Fabiola León-Velarde

Effects of nifedipine-induced pulmonary vasodilatation on cardiac receptors and protein kinase C isoforms in the chronically hypoxic rat

In chronic hypoxia, pulmonary hypertension induces a right ventricular (RV) hypertrophy (RVH) and the catecholamine-activated adrenergic system modulates cardiovascular responses through α- and β-adrenergic pathways. The α1-adrenergic receptor (α1-AR) and protein kinase C (PKC) may play an important role in the signaling pathway leading to RVH. The aim of this study was to examine the relationship between nifedipine-induced pulmonary vasodilatation, the blunting of RVH and the modifications in the density of α1-AR, PKC activity and expression of PKC isoforms. In rats exposed to 15xa0days of hypoxia (380xa0torr, 50.66xa0kPa), RV pressure increased and RVH developed. Nifedipine, a calcium antagonist, given through gastric administration, partially decreased RV pressure and RVH. In both ventricles, hypoxia decreased α1-AR and β-AR density and increased muscarinic acetylcholine receptor density. Nifedipine decreased α1-AR density only in normoxia. Expression of ε, δ and ζ PKC isoforms increased with RVH and normalized with nifedipine treatment. In conclusion, in this in vivo model of hypoxic rat, no relation was found between a RVH decrease and cardiac receptor densities. However, the development and regression of pulmonary hypertension and RVH were related to the expression of some PKC isoforms suggesting that pathways other than α1-AR might be involved in hypoxia-induced ventricular hypertrophy.

Time course of ventilatory acclimatisation to hypoxia in a model of anemic transgenic mice.

We questioned the assumption that polycythemia is essential for adaptation to chronic hypoxia. Thus, the objective of our study was to determine if anemic Epo-TAg(h) mice could survive in hypoxia despite low oxygen carrying capacity. We explored the possibility that ventilatory acclimatisation is involved in the strategy used by anemic transgenic mice to adapt to chronic hypoxia. Epo-TAg(h) and Wild Type mice were exposed during 2 weeks at a barometric pressure of 450 Torr. After 1, 5 and 14 days of exposure, ventilation at different inspired oxygen fraction was measured in both groups. Ventilation during acclimatisation to hypoxia was significantly greater in Epo-TAg(h) than in Wild Type. The difference was mainly due to a higher tidal volume that could explain a higher arterial PO2 in Epo-TAg(h) mice. Epo-Tag(h) mice did not develop right ventricle hypertrophy after 2 weeks of exposure to hypoxia while Wild Type did. Hemoglobin concentration was 60% lower in anemic mice versus Wild Type after acclimatisation. In conclusion, ventilatory acclimatisation contributed to the adaptation of Epo-Tag(h) mice in chronic hypoxia despite low arterial oxygen carrying capacity.

Characterisation of the ventilatory response to hypoxia in a model of transgenic anemic mice

Both polycythemia and the increase in hypoxic ventilatory response (HVR) are considered as important factors of acclimatization to hypoxia. The objective of this study was to characterise the ventilation pattern at different inspired oxygen fraction in a model of chronic anemic mice. These mice have a targeted disruption in the 5 untranslated region of the Epo gene that reduces Epo expression such that the homozygous animal is severely anemic. Ventilation in normoxia in Epo-TAg(h) mice was significantly greater than in wild type, and the difference was mainly due to a higher tidal volume. HVR was higher in Epo-TAg(h) mice at every FIO2 suggesting a higher chemosensitivity. Resting oxygen consumption was maintained in anemic mice. Maximal oxygen consumption was 30% lower while hemoglobin was 60% lower in anemic mice compared to wild type. This small decrease in maximal oxygen consumption is probably due a greater cardiac output and/or a better tissue oxygen extraction and would allow these anemic mice to acclimatize to hypoxia in spite of low oxygen carrying capacity. In conclusion, Epo-TAg(h) anemic mice showed increased ventilation and hypoxic ventilatory response. However, whether these adaptations will contribute to acclimatization in chronic hypoxia remains to be determined.