonary blood pressure was unchanged. The content and concentration of collagen was reduced in both ventricles of enalapril-treated hypoxic and control animals by 10-26% compared with the corresponding untreated groups. These data suggest that the partial regression of cardiac fibrosis due to enalapril may be independent of the pressure load.

Cardiac phosphocreatine deficiency induced by GPA during postnatal development in rat.

The effect of chronic administration of beta-guanidinopropionic acid (GPA) on the protein profiling, energy metabolism and right ventricular (RV) function was studied in the rat heart during the weaning and adolescence period. GPA was given in tap water (1-1.5%) using pair drink controls. The feeding of animals with GPA solution for a six week period resulted in elevation of heart to body weight ratio due to body growth retardation. GPA accumulated in the myocardium up to 67.37 +/- 5.3 mumoles.g dry weight and the tissue content of total creatine, phosphocreatine and ATP was significantly decreased to 15%, 9% and 65% of control values respectively. Total activity of creatine kinase (CK) was not changed, but the proportion of mitochondrial (Mi) CK isoenzyme was decreased; the percentage of MB isoenzyme of CK was significantly higher. GPA treatment resulted in an elevation of the content of cardiac collagenous proteins and decrease of non-collagenous proteins in the heart; in parallel, a decrease of the collagen I to collagen III ratio was detected. The function of the RV was assessed using an isolated perfused heart with RV performing pressure-volume work. As compared to pair-drink controls, RV function was significantly impaired the GPA group: at any given right atrial filling pressure, the RV systolic pressure and the rate of pressure development were decreased by almost a factor of two. Elevation of the RV diastolic pressure with increasing pulmonary artery diastolic pressure was also significantly steeper in the GPA group which also showed decrease of cardiac output, especially at high outflow resistance. It may be assumed that chronic administration of GPA deeply influenced metabolic parameters, protein profiles and contractile function of the developing heart. On the other hand, concentrations of glucose, total lipids and triglycerides in blood plasma were not affected. All these data confirm the concept that the CK system is of central importance both for heart function and for the regulation of normal growth of cardiac myocytes.

Inotropic effect of low extracellular sodium on perfused perinatal rat heart.

The purpose of the present study was to estimate the development of the inotropic response to low extracellular sodium (LES) during the perinatal period. The effect of LES (35 mmol.L-1) was measured in isolated perfused control and ryanodine-pretreated rat hearts on prenatal day 20 and postnatal days 1, 2, 4, and 7. The effect of LES on the developed force (DF) of control hearts changes significantly day by day: whereas a persisting increase of magnitude of contractions was recorded in the prenatal hearts, this increase was only transient on postnatal day 1 and 2. Starting from day 4, the initial signs of a triphasic response, typical for adult hearts, appeared (an initial increase of DF, followed by a decrease of DF and a rise of resting force, and finally a delayed increase of DF); this trend was more pronounced on day 7. The LES-induced increase of resting force was recorded only in 2-, 4-, and 7-day-old hearts. The negative inotropic effect of ryanodine (10(-6) mol.L-1) was observed already prenatally (60% of the controls) and continued during the whole period of investigation; in contrast, a ryanodine-induced increase of resting force was recorded only postnatally. However, pretreatment with ryanodine abolished the day-by-day changes in the response to LES: in all the hearts studied, the first phase (initial increase of DF) was followed by a severe depression of the magnitude of contractions, together with increased resting force. Our data show significant age-dependent differences in the cardiac contractile response to LES.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of verapamil on contractile function of the isolated perfused rat heart during postnatal ontogeny.

The negative inotropic effect of the calcium antagonist, verapamil, was compared in isolated hearts from 15-, 30-, 45-, 60-, and 90-day-old rats. Electrically paced hearts were perfused in vitro according to Langendorff, either under constant pressure or under constant flow conditions. An intraventricular-pressure curve was measured isovolumetrically and analyzed on-line using a microcomputer. Changes in pressure amplitude and maximum rate of pressure development were evaluated during a stepwise increase of the verapamil concentration in the perfusion solution (10(-9) - 3.3 x 10(-7) mol.l-1). It was found that the sensitivity of cardiac contractile function to verapamil declines gradually in the course of postnatal ontogeny. The higher sensitivity of the developing heart to calcium channel blockade is probably a consequence of a higher functional dependence of the immature myocardium on trans-sarcolemmal calcium influx.

[Tracheobronchography in neonates and infants with obstruction of the upper respiratory tract]. / Tracheobronchografie novorozencu a kojencu s obstrukcí horních dýchacích cest.

In the period of 1980 to 1989 the authors performed contrast examinations of tracheobronchial tree in 38 children up to one year of age, three of them being newborns. In 29 examined children (74.4%) there was an anatomical defect causing the obstruction of upper respiratory pathways. In 15 of them the trachea compression was caused by pressure of hyperplastic thymus on the brachiocephalic arterial truncus crossing trachea. For visualization of upper respiratory pathways Hexabrix 320 (Byk Gulden) was used in 30 children, administered in 10 cases by jet ventilation. The filling was recorded by radiocinematographic method.