Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3 (original) (raw)
Related papers
Regulation of diaphragmatic nitric oxide synthase expression during hypobaric hypoxia
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2000
Nitric oxide (NO) is normally synthesized inside skeletal muscle fibers by both endothelial (eNOS) and neuronal (nNOS) nitric oxide synthases. In this study, we evaluated the influence of hypobaric hypoxia on the expression of NOS isoforms, argininosuccinate synthetase (AS), argininosuccinate lyase (AL), and manganese superoxide dismutase (Mn SOD) in the ventilatory muscles. Rats were exposed to hypobaric hypoxia (∼95 mmHg) from birth for 60 days or 9–11 mo. Age-matched control groups of rats also were examined. Sixty days of hypoxia elicited approximately two- and ninefold increases in diaphragmatic eNOS and nNOS protein expression (evaluated by immunoblotting), respectively, and about a 50% rise in diaphragmatic NOS activity. In contrast, NOS activity and the expression of these proteins declined significantly in response to 9 mo of hypoxia. Hypoxia elicited no significant alterations in AS, AL and Mn SOD protein expression. Moreover, the inducible NOS (iNOS) was not detected in n...
Activation of nitric oxide synthase gene expression by hypoxia in central and peripheral neurons
Molecular Brain Research, 1996
Ž . Ž . In the present study we examined the effects of hypobaric hypoxia on neuronal n and endothelial e nitric oxide synthase NOS Ž . gene expression in the central and peripheral nervous system. Adult rats were exposed either to normoxia room air or to hypobaric Ž . hypoxia 0.4 atm for 4, 12 or 24 h and cerebellum and nodose ganglion representing the central and peripheral neurons, respectively, were removed. Messenger RNAs encoding n-and eNOS as well as b-actin were analyzed by reverse transcriptase polymerase chain Ž . reaction RT-PCR technique. Hypoxia increased nNOS mRNA expression with maximal changes occurring after 12 h wherein mRNA levels were increased by 10.4 " 1.3 and 2 " 0.4 fold in nodose ganglion and cerebellum, respectively. Hypoxia, on the other hand, had no significant effect on eNOS and b-actin mRNA levels. Analysis of nNOS protein and enzyme activity showed near doubling of these variables in both tissues after 24 h of hypoxia, indicating that nNOS protein levels are increased and that the protein is functionally active. These observations demonstrate that 12-24 h of hypobaric hypoxia selectively activates nNOS gene expression, which is reflected in an increase in nNOS protein in central and peripheral neurons. It is suggested that up-regulation of nNOS leads to increased generation of nitric oxide, which in turn may contribute to the readjustments of cardio-respiratory systems during the early stages of chronic hypoxia.
Nitric oxide production in the hypoxic lung
American Journal of Physiology- …, 2001
Nitric oxide (NO) is a potent vasodilator and inhibitor of vascular remodeling. Reduced NO production has been implicated in the pathophysiology of pulmonary hypertension, with endothelial NO synthase (NOS) knockout mice showing an increased risk for pulmonary hypertension. ...
The Chinese journal of physiology, 2006
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challeng...
Role of neuronal nitric oxide synthase in hypoxia-induced anapyrexia in rats
Journal of Applied Physiology, 2000
Anapyrexia (a regulated decrease in body temperature) is a response to hypoxia that occurs in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Recently, it has been shown that the NO pathway plays a major role in hypoxia-induced anapyrexia. However, very little is known about which of the three different nitric oxide synthase isoforms (neuronal, endothelial, or inducible) is involved. The present study was designed to test the hypothesis that neuronal nitric oxide synthase (nNOS) plays a role in hypoxia-induced anapyrexia. Body core temperature (Tc) of awake, unrestrained rats was measured continuously using biotelemetry. Rats were submitted to hypoxia, 7-nitroindazole (7-NI; a selective nNOS inhibitor) injection, or both treatments together. Control animals received vehicle injections of the same volume. We observed a significant ( P < 0.05) reduction in Tc of ∼2.8°C after hypoxia (7% inspired O2), whereas intraperitoneal inje...
Scientific Reports
Decreases in arterial blood oxygen stimulate increases in minute ventilation via activation of peripheral and central respiratory structures. This study evaluates the role of endothelial nitric oxide synthase (eNOS) in the expression of the ventilatory responses during and following a hypoxic gas challenge (HXC, 10% O2, 90% N2) in freely moving male and female wild-type (WT) C57BL6 and eNOS knock-out (eNOS–/–) mice. Exposure to HXC caused an array of responses (of similar magnitude and duration) in both male and female WT mice such as, rapid increases in frequency of breathing, tidal volume, minute ventilation and peak inspiratory and expiratory flows, that were subject to pronounced roll-off. The responses to HXC in male eNOS–/– mice were similar to male WT mice. In contrast, several of the ventilatory responses in female eNOS–/– mice (e.g., frequency of breathing, and expiratory drive) were greater compared to female WT mice. Upon return to room-air, male and female WT mice showed...
Journal of Clinical Investigation, 1998
Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35 Ϯ 2 vs 28 Ϯ 1 mmHg, x Ϯ SE, P Ͻ 0.001). Pulmonary artery pressure (P PA ) and incremental total pulmonary vascular resistance (R PI ) were greater in NOS3-deficient than in wild-type mice (P PA 22 Ϯ 1 vs 19 Ϯ 1 mmHg, P Ͻ 0.05 and R PI 92 Ϯ 11 vs 55 Ϯ 5 mmHg·min·gram·ml Ϫ 1 , P Ͻ 0.05). Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wildtype mice (RV wall thickness 0.67 Ϯ 0.05 vs 0.48 Ϯ 0.02 mm, P Ͻ 0.01 and RV weight/body weight ratio 2.1 Ϯ 0.2 vs 1.6 Ϯ 0.1 mg·gram Ϫ 1 , P Ͻ 0.05). RV hypertrophy produced by chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress. (
Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia
American Journal of Respiratory and Critical Care Medicine, 2005
Long-term intermittent hypoxia exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions. Objectives: We sought to determine if long-term intermittent hypoxia activates inducible nitric oxide synthase in sleep/wake regions, and if this source of nitric oxide contributes to the long-term intermittent hypoxia-induced proinflammatory gene response, oxidative injury and wake impairments. Methods: Mice with genetic absence of inducible nitric oxide synthase activity and wild type controls were exposed to 6 weeks of long-term hypoxia/reoxygenation prior to behavioral state recordings, molecular and biochemical assays and a pharmacological intervention. Measurements and main results: Two weeks after recovery from hypoxia/reoxygenation exposures, wild type mice showed increased inducible nitric oxide synthase activity in representative wake-active regions, increased sleep times and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep times latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor-and cyclooxygenase-2). Inhibition of inducible nitric oxide synthase following long-term hypoxia/reoxygenation in wild type mice was effective in reversing the proinflammatory gene response. Conclusions: These data support a critical role for inducible nitric oxide activity in the development of long-term intermittent hypoxia wake impairments, lipid peroxidation and proinflammatory responses in wake-active brain regions and suggest a potential role for inducible nitric oxide inhibition in protection from proinflammatory responses, oxidative injury and residual hypersomnolence in obstructive sleep apnea.