Systemic Inhibition of the Na+/H+ Exchanger Type 3 in Intact Rats Activates Brainstem Respiratory Regions

Pásaro, Rosario; Ribas-Salgueiro, Juan Luis; Matarredona, Esperanza R.; Sarmiento, Manuel; Ribas, J.

doi:10.1007/978-90-481-2259-2_45

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…There is evidence that manipulation of the sodium–proton exchanger, which would occur with elevated extracellular sodium ion concentration, can influence phrenic nerve activity in vivo (Wiemann et al . 2008; Pasaro et al . 2009).…”

Section: Discussionmentioning

confidence: 99%

Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

Colombari

Freiria-Oliveira

Antunes

et al. 2011

The Journal of Physiology

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Non-technical summary Dehydration, a life-threatening condition, occurs when the body does not replace adequate water lost through urination, sweating or when ill with diarrhoea. This presents the body with a major challenge of maintaining blood pressure -essential for consciousness that is dependent on the degree of body hydration, which dictates blood volume. We know that a major control mechanism involves a brain region called the hypothalamus that automatically maintains blood pressure. Our study has described the gene networks in key brain regions involved in the response to dehydration. We reveal a new structure in the brain that regulates blood pressure in dehydration and a unique genetic mechanism that exists within it. Moreover, our study unearths a remarkable form of flexibility within the brain during dehydration that involves switching control of blood pressure between two spatially distinct structures. We have provided new mechanistic insight to explain how the brain maintains body stability in face of the significant challenge of low water content.Abstract We investigated the mechanisms responsible for increased blood pressure and sympathetic nerve activity (SNA) caused by 2-3 days dehydration (DH) both in vivo and in situ preparations. In euhydrated (EH) rats, systemic application of the AT 1 receptor antagonist Losartan and subsequent pre-collicular transection (to remove the hypothalamus) significantly reduced thoracic (t)SNA. In contrast, in DH rats, Losartan, followed by pre-collicular and pontine transections, failed to reduce tSNA, whereas transection at the medulla-spinal cord junction massively reduced tSNA. In DH but not EH rats, selective inhibition of the commissural nucleus tractus solitarii (cNTS) significantly reduced tSNA. Comparable data were obtained in both in situ and in vivo (anaesthetized/conscious) rats and suggest that following chronic dehydration, the control of tSNA transfers from supra-brainstem structures (e.g. hypothalamus) to the medulla oblongata, particularly the cNTS. As microarray analysis revealed up-regulation of AP1 transcription factor JunD in the dehydrated cNTS, we tested the hypothesis that AP1 transcription factor activity is responsible for dehydration-induced functional plasticity. When AP1 activity was blocked in the cNTS using a viral vector expressing a dominant negative FosB, cNTS inactivation was ineffective. However, tSNA was decreased after pre-collicular transection, a response similar to that seen in EH rats. Thus, the dehydration-induced switch in control of tSNA from hypothalamus to cNTS seems to be mediated via activation of AP1 transcription factors in the cNTS. If AP1 activity is blocked in the cNTS during dehydration, sympathetic activity control reverts back to forebrain regions. This unique reciprocating neural structure-switching plasticity between brain centres emphasizes the multiple mechanisms available for the adaptive response to dehydration.

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Section: Discussionmentioning

confidence: 99%

Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

Colombari

Freiria-Oliveira

Antunes

et al. 2011

The Journal of Physiology

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“…Two potent SLC9A3 inhibitors that cross the blood-brain barrier, AVE1599 and AVE0657 (developed by Sanofi-Aventis),were shown to activate the phrenic nerve and increase respiration rate [62][63][64]. AVE0657 was tested in Phase II clinical trials for sleep apnea (NCT00614250), but the drug was subsequently dropped from further clinical development.…”

Section: Gene Modifier Studies Highlight Ion Exchangers and Alternatimentioning

confidence: 99%

Modifier Gene Studies to Identify New Therapeutic Targets in Cystic Fibrosis

Dorfman

2012

CPD

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Since the discovery of the CFTR gene mutations which cause cystic fibrosis (CF) in 1989 the average life expectancy of CF patients has almost doubled and now exceeds 37 years. The advances in molecular diagnostics and medical treatments expanded beyond the CF patient population as some of the newest treatments are also being tested for treatment of complex diseases such as COPD and other inherited disorders. Rapid development of CF therapeutics is important for the cystic fibrosis community and is an excellent example for other nonprofit organizations, disease foundations and pharmaceutical companies alike. Better understanding of disease variability and underlying molecular mechanisms through genetic association studies aimed to identify novel CF modifier genes opens new venues for targeted drug design. Furthermore, these genetic studies allow development of molecular diagnostic tests for patient population stratification and treatment personalization, which is already being done for CF patients with specific mutations in the CFTR gene, as well as implementation of new molecular tests for reliable assessment of disease progression and severity.

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Interactions Between Postnatal Sustained Hypoxia and Intermittent Hypoxia in the Adulthood to Alter Brainstem Structures and Respiratory Function

Olea

Gaytán

Obeso

et al. 2012

Advances in Experimental Medicine and Biology

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Neural plasticity is defined as a persistent change in the morphology and/or function based on prior experiences. Plasticity is well evident when the triggering experience occurs early in life, but in the case of respiratory control plasticity, it also can be triggered in adult life. We have combined a 10 days postnatal hypoxic (PH) (0-10 days of age;11% O(2)) and a 15 days intermittent hypoxia (IH) exposures in the adulthood (90-105 days of age; 5% O(2), 40 s/20% O(2), 80 s; 8 h/day) to test if early PH interacts with IH of the adulthood to generate detrimental plastic changes. After recording of ventilatory parameters, the brains were studied immunocytochemically for localization of the organization pattern of non-phosphorylated subunit of neurofilament H (NFH) and tyrosine hydroxylase (TH) expression in the nucleus tractus solitarius (Sol) and caudal (CVL) and rostral ventrolateral reticular (RVL) nuclei, areas related to central cardio-respiratory regulation. In comparison to control, PH male rats (but not females) at 1 month of age hyperventilated at rest, in response to moderate hypoxia (12% O(2)) and 5% CO(2), the effect being due to increased tidal volume. At 3.5 months sex differences in ventilation disappeared and it was indistinguishable between control and PH. IH tended to decrease ventilation in both control (C) and PH animals. PH augmented PENH values in air and in hypoxic conditions when compared with C group. IH in both groups, tended to decrease the PENH value, being statistically different in PH+IH. Results also show an increment of disorganization of NFH-positive labeled structures at the level of Sol and CVL/RVL nuclei in PH, IH and HP+HI groups. PH rats showed differences in the number of TH-positive neurons at the level of CVL/RVL nuclei, which was increased in the PH and PH+IH groups with respect to C one. In conclusion, PH alters the central morpho-physiological organization and the catecholaminergic components of cardio-respiratory nuclei, whose effects were enhanced after a period of IH in the adulthood.

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Systemic Inhibition of the Na+/H+ Exchanger Type 3 in Intact Rats Activates Brainstem Respiratory Regions

Cited by 5 publications

References 20 publications

Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

Modifier Gene Studies to Identify New Therapeutic Targets in Cystic Fibrosis

Interactions Between Postnatal Sustained Hypoxia and Intermittent Hypoxia in the Adulthood to Alter Brainstem Structures and Respiratory Function

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