Carvedilol inhibits right ventricular hypertrophy induced by chronic hypobaric hypoxia.

Right ventricular hypertrophy induced by chronic hypoxia is mainly due to a mechanical stress upon the ventricular wall secondary to pulmonary arterial hypertension. However, the hypoxic chronic activation of the sympathetic nervous system can contribute to the development of right ventricular hypertrophy either via myocardial adrenergic receptors and/or a vasoconstriction and remodeling of pulmonary arteries. To highlight the specific role of the sympathetic nervous system on hypoxia-induced right ventricular hypertrophy and particularly the efficiency of carvedilol, our study compared physiological, myocardial, and pulmonary arterial morphometric data in rats treated by alpha-(prazosin), or beta-(propranolol) or alphabeta-(carvedilol) antagonist and exposed to chronic hypobaric hypoxia (2 weeks at 380 mmHg barometric pressure). In chronic hypoxia, both systolic right ventricular pressure and Fulton's ratio (right/(left+septum) ventricular weight) were lower in rats treated by prazosin (-16.7 and -13.6%), propranolol (-28.6 and -12.7%) and carvedilol (-15.9 and -14.3%) respectively when compared to glucose (p<0.05). Surprisingly, prazosin was unable to reduce right ventricular hypertrophy induced by chronic hypoxia, whereas, left ventricular weight increased. Wall thickness index of pulmonary arteries increased in chronic hypoxia and was reduced by carvedilol. In conclusion, the hypoxia-induced activation of the adrenergic system participates in the development of right ventricular hypertrophy. Carvedilol is effective in reducing hypoxia-induced right ventricular hypertrophy, pulmonary arterial hypertension, and muscularization of pulmonary arteries.

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.