Brain stem NO modulates ventilatory acclimatization to hypoxia in mice

Abstract

The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.

Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells

“…These data indicated a role for adiponectin in upregulating NOS in non-parenchymal cells. Since NO metabolism is rapid (t 1/2 =4 s) in vivo and the final products are nitrite (NO 2− ) and nitrate (NO 3− ), the best index of total NO production is the sum of both NO 2− and NO 3− [24]. Thus, we quantified total NO 2− and NO 3− using a fluorometric assay.…”

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

“…In contrast, NTS-specific NOS antagonism blunts the potassium cyanide-mediated increase in breathing at 5 and 10 min but not 30 min after treatment (134), and prevents the acute HVR after 1 minute (287). Conversely, others have reported that systemic or NTS-specific nNOS inhibition does not block STP in conscious mice (83), or rats (301). However, since this pathway is a common form of short-term synaptic plasticity that is conserved at glutamatergic synapses throughout the CNS, it is likely that enhanced synaptic sensitivity due to the activation of this pathway occurs not only at the synapse between the carotid body and the NTS, but also at the synapses between NTS secondary neurons and other respiratory centers in the CNS.…”

“…Indeed, in other areas of the CNS, it has been demonstrated that with prolonged activation of the canonical glutamate/NO LTP pathway, the expression of involved proteins, such as NMDARs and nNOSs increase to further enhance the sensitivity of the system (10). Similarly, in mice and rats exposed to chronic hypoxia, the expression of phosphorylated AMPAR and NMDAR subunits and also nNOS increase in the NTS (83, 299, 301, 335, 434). Overall though, while there is clear evidence that glutamatergic neurotransmission is central to the CNS component of VAH, the role of NO and nNOS in mediating this effect remains controversial, and results to date point at potential species differences.…”

“…There is also some evidence supporting a potential role for NO in VAH. For example, nNOS mRNA, protein expression, and enzymatic activity increase following 24 h of hypoxia in rat CNS (324), and following 2 weeks of chronic sustained hypoxia in murine medulla (83); however, these authors did not attempt to manipulate NMDARs or examine the underlying mechanism of LTP directly. Controversially, these authors also reported that systemic injection of a nNOS antagonist reduces murine VAH, while others have shown that normoxic respiration increases and the HVR is augmented in nNOS null mice (193).…”

HIF-1 and ventilatory acclimatization to chronic hypoxia

“…Selective inhibition nNOS in the brainstem has no effect on ventilation or the HVR in control mice but it decreases ventilation in chronically hypoxic mice (Hasnaoui-Saadani et al, 2007). Hence, effects of HIF-1α on NO appear to enhance O 2 delivery from effects on ventilation in chronic hypoxia, as well as from the effects of NO-induced vasodilation on vascular O 2 delivery.…”