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Age and sex play an essential role in the cardiac tolerance to ischemia-reperfusion injury: cardiac resistance significantly decreases during postnatal maturation and the female heart is more tolerant than 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 ischemia-reperfusion injury. We have observed that the MPTP sensitivity to the calcium load differs in mitochondria isolated from neonatal and adult myocardium, as well as from adult male and female hearts. Neonatal and female mitochondria are more resistant both in the extent and in the rate of mitochondrial swelling induced by high calcium concentration. Our data further suggest that age- and sex-dependent specificity of the MPTP is not the result of different amounts of ATP synthase and cyclophilin D: neonatal and adult hearts, similarly as the male and female hearts, contain comparable amounts of MPTP and its regulatory protein cyclophilin D. We can speculate that the lower sensitivity of MPTP to the calcium-induced swelling may be related to the higher ischemic tolerance of both neonatal and female myocardium. Key words: neonatal heart, female heart, ischemia-reperfusion injury, cardiac ischemic tolerance, mitochondrial permeability transition pore, calcium-induced swelling. L'age et le sexe jouent un role essentiel dans la tolerance du coeur aux lesions d'ischemie-reperfusion : la resistance du coeur diminue nettement pendant le murissement postnatal, et le coeur femelle est plus tolerant que le myocarde male. Il est largement accepte que le dysfonctionnement myocardique, et plus particulierement l'ouverture des pores de transition de permeabilite mitochondriale (PTPM), joue un role majeur dans la determination de l'etendue des lesions d'ischemie-reperfusion dans le coeur. Nous avons observe que la sensibilite des PTPM a la charge en calcium des mitochondries isolees de myocarde neonatal est differente de celle du myocarde adulte, ainsi qu'entre les coeurs males et femelles. Les mitochondries neonatales et femelles sont plus resistantes quant a l'ampleur et a la vitesse du gonflement mitochondrial provoque par des concentrations elevees de calcium. Nos donnees laissent aussi entendre que la specificite des PTPM en fonction de l'age et du sexe n'est pas le resultat de differences quant aux quantites d'ATP synthase et de cyclophiline D : les coeurs neonataux comme adultes, de maniere similaire aux coeurs males et femelles, contiennent des quantites comparables de PTPM et de cyclophiline D, leur proteine regulatrice. Nous sommes en mesure de speculer que la plus faible sensibilite des PTPM au gonflement provoque par le calcium pourrait etre liee a la plus grande tolerance a l'ischemie du myocarde neonatal comme du myocarde femelle. [Traduit par la Redaction] Mots-cles : coeur neonatal, coeur femelle, lesions d'ischemie-reperfusion, tolerance a l'ischemie cardiaque, pore de transition de permeabilite mitochondriale, gonflement provoque par le calcium., Introduction The most frequent (and hence the most widely studied) cardiovascular diseases of modern times undoubtedly include hypoxic states. They originate as a result of disproportion between the amount of [...]

Catecholamines are involved in the regulation of a wide variety of vital functions. The [beta]-adrenergic receptor ([beta]-AR)-adenylyl cyclase system has been identified early in embryogenesis before the heart has received adrenergic innervation. The structure of [beta]-receptors in the immature myocardium is similar to that in adults; there are, however, significant quantitative developmental changes in the inotropic and chronotropic responsiveness. Information on the toxic effect of the [beta]-AR agonists in the immature heart is surprisingly scarce, even though these agents are used in clinical practice both during pregnancy and in early postnatal development. Large doses of [beta]-AR agonists induce malformations of the cardiovascular system; the type of change depends upon the time at which the [beta]-AR agonist was administered during embryogenesis. During postnatal ontogeny, the cardiotoxicity of [beta]-AR agonists increased from birth to adulthood. It seems likely that despite interspecies differences, developmental changes in the cardiac sensitivity to [beta]-AR agonists may exist in all mammals, depending on the degree of maturation of the system involved in [beta]-adrenergic signaling. All the existing data draw attention to the possible harmful consequences of the clinical use of [beta]-AR agonists during early phases of cardiac development. Late effects of the early disturbances of the cardiac muscle cannot be excluded. Key words: beta-mimetic catecholamines, cardiotoxicity, immature heart, preterm labor, tocolysis. Les catecholamines jouent un role dans la regulation d'une grande variete de fonctions vitales. On a etabli la presence du systeme recepteur [beta] adrenergique ([beta]-RA)--adenylyl cyclase precocement au cours de l'embryogenese, avant que le creur n'ait recu d'innervation adrenergique. La structure des recepteurs [beta] dans le myocarde immature est similaire a celle des adultes; il existe toutefois des variations quantitatives importantes quant a la reactivite sur le plan inotrope et chronotrope. Les donnees quant a l'effet toxique des agonistes des [beta]-RA dans le creur immature sont etonnamment rares, meme si ces agents sont utilises en pratique clinique pendant la grossesse comme au cours du developpement neonatal precoce. Des doses elevees d'agonistes des [beta]-RA entrainent des malformations du systeme cardiovasculaire; ce type de changements depend du moment ou les agonistes des [beta]-RA sont administres au cours de l'embryogenese. Pendant l'ontogenie postnatale, la cardiotoxicite des recepteurs [beta]-RA augmente de la naissance a l'age adulte. Il semble probable qu'en depit des differences entre les especes, les changements developpementaux de la sensibilite du creur aux agonistes des [beta]-RA pourraient exister chez tous les mammiferes, dependant du degre de maturite du systeme influence par la signalisation p adrenergique. Toutes les donnees existantes attirent l'attention sur les consequences potentiellement nefastes de l'utilisation clinique d'agonistes des [beta]-RA au cours des phases precoces du developpement du creur. On ne peut exclure la presence de consequences tardives des perturbations precoces du muscle cardiaque. [Traduit par la Redaction] Mots-cles: catecholamines beta mimetiques, cardiotoxicite, creur immature, travail avant terme, tocolyse., Introduction Catecholamines are involved in the regulation of a wide variety of vital functions, including heart rate, myocardial contractility, smooth muscle tone, blood pressure, as well as metabolism of fats [...]

Rakusan, Karel, N. Cicutti, and F. Kolar. Cardiac function, microvascular structure, and capillary hematocrit in hearts of polycythemic rats. Am J Physiol Heart Circ Physiol 281: H2425-H2431, 2001.--The effect of polycythemia on the coronary microcirculation was studied in young male rats. Two experimental models of polycythemia were employed: cobalt-induced polycythemia, which mimics hypoxia-induced changes, and erythropoietin-induced polycythemia, which circumvents these changes. In both models, baseline left ventricular function was normal, whereas maximal systolic and developed pressures were decreased. In cobalt-treated rats the left ventricular functional reserve was also compromised. Morphometric analysis of the left ventricle confirmed previously described improved geometric conditions for oxygen supply at the distal portions of capillaries (smaller domain areas and shorter capillary segments). In cobalt-treated but not in erythropoietin-treated rats, increased capillary angiogenesis was also detected. In the hearts from rats with both types of polycythemia, a small but significant increase in the formation of arterioles was found. Capillary linear hematocrit was within the normal range in both types of polycythemia despite sizeable increases in systemic hematocrit. Significant differences in red blood cell distribution within capillaries were found between proximal and distal portions in all experimental groups. coronary microcirculation; arterioles; capillaries; cobalt; erythropoietin Received 19 March 2001; accepted in final form 13 August 2001

The effect of anemia on the coronary microcirculation was studied in young male rats. Chronic anemia resulted in increased left ventricular end-diastolic pressure and decreased functional reserve. Cardiac mass in anemic animals increased by 25%. Capillary and arteriolar densities in these hearts remained unchanged, indicating angiogenesis in this experimental situation (estimated aggregate capillary length in the left ventricle of anemic hearts was 3.06 km compared with 2.35 km in control hearts). Capillary hematocrit was decreased in chronic anemia less than systemic hematocrit: from 25 to 18% in anemia versus 45 to 28% in controls. Capillary hematocrit and red blood cell spacing were also studied after acute blood withdrawal. Here, capillary hematocrit was preserved even more: 22 versus 24% in systemic hematocrit. Finally, the same was studied in isolated hearts perfused with solutions of various hematocrits. After perfusion with low-hematocrit solution (14%), the capillary hematocrit (24%) was even higher than the perfusate hematocrit! In conclusion, we found evidence of angiogenesis in cardiomegaly induced by chronic anemia. Microvascular growth was accompanied by advantageous regulation of red blood cell spacing within these vessels. This was even more pronounced during acute hemodilution and in isolated perfused hearts. coronary microcirculation; hemodilution; arterioles; capillaries