Biomedical subjects

Y R Kou

Publications and source records attributed to Y R Kou.

At least 19 recordsLinked to original sources

PubMed2006

Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors.

In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca(2+)](i)) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca(2+)](i) in approximately 34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.

Adult↗

PubMed2001

Alleviation of wood smoke-induced lung injury by tachykinin receptor antagonist and hydroxyl radical scavenger in guinea pigs.

We recently reported that wood smoke inhalation initially (within 5 min) causes airway injury and subsequently produces both airway and parenchymal injury after a delay (within 2 h). In this study, we investigated the mediator mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either air or 40 tidal breaths of wood smoke. Two hours after inhalation, wood smoke produced various injurious responses, including increases in alveolar-capillary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK1 receptor antagonist; (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combination of these two drugs largely alleviated both the airway and parenchymal responses, whereas pre-treatment with SR-48,968 [a tachykinin NK2 receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR-48,965 (inactive enantiomers) failed to do so. Post-treatment given at 5 min after smoke challenge with CP-96,345 or dimethylthiourea significantly alleviated the parenchymal responses, while having no effect on the airway responses. Pre-treatment with dimethylthiourea prevented the smoke-induced reduction in airway neutral endopeptidase activity (an enzyme for tachykinin degradation). We concluded that (1) tachykinins and hydroxyl radical play important roles in producing smoke-induced delayed lung injury in guinea pigs, and both may be involved in the spread of injury from the airways to the pulmonary parenchyma, and (2) the contribution of tachykinins is mediated via the activation of tachykinin NK1 receptors, and is associated with the hydroxyl radical-induced inactivation of airway neutral endopeptidase.

Animals↗

PubMed2001

Airway hyperresponsiveness to bronchoconstrictor challenge after wood smoke exposure in guinea pigs.

Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.

Acetylcholine↗

PubMed2000

Different roles of two subgroups of lung vagal C-fiber afferents in the tachypneic response to pulmonary air embolism in dogs.

It is known that lung vagal C-fiber afferents play an important role in eliciting the tachypneic response to pulmonary air embolism (PAE), and can be subgrouped as those with low resistance (LRC) and those with high resistance (HRC) to perivagal capsaicin. In this study, we investigated the relative contributions of vagal LRC and HRC C-fiber afferents to the PAE-induced tachypneic response. Phrenic activity was recorded from 10 anesthetized, paralyzed, and artificially ventilated dogs. PAE was induced by infusion of air into the vein (2 ml/min, 1 ml/kg). During control conditions, induction of PAE produced a shortening in expiratory duration with no significant change in inspiratory duration, resulting in tachypnea. The PAE-induced tachypneic response was totally abolished by perivagal capsaicin treatment with a method (capsaicin concentration, 6 mg/ml; treatment duration, 25-30 min) that blocks the conduction of LRC C-fiber afferents, but not that of HRC C-fiber afferents. This tachypneic response was not affected by cooling of both vagi to a temperature (4.5 degrees C) that blocks the conduction of HRC C-fiber afferents, but not that of LRC C-fiber afferents. A bilateral cervical vagotomy virtually eliminated this tachypneic response. These results suggest that LRC C-fiber afferents are responsible for eliciting the reflex tachypneic response to PAE, whereas HRC C-fiber afferents play no vital role.

Anesthesia↗

PubMed2000

Acute neurogenic airway plasma exudation and edema induced by inhaled wood smoke in guinea pigs: role of tachykinins and hydroxyl radical.

We studied the mechanisms underlying the wood smoke-induced acute airway injury in 120 anaesthetized guinea pigs. Five minutes after airway exposure, various doses of wood smoke produced a dose-dependent increase in Evans blue dye contents at all airway levels measured. Additionally, inhaled wood smoke produced submucosal edema of the trachea and bronchus, and peribronchial edema. These acute airway responses were nearly abolished by pretreatment with CP-96,345 alone [a tachykinin NK(1) receptor antagonist; (2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyc lo( 2.2.2.)-octan-3-amine] or with a combination of CP-96,345 and dimethylthiourea (a hydroxyl radical scavenger), and were attenuated by pretreatment with dimethylthiourea alone, yet were not affected by pretreatment with SR-48,968 [a tachykinin NK(2) receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl)benzamide], with a combination of CP-96,344 and SR-48,965 (inactive enantiomers), with MK-886 [a leukotriene biosynthesis inhibitor; L-663, 536(3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl)-2, 2-dimethylpropanoic acid], with indomethacin (a cyclooxygenase inhibitor), or with N(G)-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor). The activity of airway neutral endopeptidase (an enzyme for tachykinin degradation) was not influenced by wood smoke at 5-min post-exposure. We conclude that both endogenous tachykinins and hydroxyl radical play an important role in producing smoke-induced acute airway plasma exudation and airway edema in guinea pigs. The contribution of tachykinins to these neurogenic responses is mediated via the activation of tachykinin NK(1) receptors and partly via a hydroxyl radical mechanism, and is not associated with inactivation of neutral endopeptidase.

Animals↗

PubMed2000

Laryngeal C-fiber afferents are not involved in the apneic response to laryngeal wood smoke in anesthetized rats.

Laryngeal exposure to wood smoke in rats evokes a reflex apnea which is mediated through superior laryngeal afferents (J. Appl. Physiol. 83: 723-730, 1997). To study the role of laryngeal C-fiber afferents in eliciting this response, capsaicin aerosol (0.05 - 0.2 microg/ml) and 5 ml of wood smoke were delivered separately into a functionally isolated larynx of anesthetized Sprague-Dawley rats at a constant flow rate of 1.4 ml/s, while animals breathed spontaneously. Studies were repeated after either an intravenous injection of ruthenium red (2 mg/kg; n = 8), a perineural capsaicin treatment (200 microg/ml for 5 min; n = 8) of the superior laryngeal nerves, or a perineural sham treatment (n = 8); Ruthenium red inhibits the stimulation of afferent C-fiber nerve endings by capsaicin, whereas perineural capsaicin treatment selective blocks the conduction of C-fiber afferents. Either ruthenium red or perineural capsaicin treatment abolished the apneic response to laryngeal capsaicin, but did not significantly affect the apneic response to laryngeal wood smoke. Furthermore, the apneic responses to both types of irritants were not significantly altered by perineural sham treatment, yet were completely eliminated by a subsequent denervation of superior laryngeal nerves. Our results suggest that superior laryngeal C-fiber afferents are not involved in eliciting the reflex apneic response to laryngeal wood smoke in anesthetized rats. It is speculated that this response may result mainly from the stimulation of myelinated afferents, possibly laryngeal irritant receptors.

Aerosols↗

PubMed2000

Wood smoke-induced airway hyperreactivity in guinea pigs: time course, and role of leukotrienes and hydroxyl radical.

A prior airway exposure to wood smoke induces a tachykinin-dependent increase in airway responsiveness to the subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998). To further investigate the time course of, and the contribution of other chemical mediators to, this smoke-induced airway hyperresponsiveness (SIAHR), two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a respirator. In the control animals, the SIAHR was evidenced by the bronchoconstrictive response to the second smoke challenge (SM2) which was approximately 5.2-fold greater than that to the first challenge (SM1). This SIAHR was alleviated by shortening the elapsed time between SM1 and SM2 to 10 min or by extending it to 60 min, and was abolished by extending it to 120 min. This SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D4-receptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H1-receptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke-induced reduction in the neutral endopeptidase activity (a major enzyme for tachykinin degradation) measured in airway tissues excised 30 min post SM1 was largely prevented by pretreatment with dimethylthiourea. However, this reduction was not seen in airway tissues excised 120 min post SM1. These results suggest that 1) the SIAHR to inhaled wood smoke has a rapid onset time following smoke inhalation and lasts for less than two hours, 2) leukotrienes and hydroxyl radical may play contributory roles in the development of this SIAHR, and 3) hydroxyl radical is the major factor responsible for the smoke-induced inactivation of airway neutral endopeptidase, which may possibly participate in the development of this SIAHR.

Animals↗

PubMed2000

Involvement of substance P in neutral endopeptidase modulation of carotid body sensory responses to hypoxia.

Previously, we showed that carotid bodies express neutral endopeptidase (NEP)-like enzyme activity and that phosphoramidon, a potent inhibitor of NEP, potentiates the chemosensory response of the carotid body to hypoxia in vivo. NEP has been shown to hydrolyze methionine enkephalin (Met-Enk) and substance P (SP) in neuronal tissues. The purpose of the present study is to determine whether NEP hydrolyzes Met-Enk and SP in the carotid body and if so whether these peptides contribute to phosphoramidon-induced potentiation of the sensory response to hypoxia. Experiments were performed on carotid bodies excised from anesthetized adult cats (n = 72 carotid bodies). The hydrolysis of Met-Enk and SP was analyzed by HPLC. The results showed that both SP and Met-Enk were hydrolyzed by the carotid body, but the rate of Met-Enk hydrolysis was approximately fourfold higher than that of SP. Phosphoramidon (400 microM) markedly inhibited SP hydrolysis ( approximately 90%) but had only a marginal effect on Met-Enk hydrolysis ( approximately 15% inhibition). Hypoxia (PO(2), 68 +/- 6 Torr) as well as exogenous administration of SP (10 and 20 nmol) increased the sensory discharge of the carotid body in vitro. Sensory responses to hypoxia and SP (10 nmol) were potentiated by approximately 80 and approximately 275%, respectively (P < 0.01), in the presence of phosphoramidon. SP-receptor antagonists Spantide (peptidyl) and CP-96345 (nonpeptidyl) either abolished or markedly attenuated the phosphoramidon-induced potentiation of the sensory response of the carotid body to hypoxia as well as to SP. These results demonstrate that SP is a preferred substrate for NEP in the carotid body and that SP is involved in the potentiation of the hypoxic response of the carotid body by phosphoramidon.

Animals↗

PubMed2000

Protective and defensive airway reflexes evoked by nasal exposure to wood smoke in anesthetized rats.

We investigated the airway responses evoked by nasal wood smoke in anesthetized Sprague-Dawley rats. Wood smoke (5 ml, 1.4 ml/s) was delivered into an isolated nasal cavity while animals breathed spontaneously. In study 1, nasal wood smoke triggered either an apneic response (n = 26) or a sniff-like response (n = 16) within 1 s after smoke exposure in 42 normal rats. Both airway responses were abolished by trigeminal nerve denervation and by nasal application of a local anesthetic or a hydroxyl radical scavenger, but they were not significantly affected by removal of smoke particulates or nasal application of a saline vehicle. In study 2, nasal wood smoke only triggered a mild apneic response in two rats neonatally treated with capsaicin and had no effect on breathing in the other six; the treatment is known to chronically ablate C fibers and some Adelta fibers. In contrast, nasal wood smoke evoked an apneic response in six rats neonatally treated with the vehicle of capsaicin and elicited a sniff-like response in the other two. These results suggest that the apneic and sniff-like responses evoked by nasal wood smoke result from the stimulation of trigeminal nasal C-fiber and Adelta-fiber afferents by the gas-phase smoke and that hydroxyl radical is the triggering chemical factor.

Animals↗

PubMed2000

Vagal and mediator mechanisms underlying the tachypnea caused by pulmonary air embolism in dogs.

We investigated the vagal and mediator mechanisms underlying the tachypnea caused by pulmonary air embolism (PAE) in anesthetized and spontaneously breathing dogs. PAE was induced by infusion of air into the right atrium (0.2 ml. kg(-1). min(-1) for 10 min). The first PAE induction caused an increase in respiratory frequency accompanied by a decrease in tidal volume in each of the 30 animals studied. Subsequently, animals were evenly divided into five groups, and a second PAE induction was repeated after various experimental interventions. The tachypneic response to PAE was not significantly altered by pretreatment with a saline vehicle but was largely attenuated by either perivagal capsaicin treatment (a technique that selectively blocks the conduction of unmyelinated C fibers), pretreatment with ibuprofen (a cyclooxygenase inhibitor), or pretreatment with dimethylthiourea (a hydroxyl radical scavenger). Ultimately, the tachypneic response was nearly abolished by a bilateral cervical vagotomy. These results suggest that 1) lung vagal unmyelinated C-fiber afferents play a predominant role in evoking the reflex tachypneic response to PAE and 2) both cyclooxygenase products and hydroxyl radical are important in eliciting this vagally mediated response.

Animals↗

PubMed1999

Two subgroups of lung vagal C-fibers with different vulnerabilities to blockades by perivagal capsaicin and vagal cooling in dogs.

Perivagal capsaicin treatment and vagal cooling are two techniques that have been widely used to study the respiratory reflexes mediated by lung vagal C-fibers because they can block the neural conduction of unmyelinated fibers. We hypothesized that there are two subgroups of lung vagal C-fibers which have different vulnerabilities to blockades by these two techniques. To test this hypothesis, afferent activity arising from lung vagal C-fibers was recorded in 29 anesthetized, paralyzed, and artificially ventilated dogs. Afferent C-fiber activity was recorded before and after various concentrations of perivagal capsaicin treatment or before and during various temperatures of vagal cooling. Of the 89 lung vagal C-fibers studied, 73 fibers were classified as the group of "low resistance" to capsaicin, while the other 16 were classified as the group of "high resistance". The former group differed from the latter due to their afferent activity being blocked at relatively low concentrations of perivagal capsaicin and at relatively low temperatures of vagal cooling. Our results suggest that lung vagal C-fibers can be categorized into two subgroups, based upon their different blocking thresholds for perivagal capsaicin and vagal cooling. Our data may provide information for researchers to further differentiate the respiratory reflexes originating from these two subgroups of lung vagal C-fibers.

Animals↗

PubMed1999

Neonatal capsaicin treatment alters immediate ventilatory responses to inhaled wood smoke in rats.

Neonatal capsaicin treatment chronically ablates unmyelinated C fibers, yet also destroys a small amount of myelinated fibers. Inhalation of wood smoke evokes respiratory reflexes resulting from stimulation of both lung C-fiber nerve endings (unmyelinated afferents) and irritant receptors (myelinated afferents). This study investigated the influences of neonatal capsaicin treatment on the immediate ventilatory responses to inhaled wood smoke in adult rats. Inhalation of wood smoke (approximately 6 ml) via a tracheostomy immediately triggered only an augmented inspiration in 16 rats neonatally treated with capsaicin (50 mg/kg, subcutaneous injection). In contrast, inhaled wood smoke evoked a slowing of respiration in 11 neonatal vehicle-treated rats and an augmented inspiration in another five. The inability to exhibit the slowing of respiration and the persistence of the augmented inspiration in capsaicin-treated rats are consistent with our hypothesis that these two reflex responses originate from stimulation of lung vagal C-fiber afferents and irritant receptors, respectively. Since all capsaicin-treated rats responded to smoke with an augmented inspiration, it is further suggested that neonatal capsaicin treatment selectively impairs the reflex functions of C-fiber afferents and well preserves the reflex functions of lung irritant receptors.

Animals↗

PubMed1999

Abdominal weight and inspiratory resistance: their immediate effects on inspiratory muscle functions during maximal voluntary breathing in chronic tetraplegic patients.

OBJECTIVE: To study the immediate effects of maximal voluntary (MV) breathing, with and without abdominal weight (AW) or inspiratory resistance (IR), on inspiratory muscle functions in chronic tetraplegic patients. DESIGN: A crossover trial design. SETTING: Rehabilitation department of a university hospital. PARTICIPANTS: Nine tetraplegic men injured at the C4 to T1 levels, with a mean duration of injury of 72.8 months. INTERVENTIONS: Each subject performed MV breathing without and with AW load (AWMV breathing) and IR load (IRMV breathing) separately. MAIN OUTCOME MEASURES: Electromyographic (EMG) activity of the inspiratory muscles, mouth pressure, inspiratory flow, and inspiratory volume. RESULTS: AWMV breathing evoked greater diaphragmatic EMG activity, inspiratory flow, and inspiratory volume than did IRMV breathing, although the increase of diaphragmatic EMG activity was not statistically significant. Conversely, IRMV breathing produced greater sternocleidomastoid EMG activity and negative mouth pressure than did AWMV breathing. Both AWMV and IRMV breathing evoked greater inspiratory muscle EMG activity than did MV breathing. CONCLUSION: AW and IR loads have differential immediate effects on the inspiratory muscle functions during MV breathing in patients with chronic tetraplegia, suggesting that these two breathing maneuvers may have dissimilar mechanisms of training in such patients. The muscle EMG activity evoked during MV breathing with AW or IR is greater than that without a mechanical load, implying that mechanically loaded training in tetraplegic patients results in load compensatory adjustments via their respiratory motor output to improve respiratory function.

Abdomen↗

PubMed1998

Acetylcholine and tachykinin receptor antagonists attenuate wood smoke-induced bronchoconstriction in guinea pigs.

To study the mechanisms of wood smoke-induced bronchoconstriction, we measured total lung resistance (RL) and dynamic lung compliance (Cdyn) in anesthetized and mechanically ventilated guinea pigs. Airway exposure to various doses of wood smoke (lauan wood; 5, 10, and 15 breaths) resulted in a dose-dependent increase in RL and decrease in Cdyn. The smoke-induced changes in RL and Cdyn were significantly attenuated by pretreatment with atropine, CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine; a tachykinin NK1 receptor antagonist], and SR-48,968 [(S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl)-butyl)benzamide; a tachykinin NK2 receptor antagonist] in combination, atropine alone, and SR-48,968 alone, but were not significantly affected by pretreatment with the inactive enantiomers of CP-96,345 and SR-48,968, CP-96,345 alone, indomethacin (a cyclooxygenase inhibitor), and MK-571 [((3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl((3-dimethyl amino-3-oxo-propyl)thio)methyl)propanoic acid; a leukotriene D4 receptor antagonist]. The activity of airway neutral endopeptidase, a major enzyme for tachykinin degradation, was not significantly influenced by wood smoke during the development of bronchoconstriction. We conclude that: (1) both cholinergic mechanisms and endogenous tachykinins, but not cyclooxygenase products or leukotriene D4, play an important role in the acute bronchoconstriction induced by wood smoke, and (2) the contribution of tachykinins to this airway response is primarily mediated via the activation of tachykinin NK2 receptors, but is not associated with inactivation of the airway neutral endopeptidase.

Animals↗

PubMed1998

Stimulation of pulmonary rapidly adapting receptors by inhaled wood smoke in rats.

1. The stimulation of pulmonary rapidly adapting receptors (RARs) by wood smoke was investigated. Impulses from seventy RARs were recorded in fifty-nine anaesthetized, open-chest and artificially ventilated rats; responses to delivery of 6 ml of wood smoke into the lungs were studied in sixty-one receptors whereas responses to histamine (10 or 100 microg kg-1, i.v.) were studied in the other nine. 2. Delivery of wood smoke stimulated fifty-two of the sixty-one RARs studied. When stimulated, an intense burst of discharge was evoked within 1 or 2 s of smoke delivery. This increased activity quickly peaked in 1-3 s (Delta = 15.8 +/- 1.6 impulses s-1; n = 61; mean +/- s.e.m.), then declined and yet remained at a level higher than the baseline activity. The mean duration of the stimulation was 25.1 +/- 2.7 s. In contrast, smoke delivery did not affect tracheal pressure. 3. Peak responses of RARs to wood smoke were partially reduced by removal of smoke particulates and were largely attenuated by pretreatment with dimethylthiourea (DMTU, a hydroxyl radical scavenger), indomethacin (Indo, a cyclo-oxygenase inhibitor), or both DMTU and Indo (DMTU + Indo). Conversely, the peak responses of RARs were not significantly affected by pretreatment with isoprenaline (a bronchodilator) or vehicle for these chemicals. Additionally, pretreatment with DMTU, Indo, or DMTU + Indo did not significantly alter the RAR sensitivity to mechanical stimulation (constant-pressure lung inflation; 20 cmH2O). 4. Of the nine RARs tested, six were stimulated by histamine and their sensitivity to this chemical irritant was not altered by pretreatment with DMTU + Indo. 5. The results suggest that both the particulates and gas phases are responsible for, and both the hydroxyl radical and cyclo-oxygenase products are involved in, the stimulation of RARs by wood smoke. Furthermore, changes in lung mechanics following smoke delivery are not the cause of this afferent stimulation.

Animals↗

PubMed1998

Smoke-induced airway hyperresponsiveness to inhaled wood smoke in guinea pigs: tachykininergic and cholinergic mechanisms.

The smoke-induced airway hyperresponsiveness (SIAHR) to inhaled wood smoke was investigated in anesthetized guinea pigs. Two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs by a respirator. In control animals, SIAHR was evidenced by an average bronchoconstrictive response (an increase in total lung resistance) to the second smoke challenge (SM2) that was approximately 4.3-fold greater than that to the first challenge (SM1). Pretreatment with CP-96,345 and SR-48,968 (neurokinin-1 and -2 receptor antagonists; each 1 mg/kg) in combination totally prevented this SIAHR, while pretreatment with CP-96,344 and SR48,965 (inactive enantiomers of CP-96,345 and SR-48,968, each 1 mg/kg) in combination failed to do so. Pretreatment with CP-96,345 (1 mg/kg), SR48,968 (1 mg/kg), or atropine (50 microg/kg) significantly alleviated this SIAHR. Pretreatment with phosphoramidon [an inhibitor of neutral endopeptidase (NEP); 2 mg/kg], which suppresses the degradation of tachykinins, induced an increase in airway reactivity that largely mimicked this SIAHR. The NEP activity measured in airway tissues excised 30 min after SM1 was significantly lower than that in air control value. These results suggest that 1) a prior wood smoke exposure induces an airway hyperresponsiveness to the subsequent wood smoke inhalation, 2) a tachykininergic mechanism involving both neurokinin-1 and -2 receptors is essential for, and a cholinergic mechanism is also involved in the development of this SIAHR, and 3) inactivation of airway NEP by wood smoke may contribute to this SIAHR.

Airway Resistance↗

PubMed1998

Carotid body I1-imidazoline receptors: binding, visualization and modulatory function.

The carotid body is influenced by many neurotransmitter receptors. A novel receptor specific for imidazolines has been implicated in cardiorespiratory regulation in the brain. To test for both I1-imidazoline and alpha2-adrenergic receptors, which also recognize imidazolines, specific [125I]p-iodoclonidine binding to carotid body membranes was characterized. The specific alpha2-agents epinephrine (100 microM) or SK&F 86466 (10 microM) inhibited only a portion of specific [125I]p-iodoclonidine binding in both cat and rabbit carotid bodies, indicating the presence of I1-imidazoline as well as alpha2-adrenergic sites. The distribution of [125I]p-iodoclonidine binding sites was visualized autoradiographically. The cat carotid body was intensely labeled by [125I]p-iodoclonidine, with both I1-imidazoline and alpha2-adrenergic sites expressed. The relevance of I1-imidazoline receptors in modulation of chemosensory discharge was determined in seven cats after alpha2-adrenergic blockade. Clonidine (100 microg/kg) facilitated chemosensory activity particularly under hypoxia. We conclude that I1-imidazoline receptors are expressed within the carotid body and may potentiate chemosensory discharge, in contrast to the inhibitory action of alpha2-adrenergic receptors.

Adrenergic alpha-Agonists↗

PubMed1998

Peripheral neural modulation of endotoxin-induced hyperventilation.

OBJECTIVE: To delineate the role of the peripheral neural reflexes involved in modulating hyperventilation during endotoxemia. DESIGN: A prospective, randomized, controlled, multigroup study. SETTING: Research animal laboratory. SUBJECTS: Adult Sprague-Dawley rats (n=43; 354+/-24 g) of either gender. INTERVENTIONS: Eight rats received a sham operation on their vagus, carotid sinus, and aortic nerves before the administration of a saline vehicle to serve as the time control. In the endotoxin group, 11 rats received a sham operation before endotoxin challenge. The remaining 24 rats received bilateral vagotomy (n=8), perivagal capsaicin treatment (n=8), or denervation of peripheral chemoreceptors (n=8) before endotoxin challenge. After the breathing pattern returned to a steady state, endotoxin (L-4130, serotype 0111, B4 lipopolysaccharide; 50 mg/kg) was injected into the vein. The rat's respiration was then monitored continuously for 5 hrs or until the animal died. MEASUREMENTS AND MAIN RESULTS: The respiratory rate and tidal volume did not change over the 5-hr observation period in the time control group. In the endotoxin group, the respiratory rate increased significantly from baseline (135.4%) 2 hrs after endotoxin challenge and increased persistently until the rats died. The tidal volume increased gradually to < or =132.8% of baseline 4 hrs after endotoxin challenge. Bilateral cervical vagotomy and perineural capsaicin treatment of the vagus nerves eliminated the tachypnea response to endotoxin injection. Denervation of the peripheral chemoreceptor accentuated the hyperventilation response to endotoxin, and resulted in the shortest survival time. CONCLUSIONS: Both lung vagal C-fiber afferents and peripheral chemoreceptors are involved in modulating the hyperventilation response after endotoxin challenge in rat models. Stimulation of vagal C-fiber afferents increased the respiratory rate. Conversely, the role of peripheral chemoreceptors was to restrain the hyperventilatory response and these receptors may play a protective role during endotoxemia.

Animals↗