The effect of prenatal hypoxic stress on the cardiac contractile function and responsiveness to calcium was studied in rats during the perinatal period. Pregnant rats were exposed to intermittent high altitude hypoxia from day 14 to 18 of pregnancy. Foetal hearts (prenatal day 22) and the hearts of offsprings (days 1, 4 and 7) were isolated and perfused in the Langendorff mode. Developed force of contraction (DF) as well as the rate of force development and fall were measured a) at the Ca2+ concentration of 1.25 mmol.l-1, b) under increasing Ca2+ concentration (from 0.6 to 10.0 mmol.l-1). Body and heart weights were significantly smaller in hypoxic than in matched control rats starting from day 1. The contractile performance of hypoxic hearts did not differ from controls. Their inotropic response to increasing Ca2+ concentrations was, however, significantly reduced on prenatal day 22 and postnatal day 7. Our results suggest that prenatal maternal hypoxia affects the cardiac inotropic responsiveness to Ca2+ even postnatally.
To examine a possible involvement of p21 protein, an inhibitor of cyclin-dependent kinases (CDKs), in the transition from hyperplastic to hypertrophic growth of rat ventricular myocytes during the first postnatal week, we analysed day-by-day changes in the number of p21 positive cells using specific antibodies against this protein. Paraffin-embedded sections of the left ventricular myocardium were examined by means of immunoperoxidase technique and hematoxylin-eosin counterstaining. While during the first three postnatal days, the positive reaction for p21 was detected only in a small fraction of myocytes (12-20 %), a sudden increase in positivity occurred on day 4 (54 %) and continued till day 6 when the fraction of cells expressing p21 reached 87 %. Our results show that the induction of CDK inhibitor p21 in rat ventricular myocytes is developmentally regulated. Moreover, the fact that the sudden increase in p21 positivity occurred at the same stage when the myocyte proliferation rapidly ceases, suggests that this protein is likely to be involved in mediating this key event of cardiac development.
Continuous normobaric hypoxia (CNH) renders the heart more tolerant to acute ischemia/reperfusion injury. Protein kinase C (PKC) is an important component of the protective signaling pathway, but the contribution of individual PKC isoforms under different hypoxic conditions is poorly understood. The aim of this study was to analyze the expression of PKCε after the adaptation to CNH and to clarify its role in increased cardiac ischemic tolerance with the use of PKCε inhibitory peptide KP-1633. Adult male Wistar rats were exposed to CNH (10 % O2, 3 weeks) or kept under normoxic conditions. The protein level of PKCε and its phosphorylated form was analyzed by Western blot in homogenate, cytosolic and particulate fractions; the expression of PKCε mRNA was measured by RT-PCR. The effect of KP-1633 on cell viability and lactate dehydrogenase (LDH) release was analyzed after 25-min metabolic inhibition followed by 30-min reenergization in freshly isolated left ventricular myocytes. Adaptation to CNH increased myocardial PKCε at protein and mRNA levels. The application of KP-1633 blunted the hypoxiainduced salutary effects on cell viability and LDH release, while control peptide KP-1723 had no effect. This study indicates that PKCε is involved in the cardioprotective mechanism induced by CNH., K. Holzerová, M. Hlaváčková, J. Žurmanová, G. Borchert, J. Neckář, F. Kolář, F. Novák, O. Nováková., and Obsahuje bibliografii
We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K+ (mitoKATP) channels and activator of sarcolemmal ATP-sensitive K+ (sarcKATP) 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.
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 eviden
ce for the involvement of ATP-sensitive potassium channels, reactive oxygen species, nitric oxide and various protein kinases in cardioprotective effects of 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 l/lll 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.
It has been suggested that increase in acute nitric oxide (NO) or cyclic guanosine monophosphate production may be involved in cardioprotection induced by chronic hypoxia (CH). We studied the effect of NO donor molsi domine and phosphodiesterase type 5 inhibitor sildenafil on myocardial ischemia/reperfusion (I/R) injury in rats adapted to CH. Male Wistar rats were exposed to continuous hypoxia in a normobaric chamber (10 % O 2 , 4 weeks). Rats received either saline, mol sidomine (10 mg/kg body weight, i.v.) or sildenafil (0.7 mg/kg body weight, i.v.) 30 min before ischemia. Control rats were kept under normoxia and treated in a corresponding manner. Adaptation to CH increased the myocardial ischemic tolerance. Acute treat ment with either molsidomine or sildenafil significantly reduced infarct size in normoxic rats and further enhanced cardioprotection induced by CH. However, the cardioprotective effect of CH on I/R injury was not additive to the cardioprotection provided b y the drugs., P. Alánová, F. Kolář, B. Ošťádal, J. Neckář., and Obsahuje bibliografii
Risk factors (RF) of cardiovascular diseases associated with modern lifestyle, such as stress, chronically increased blood pressure, hyperglycemia and dyslipidemia have a negative impact on the heart exposed to ischemia: their may facilitate its lethal injury (myocardial infarction) and occurrence of sudden death due to ventricular arrhythmias. On the other hand, some stressful stimuli related to RF including reactive oxygen species, transient episodes of ischemia (hypoxia), high glucose and other may play a dual role in the pathogenesis of ischemia/reperfusion (I/R) injury (IRI). Besides their deleterious effects, these factors may trigger adaptive processes in the heart resulting in greater resistance against IRI, which is also a characteristic feature of the female myocardium. However, sensitivity to ischemia is increasing with age in both genders. Current research indicates that comorbidity related to lifestyle may impair the cardiac response to acute ischemia not only by interference with pathophysiological mechanisms of IRI per se, but via suppression of intrinsic protective mechanisms in the heart and its ability to tolerate the ischemic challenges, although the role of RF has not been unequivocally proven. Moreover, even pathologically altered myocardium need not completely lose its adaptive potential. In addition, increased ischemic tolerance can be induced by the pleiotropic (independent of the primary) effects of some hypolipidemic and antidiabetic drugs, even in the diseased myocardium. This review addresses the issue of the impact of RF on cellular cardioprotective mechanisms and the possibilities to restore adaptive potential in subjects challenged with several RF. Reactivation of adaptive processes in the myocardium taking into consideration gender and age can contribute to optimalization of antiischemic therapy., T. Ravingerová, ... [et al.]., and Obsahuje seznam literatury
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.