Cortisol was reported to downregulate body-fluid Ca2+ levels in mammals but was proposed to show hypercalcemic effects in teleostean fish. Fish, unlike terrestrial vertebrates, obtain Ca2+ from the environment mainly via the gills and skin rather than by dietary means, and have to regulate the Ca2+ uptake functions to cope with fluctuating Ca2+ levels in aquatic environments. Cortisol was previously found to regulate Ca2+ uptake in fish; however, the molecular mechanism behind this is largely unclear. Zebrafish were used as a model to explore this issue. Acclimation to low-Ca2+ fresh water stimulated Ca2+ influx and expression of epithelial calcium channel (ecac), 11β-hydroxylase and the glucocorticoid receptor (gr). Exogenous cortisol increased Ca2+ influx and the expressions of ecac and hydroxysteroid 11-beta dehydrogenase 2 (hsd11b2), but downregulated 11β-hydroxylase and the gr with no effects on other Ca2+ transporters or the mineralocorticoid receptor (mr). Morpholino knockdown of the GR, but not the MR, was found to impair zebrafish Ca2+ uptake function by inhibiting the ecac expression. To further explore the regulatory mechanism of cortisol in Ca2+ uptake, the involvement of vitamin D3 was analyzed. Cortisol stimulated expressions of vitamin D-25hydroxylase (cyp27a1), cyp27a1 like (cyp27a1l), 1α-OHase (cyp27b1) at 3 dpf through GR, the first time to demonstrate the relationship between cortisol and vitamin D3 in fish. In conclusion, cortisol stimulates ecac expression to enhance Ca2+ uptake functions, and this control pathway is suggested to be mediated by the GR. Lastly, cortisol also could mediate vitamin D3 signaling to stimulate Ca2+ uptake in zebrafish.

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The present study was designed to investigate the impact of midcervical spinal cord injury on respiratory outputs and compare respiratory recovery following high- vs. midcervical spinal injury. A unilateral hemisection (Hx) in the spinal cord at C2 or C4 was performed in adult rats. Respiratory behaviors of unanesthetized animals were measured at normoxic baseline and hypercapnia by whole body plethysmography at 1 day and 1, 2, 4, and 8 wk after spinal injury. C2Hx and C4Hx induced a similar rapid shallow breathing pattern at 1 day postinjury. The respiratory frequency of C4Hx animals gradually returned to normal, but the tidal volume from 1 to 8 wk postinjury remained lower than that of the control animals. Linear regression analyses indicated that the tidal volume recovery was greater in the C4Hx animals than in the C2Hx animals at the baseline, but not at hypercapnia. The bilateral phrenic nerve activity was recorded in anesthetized animals under different respiratory drives at 8-9 wk postinjury. The phrenic burst amplitude ipsilateral to the lesion reduced following both high- and midcervical Hx; however, the ability to increase activity was lower in the C4Hx animals than in the C2Hx animals. When the data were normalized by the maximal inspiratory effort during asphyxia, the phrenic burst amplitude enhanced in the C4Hx animals, but reduced in the C2Hx animals compared with the control animals. These results suggest that respiratory deficits are evident following midcervical Hx, and that respiratory recovery and neuroplasticity of phrenic outputs are different following high- vs. midcervical spinal injury.

Bronchopulmonary C fibers are the primary chemosensitive afferents in the lung. The activation of bronchopulmonary C fibers evokes the pulmonary chemoreflex, which is characterized by apnea, hypotension, and bradycardia and is a critical reflex that modulates cardiorespiratory responses under physiological and pathological conditions. The present study was designed to investigate whether the pulmonary chemoreflex is altered following acute cervical spinal injury. A unilateral hemisection (Hx) or laminectomy (uninjured) in the second cervical spinal cord was performed in adult male Sprague-Dawley rats. The pulmonary chemoreflex induced by intrajugular capsaicin administration was evaluated by measuring respiratory airflow in spontaneously breathing rats and phrenic nerve activity in mechanically ventilated rats. Capsaicin treatment evoked a cessation of respiratory airflow and phrenic bursting in uninjured animals, but not in C2Hx animals. To clarify whether the attenuation of the pulmonary chemoreflex in C2Hx animals is restricted to capsaicin-induced stimuli, or generally applied to other stimuli that excite bronchopulmonary C fibers, another bronchopulmonary C-fiber stimulant (phenylbiguanide) was used to evoke the pulmonary chemoreflex in spontaneously breathing rats. We observed that phenylbiguanide-induced apnea was also blunted in C2Hx animals, suggesting that the respiratory response induced by bronchopulmonary C-fiber activation was attenuated following acute cervical spinal Hx. The blunted inhibitory respiratory response may represent a compensatory respiratory plasticity to preserve the breathing capacity and may also reduce the capability of preventing inhaled irritants in this injured condition.

Pulmonary C‐fibers are the main chemosensitive afferents in the lung. Activation of pulmonary C‐fibers can evoke pulmonary chemoreflex characterized by apnea, hypotension and bradycardia which is a critical defense reflex to modulate cardiorespiratory responses. The present study was designed to investigate whether pulmonary chemoreflex is altered following acute cervical spinal injury. Adult Sprague Dawley rats received high cervical unilateral hemisection (C2Hx) or C2 laminectomy (sham) were used. Intra‐jugular capsaicin induced pulmonary reflex was evaluated by measuring respiratory airflow in spontaneously breathing rats and phrenic nerve activity in mechanically‐ventilated rats. Capsaicin treatment evoked a cessation of respiratory airflow and phrenic bursting in sham but not C2Hx animals. In order to clarify whether attenuation of pulmonary chemoreflex in C2Hx animals is merely induced by capsaicin or generally applied to other stimuli that can excite pulmonary C‐fibers, another pulmonary C‐fiber stimulant (phenylbiguanide, PBG) was used to evoke pulmonary chemoreflex in spontaneously breathing rats. We observed that PBG‐induced pulmonary chemoreflex was also blunted in C2Hx animals. These results suggested that pulmonary chemoreflex is attenuated after acute C2Hx and the blunted reflex may unfavorably impact the ability to prevent inhaling respiratory irritants. Grant Funding Source: Supported by NSC 102‐2320‐B‐110‐004‐MY3, NHRI‐EX102‐10223NC