Effects of the thromboxane A2 mimetic, U46,619, on pulmonary vagal afferents in the cat

Karla, W.; Shams, H.; Orr, Joseph A.; Scheid, P.

doi:10.1016/0034-5687(92)90019-s

Cited by 52 publications

(57 citation statements)

References 25 publications

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“…Previous studies have demonstrated that U-46619 facilitates airway smooth muscle constriction through an M 3 muscarinic acetylcholine receptor-dependent mechanism (2). It has been suggested that this mechanism likely involves afferent and efferent neural signaling (1,2,15). This leaves open the possibility that polymorphisms in NPSR1/GPRA could alter neurally mediated mechanisms affecting smooth muscle constriction and airway function and in this way increase the risk for asthma.…”

Section: Discussionmentioning

confidence: 99%

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

Allen¹,

Pace²,

Jania³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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A genetic contribution to asthma susceptibility is well recognized, and linkage studies have identified a large number of genes associated with asthma pathogenesis. Recently, a locus encoding a seven-transmembrane protein was shown to be associated with asthma in founder populations. The expression of the protein GPRA (G protein-coupled receptor for asthma susceptibility) in human airway epithelia and smooth muscle, and its increased expression in a mouse model of asthma, suggested that a gain-of-function mutation in this gene increased the disease risk. However, we report here that the development of allergic lung disease in GPRA-deficient mice is unaltered. A possible explanation for this finding became apparent upon reexamination of the expression of this gene. In contrast to initial studies, our analyses failed to detect expression of GPRA in human lung tissue or in mice with allergic lung disease. We identify a single parameter that distinguishes GPRA-deficient and wild-type mice. Whereas the change in airway resistance in response to methacholine was identical in control and GPRA-deficient mice, the mutant animals showed an attenuated response to thromboxane, a cholinergic receptor-dependent bronchoconstricting agent. Together, our studies fail to support a direct contribution of GPRA to asthma pathogenesis. However, our data suggest that GPRA may contribute to the asthmatic phenotype by altering the activity of other pathways, such as neurally mediated mechanisms, that contribute to disease. This interpretation is supported by high levels of GPRA expression in the brain and its recent identification as the neuropeptide S receptor.

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Section: Discussionmentioning

confidence: 99%

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

Allen¹,

Pace²,

Jania³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…*P Ͻ 0.05 vs. corresponding baseline value. these two types of lung sensory receptors by mechanical stimuli, such as an increase in interstitial fluid volume (15,36) and changes in lung mechanics (8,11,19,20), has been reported. Furthermore, ⅐OH and cyclooxygenase metabolites may cause pulmonary edema (13,26).…”

Section: Discussionmentioning

confidence: 99%

“…Several investigators have demonstrated that administration of exogenous reactive oxygen metabolites or cyclooxygenase metabolites may stimulate lung C fibers and RARs (2,10,20,28,38,39). Our previous studies have shown that endogenous ⅐OH and/or cyclooxygenase metabolites are important activators for the stimulation of these two types of lung sensory receptors when the airway is insulted by inhaled wood smoke (22,23) or when air emboli are lodged in the pulmonary vessels (6,7,8).…”

Section: Discussionmentioning

confidence: 99%

“…A direct stimulation of these two types of lung sensory receptors by chemical mediators, including ⅐OH and cyclooxygenase metabolites, has been postulated (8,10,20,22,23,25,40). Therefore, one possibility is that the involvement of ⅐OH and cyclooxygenase metabolites may arise from their direct actions on pulmonary C fibers and RARs or are part of a signaling cascade leading to receptor stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclooxygenase metabolites, including various types of prostaglandins and thromboxane, are produced from the metabolism of arachidonic acid via an enzymatic reaction (1). Both ⅐OH and cyclooxygenase metabolites, either administered exogenously (2,10,20,28,38,39) or formed endogenously (6,7,8,22,23), can chemically or mechanically stimulate lung C fibers and RARs in several species. On the other hand, endotoxin produces an increase in total lung resistance (RL) and a decrease in dynamic lung compliance (Cdyn) (21,43,44), both of which are potential mechanical stimuli for RARs (11,19).…”

mentioning

confidence: 99%

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The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

Lai

Ruan

Kou

2005

Journal of Applied Physiology

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The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats. J Appl Physiol 98: 620 -628, 2005. First published October 1, 2004; doi:10.1152/japplphysiol.00539.2004.-Circulatory endotoxin can stimulate vagal pulmonary C fibers and rapidly adapting receptors (RARs) in rats, but the underlying mechanisms are not clear. We investigated the involvement of hydroxyl radicals and cyclooxygenase metabolites in the stimulation of C fibers and RARs by circulatory endotoxin (50 mg/kg) in 112 anesthetized, paralyzed, and artificially ventilated rats. In rats pretreated with the vehicle, endotoxin stimulated C fibers and RARs and caused a slight increase in total lung resistance (RL) and a decrease in dynamic lung compliance. In rats pretreated with dimethylthiourea (a hydroxyl radical scavenger) alone, indomethacin (a cyclooxygenase inhibitor) alone, or a combination of the two, C-fiber and RAR responses [C fiber: change (⌬) ϭ Ϫ62, Ϫ79, and Ϫ85%; RAR: ⌬ ϭ Ϫ80, Ϫ84, and Ϫ84%, respectively] were reduced, and the RL response was prevented. The suppressive effects of a combination of dimethylthiourea and indomethacin on the C-fiber and RAR responses were not superior to indomethacin alone. In rats pretreated with isoproterenol (a bronchodilator), the C-fiber response was not significantly affected (⌬ ϭ Ϫ26%), the RAR response was reduced (⌬ ϭ Ϫ88%), and the RL response was prevented. None of these pretreatments affected the dynamic lung compliance response. These results suggest that 1) both hydroxyl radicals and cyclooxygenase metabolites are involved in the endotoxin-induced stimulation of C fibers and RARs, and 2) the involvement of these two metabolites in the C-fiber stimulation may be due to their chemical effects, whereas that in the RAR stimulation may be due to their bronchoconstrictive effects. pulmonary C fibers; rapidly adapting receptors; reactive oxygen metabolites ENDOTOXEMIA CAUSES TACHYPNEA, leading to hyperventilation in septic shock patients (3, 4), but the causes are not completely understood. The tachypnea induced by circulatory endotoxin in rats is prevented by bilateral cervical vagotomy, suggesting that it is a vagally mediated respiratory reflex (42). Electrophysiological studies in rats have revealed that lung C-fiber nerve endings (C fibers) and pulmonary rapidly adapting receptors (RARs), two major types of lung vagal sensory receptors, are activated by circulatory endotoxin (21). Both lung C fibers and RARs play an important role in the detection of pulmonary pathophysiological conditions and eliciting resultant respiratory reflexes (9,25,40). The physiological characteristics of these two types of lung receptors are different (9,25,40). For example, lung C fibers are very sensitive to chemical stimuli (e.g., chemical mediators) but relatively insensitive to mechanical stimuli (e.g., bronchoconstriction). In contrast, RARs can be stimulated by chemical mediators and/or changes in lung mechanics. The mechanisms...

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Chemosensitivity from the Lungs of Vertebrates

Scheid

Shams

1994

Advances in Experimental Medicine and Biology

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Effects of the thromboxane A2 mimetic, U46,619, on pulmonary vagal afferents in the cat

Cited by 52 publications

References 25 publications

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

Chemosensitivity from the Lungs of Vertebrates

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