Dopaminergic metabolism in carotid bodies and high-altitude acclimatization in female rats

Abstract

We tested the hypothesis that ovarian steroids stimulate breathing through a dopaminergic mechanism in the carotid bodies. In ovariectomized female rats raised at sea level, domperidone, a peripheral D2-receptor antagonist, increased ventilation in normoxia (minute ventilation = +55%) and acute hypoxia (+32%). This effect disappeared after 10 daily injections of ovarian steroids (progesterone + estradiol). At high altitude (3,600 m, Bolivian Institute for High-Altitude Biology-IBBA, La Paz, Bolivia), neutered females had higher carotid body tyrosine hydroxylase activity (the rate-limiting enzyme for catecholamine synthesis: +129%) and dopamine utilization (+150%), lower minute ventilation (-30%) and hypoxic ventilatory response (-57%), and higher hematocrit (+18%) and Hb concentration (+21%) than intact female rats. Consistent signs of arterial pulmonary hypertension (right ventricular hypertrophy) also appeared in ovariectomized females. None of these parameters was affected by gonadectomy in males. Our results show that ovarian steroids stimulate breathing by lowering a peripheral dopaminergic inhibitory drive. This process may partially explain the deacclimatization of postmenopausal women at high altitude.

Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia

“…As previously reported by numerous studies (25,26,39,40), females reached higher levels of ventilation and have a lower hematological response than males after chronic exposure to hypoxia. This sex difference is mostly mediated by endogenous ovarian steroids, which act both on the central nervous system (7,8) and on peripheral chemoreceptors to increase ventilatory output (17,23,26,49).…”

“…As discussed above, this could be due to a stronger effect of ventilatory desensitization processes during chronic hypoxia. Experimental studies performed to date are all consistent in showing that reduced minute ventilation in chronic hypoxia is accompanied by an increased Ht, Hb, and/or plasma erythropoietin level (25,26,48), and the negative correlation between minute ventilation and hematological values as show in Fig. 4 is a clear example of this acclimatization balance in rats.…”

“…A cross talk between the level of ventilation and the hematological response has been established by experimental studies, showing that low minute ventilation under chronic hypoxia is compensated by an increased red blood cell production or plasma erythropoietin level (26,48). Although this phenomenon aims at maintaining arterial O 2 level, its beneficial effects may rapidly be overcome by the increased blood viscosity that accompanies erythrocytosis (20).…”

Divergent physiological responses in laboratory rats and mice raised at high altitude

“…In rats, females had lower mass-corrected f R than males, but V T and V˙E were similar (either mass-specific or mass-corrected data). Higher values of V˙E and V T in females compared with males likely reflects the respiratory stimulant effect of ovarian steroids (Joseph et al, 2002), and have been reported in our previous studies (Lumbroso et al, 2012). The fact that sex-specific effects were not reported in the present study in rats might be related to the reduced sample size (six males, six females), while we compared 17 males with 16 females in our previous study (Lumbroso et al, 2012).…”

Neurohumoral Control of Heart Rate

“…Regarding the chemoreflex, data from castrated male cats suggest that testosterone increases the hypoxic and hypercapnic ventilatory responses and augmented carotid body sensitivity to hypoxia (Behan et al, 2003). In adult rats, however, castration had no effect on the ventilatory response measured at the end of hypoxia (Joseph et al, 2002). On the other hand, Bairam et al (2009) demonstrated that gonadectomy increased the acute breathing frequency response to hypoxia in neonatal rats.…”