1. Cardiac tolerance to oxygen deprivation during ontogenetic development
2. Endogenous mechanisms underlying the protective effects of adaptation to chronic hypoxia
3. Cell response to pressure and volume overload during development

Research topics

1. Developmental changes in functional and metabolic properties of cardiac muscle determining its tolerance to oxygen deprivation and possibilities of protection.

2. Cardioprotective and adverse effects of adaptation to chronic hypoxia (simulated in a barochamber); responses to acute ischemia and hypoxia (ventricular arrhythmias, infarct size, recovery of contractile function), both in vivo and in vitro. Comparison of the cardioprotective effect of adaptation to chronic hypoxia and ischaemic preconditioning; their mutual relationships.

3. Endogenous mechanisms underlying the protective effect of adaptation to chronic hypoxia and ischaemic preconditioning; role of phospholipids, protein kinase C, nitric oxide, ATP-sensitive potassium channels; age-related differences. The role of mitochondria in cardiac tolerance to oxygen deprivation; developmental changes of mitochondrial function.

4. Cell response to pressure and volume overload during early heart development; hypertrophy and hyperplasia of myocytes; neurohormonal regulations, growth factors.

Main results

Thyroid control of calcium handling in the developing rat heart

Thyroid hormone levels increase in the postnatal life and are essential for maturation of myocardial calcium handling. During this time the sarcolemmal Na⁺/Ca²⁺-exchanger (NCX) function decreases and the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2) function increases. We examined the effects of postnatal hypo- or hyperthyroidism on NCX and SERCA2 in rat hearts (2 to 21 days postpartum). Ventricular steady-state mRNA and protein levels of NCX and SERCA2 were analyzed by Northern and Western blotting. In hypothyroidism, NCX mRNA and protein were elevated by 66 and 80 %, respectively, and SERCA2 mRNA and protein were reduced to 55 and 70 %, respectively. Corresponding differences were observed in the respective Ca2+ transports. Conversely, reduced NCX (by 50 %) and elevated SERCA2 (by 150 %) activities were found in hyperthyroidism. The levels of NCX and SERCA2 mRNA and protein were, however, unchanged in hyperthyroidism, indicating that functional changes are not due to altered NCX and SERCA2 expression. In conclusion, physiological thyroid hormone levels appear to be essential for normal reciprocal changes in the expression and function of myocardial NCX and SERCA2 during postnatal development.

Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart

The aim of the study was to examine whether ischaemic preconditioning - the most potent cardioprotective phenomenon - is present already in neonatal hearts. For this purpose, rat hearts isolated on days 1, 4 and 7 of postnatal life were perfused (Langendorff) under constant pressure, temperature and stimulation rate; the developed force of contraction was measured by an isometric transducer. Hearts were exposed to 40 or 60 min of global ischaemia followed by 30 min of reperfusion; preconditioning was induced by three 3-min periods of global ischaemia. Developmental changes in the expression of protein kinase C (PKC) isoforms, and their activation following preconditioning was estimated using Western blot analysis. Tolerance to oxygen deprivation as measured by recovery of contractile function decreased from day 1 (48 %) to day 7 (33 %). Preconditioning failed to improve ischaemic tolerance on day 1 and on day 4 but a significant protective effect was observed on day 7 (22 %). PKC isoforms a, d, e  and z were expressed in the ventricular myocardium during the first week of life, but there was no evidence of translocation following preconditioning on day 7. It may be assumed that ischaemic preconditioning is not an inborn phenomenon but that it develops during early postnatal life.

Role of mitochondrial ATP-sensitive potassium channels in the cardioprotective effect of adaptation to chronic hypoxia

The aim was to determine whether adaptation to chronic hypoxia protects the heart against ischemic arrhythmias and whether ATP-sensitive potassium channels (K_ATP) play a role in the antiarrhythmic mechanism. Adult male rats were therefore adapted to highaltitude hypoxia simulated in a barochamber (5000 m, 4 h/day) and susceptibility to ischaemiainduced ventricular arrhythmias was evaluated in the Langendorff-perfused hearts subjected to either an occlusion of the coronary artery for 30 min or preconditioning by brief occlusion of the same artery prior to 30-min reocclusion. It has been observed that adaptation to hypoxia reduced the total number of ventricular arrhythmias by 64 % as compared with normoxic controls. Preconditioning by a single 3-min occlusion was antiarrhythmic only in the normoxic group, while two occlusion periods (5 min each) were needed to precondition the hypoxic hearts. Glibenclamide (K_ATP blocker) increased the number of arrhythmias in the normoxic hearts by 59 % and in the hypoxic group by 179 %. In noctrast, diazoxide (K_ATP opener) decreased the number of arrhythmias only in the normoxic group (by 58 %), while its effect in the hypoxic group was not significant. It is concluded that longterm adaptation of rats to chronic hypoxia decreases the susceptibility of their hearts to ischaemic arrhythmias and increases an antiarrhythmic threshold of preconditioning. The mitochondrial K_ATP channel appears to be involved in the protective mechanism afforded by adaptation.

Publications