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We assessed ventilatory patterns and ventilatory responses to hypoxia (HVR) in high-altitude (HA) plateau pikas, repetitively exposed to hypoxic burrows, and control rats. We evaluated the role of neuronal nitric oxide synthase (nNOS) and dopamine by using S-methyl-L-thiocitrulline (SMTC) inhibitor and haloperidol antagonist, respectively. Ventilation ([V.sub.I]) was measured using a whole body plethysmograph in conscious pikas (n = 9) and low-altitude (LA) rats (n = 7) at different [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (56, 80, 111,150, and 186 mmHg) and in HA acclimatized rats (n = 9, 8 days at 4,600 m) at two different [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (56 and 80 mmHg). The effects of NaCl, SMTC, and haloperidol on ventilatory patterns were assessed in pikas at [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] = 56 and 80 mmHg. We observed a main species effect with larger [V.sub.I], tidal volume (VT), inspiratory time/total time ([T.sub.i]/[T.sub.tot]), and a lower expiratory time in pikas than in LA rats. Pikas had also a larger VT and lower respiratory frequency compared with HA rats in hypoxia. HVR of pikas and rats were not statistically different. In pikas, SMTC induced a significant increase in [V.sub.I] and VT for a [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] of 56 mmHg, but had no effect for a [P.sub.I][O.sub.2] of 80 mmHg, i.e., the living altitude of pikas. In pikas, haloperidol injection had no effect on any ventilatory parameter. Long-term ventilatory adaptation in pikas is mainly due to an improvement in respiratory pattern (VT and [T.sub.i]/[T.sub.tot]) with no significant improvement in HVR. The sensitivity to severe acute hypoxia in pikas seems to be regulated by a peripheral nNOS mechanism. adaptation; control of breathing; dopamine doi: 10.1152/ajpregu.00108.2009.

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-T[Ag.sup.h]) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-T[Ag.sup.h] mice showed an increase in transcript and protein levels of hypoxia-inducible factor l[alpha] (HIF-1[alpha], vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1[alpha], EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-T[Ag.sup.h] mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1[alpha], EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-T[Ag.sup.h] mice developed cerebral angiogenesis through the HIF-1[alpha] VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-T[Ag.sup.h], the decrease in HIF-l[alpha], VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered. chronic anemia; erythropoietin; angiogenesis; hypoxia; cerebral cortex