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- Berner, J, et al.
(författare)
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Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene
- 2007
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 103:2, s. 552-559
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Tidskriftsartikel (refereegranskat)abstract
- Substance P is known to be involved in respiratory rhythm and central pattern-generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1−/−) lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied using whole body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brain stem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo, and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity: with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1−/− animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.
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- Berner, J, et al.
(författare)
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Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids
- 2012
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 113:11, s. 1718-1726
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Tidskriftsartikel (refereegranskat)abstract
- Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1−/−) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1−/− mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1−/− during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1−/− mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1−/−. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1−/− mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.
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- Siljehav, V, et al.
(författare)
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Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice
- 2014
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 117:9, s. 1027-1036
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Tidskriftsartikel (refereegranskat)abstract
- Prostaglandin E2(PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R−/−mice ( P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R−/−preparations ( P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R−/−mice. Moreover, during severe hypoxic stress EP3R−/−mice had an increased gasping duration ( P < 0.01) as well as number of gasps ( P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R−/−mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia ( P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R−/−mice ( P < 0.05). In vitro, EP3R−/−brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium ( P < 0.05). In conclusion, PGE2exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates.
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