Transient ventilatory responses to endotoxin infusion in the cat are mediated by thromboxane A2

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

doi:10.1016/0034-5687(93)90005-u

Cited by 19 publications

(9 citation statements)

References 15 publications

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“…We have previously shown that activation of this respiratory reflex caused rapid shallow breathing or apnoea (Shams & Scheid, 1990;Karla et al, 1992;Orr et al, 1993). Our present results clearly demonstrate that LVDP not only reduced the activity of a single fibre in response to PBG but also diminished or even abolished the overall stimulation of C-fibres causing apnoea.…”

Section: Discussionsupporting

confidence: 71%

Effects of levodropropizine on vagal afferent C‐fibres in the cat

Shams

Daffonchio

Scheid

1996

British J Pharmacology

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1 Levodropropizine (LVDP) is an effective antitussive drug. Its effects on single-unit discharge of vagal afferent C-fibres were tested in anaesthetized cats to assess whether an inhibition of vagal C-fibres is involved in its antitussive properties. Vagal C-fibres, identified by their response to phenylbiguanide (PBG), were recorded via suction electrodes from the distal part of the cut vagus. Based on their response to lung inflation, C-fibres were classified as pulmonary (19 fibres) or non-pulmonary (6 fibres). 2 PBG increased the discharge rate of both C-fibre types and activated a respiratory reflex causing apnoea. This reflex was abolished when the second vagus nerve was cut as well, while PBG-mediated stimulation of the C-fibres was not affected by vagotomy. 3 LVDP was administered intravenously and the C-fibre response to PBG was compared with that before administration of the drug. LVDP reduced both the duration of apnoea and the response of the C-fibre to PBG. 4 Comparison of the C-fibre responses to PBG and to a mixture of PBG and LVDP revealed that the period of apnoea was shortened and the discharge rate of the C-fibre reduced when LVDP was present. 5 The LVDP-induced inhibition of the C-fibre response to PBG was on average 50% in pulmonary and 25% in non-pulmonary fibres. 6 These results suggest that LVDP significantly reduces the response of vagal C-fibres to chemical stimuli. It is, thus, likely that the antitussive effect of LVDP is mediated through its inhibitory action on C-fibres.

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Section: Discussionsupporting

confidence: 71%

Effects of levodropropizine on vagal afferent C‐fibres in the cat

Shams

Daffonchio

Scheid

1996

British J Pharmacology

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“…It has been reported that a 1-min infusion of E. coli endotoxin to adult cats resulted in an abrupt apnea followed by rapid shallow breathing, and this change in the breathing pattern was mediated by the release of thromboxane A 2 (2). Furthermore, a significant decrease in RR was observed after the administration of lipopolysaccharide to conscious adult rabbits (22).…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, the changes in the breathing pattern observed during E. coli infusion to adult cats were eliminated in the animals pretreated with indomethacin or thromboxane A 2 receptor antagonist (2). On the other hand, it has been demonstrated that prostaglandins and NO may mediate the ventilatory depression observed during hypoxia in newborn animals (8,9).…”

mentioning

confidence: 99%

The Effect of Escherichia coli Endotoxin Infusion on the Ventilatory Response to Hypoxia in Unanesthetized Newborn Piglets

et al. 2003

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To determine the effects of endotoxemia on the neonatal ventilatory response to hypoxia, 17 chronically instrumented and unanesthetized newborn piglets (Յ7 d) were studied before and 30 min after the administration of Escherichia coli O55:B5 endotoxin (n ϭ 8) or normal saline (n ϭ 9). Minute ventilation, oxygen consumption, heart rate, arterial blood pressure, and blood gases were measured during normoxia and 10 min of hypoxia (fraction of inspired oxygen, 0.10). Basal ventilation was not modified by E. coli endotoxin infusion (mean Ϯ SE, 516 Ϯ 49 versus 539 Ϯ 56 mL/min/kg), but the ventilatory response to hypoxia was markedly attenuated at 1 min (955 Ϯ 57 versus 718 Ϯ 97 mL/min/kg, p Ͻ 0.002, saline versus endotoxin) and at 10 min (788 Ϯ 51 versus 624 Ϯ 66 mL/min/kg, p Ͻ 0.002). A larger decrease in oxygen consumption was observed during hypoxia and endotoxemia (6.3 Ϯ 2.8 versus 18.3 Ϯ 2.7%, p Ͻ 0.03, pre-versus post-endotoxin). A significant correlation was demonstrated between the changes in minute ventilation and oxygen consumption with hypoxia during endotoxemia (r ϭ 0.9, p Ͻ 0.002). The ventilatory response to hypoxia was not modified by the saline infusion. These data show a significant attenuation in the ventilatory response to hypoxia during E. coli endotoxemia. This decrease in ventilation was associated with a significant decrease in the metabolic rate during hypoxia and endotoxemia. Changes in the breathing pattern and apnea episodes are frequently associated with neonatal sepsis, especially in the preterm infant (1). It has also been observed that the administration of Escherichia coli endotoxin to anesthetized adult cats produced an abrupt apnea followed by transient rapid and shallow breathing (2). However, the mechanisms explaining these changes in breathing pattern are not clearly understood. Respiratory muscle fatigue, a decrease in lung compliance, and an increase in pulmonary resistance have been cited as possible mechanisms for the ventilatory changes observed during Gram-positive and -negative septicemia (3-6).It is well known that a variety of inflammatory mediators such as cytokines, prostaglandins, leukotrienes, and NO are released during sepsis or endotoxemia (3, 6, 7). Furthermore, the changes in the breathing pattern observed during E. coli infusion to adult cats were eliminated in the animals pretreated with indomethacin or thromboxane A 2 receptor antagonist (2). On the other hand, it has been demonstrated that prostaglandins and NO may mediate the ventilatory depression observed during hypoxia in newborn animals (8, 9). Therefore, the increased release of these inflammatory mediators may further depress the ventilatory response to hypoxia during E. coli endotoxemia.The increased circulating cytokines during sepsis or endotoxemia can induce a systemic inflammatory response involving the microvascular system and trigger hemodynamic changes (7, 10, 11). These changes result in maldistribution of blood flow to different organs, which may be accompanied by January 31, 2002; accepted Dec...

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“…[1][2][3][4][5][6][7][8] It is interesting to note that calcium channel blockers are first-choice drugs in the treatment of pulmonary hypertension. 23,42 The present results demonstrate that PKC translocation, K V channel inactivation, membrane depolarization, and L-type Ca 2ϩ channel activation are key events mediating TXA 2 -induced pulmonary vasoconstriction, establishing the rationale for the use of calcium channel blockers in pulmonary hypertension associated with increased vasoconstrictors such as TXA 2 and isoprostanes activating TP receptors.…”

Section: Cogolludo Et Al K V Channels and Pkc In Pulmonary Arteriesmentioning

confidence: 99%

“…In fact, TXA 2 has been involved in several forms of human and experimental pulmonary hypertension, including primary 2 and secondary pulmonary hypertension induced by sepsis, endotoxemia, heparin/protamine, leukotriene D 4 , microembolism, and ischemia-reperfusion. [3][4][5][6][7][8] TXA 2 contracts vascular smooth muscle by binding to specific G q/11 protein-coupled receptors (TP receptors), which leads to an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and sensitization of the contractile proteins to Ca 2ϩ . 9 -12 Activation of TP receptors is also involved in the vasoconstrictor effects of several isoprostanes, a novel class of arachidonic acid metabolites generated by oxygen free radical-mediated peroxidation of membrane phospholipids, used as markers for many disease states, including pulmonary hypertension.…”

mentioning

confidence: 99%

Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Cogolludo

Moreno

Boscá

et al. 2003

Circulation Research

136

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Abstract-Voltage-gated K ϩ channels (K V ) and thromboxane A 2 (TXA 2 ) play critical roles in controlling pulmonary arterial tone under physiological and pathological conditions. We hypothesized that TXA 2 might inhibit K V channels, thereby establishing a link between these two major pathogenic pathways in pulmonary hypertension. The TXA 2 analogue U46619 inhibited I K(V) (E max ϭ56.1Ϯ3.9%, EC 50 ϭ0.054Ϯ0.019 mol/L) and depolarized pulmonary artery smooth muscle cells via activation of TP receptors. In isolated pulmonary arteries, U46619 simultaneously increased intracellular Ca 2ϩ concentration and contractile force, and these effects were inhibited by nifedipine or KCl (60 mmol/L). U46619-induced contractions were not altered by the inhibitors of tyrosine kinase genistein or Rho kinase Y-27632 but were prevented by the nonselective protein kinase C (PKC) inhibitors staurosporine and calphostin C. Furthermore, these responses were sensitive to Gö-6983 but insensitive to bisindolylmaleimide I and Gö-6976. Based on the specificity of these drugs, we suggested a role for an atypical PKC in U46619-induced effects. Thus, treatment with a PKC pseudosubstrate inhibitor markedly prevented the vasoconstriction, the inhibition of I K(V) , and the depolarization induced by U46619. Western blots showed a transient translocation of PKC from the cytosolic to the particulate fraction on stimulation with U46619. These results indicate that TXA 2 inhibits I K(V) , leading to depolarization, activation of L-type Ca 2ϩ channels, and vasoconstriction of rat pulmonary arteries. We propose PKC as a link between TP receptor activation and K V channel inhibition.

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Transient ventilatory responses to endotoxin infusion in the cat are mediated by thromboxane A2

Cited by 19 publications

References 15 publications

Effects of levodropropizine on vagal afferent C‐fibres in the cat

Effects of levodropropizine on vagal afferent C‐fibres in the cat

The Effect of Escherichia coli Endotoxin Infusion on the Ventilatory Response to Hypoxia in Unanesthetized Newborn Piglets

Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

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Transient ventilatory responses to endotoxin infusion in the cat are mediated by thromboxane A2

Cited by 19 publications

References 15 publications

Effects of levodropropizine on vagal afferent C‐fibres in the cat

Effects of levodropropizine on vagal afferent C‐fibres in the cat

The Effect of Escherichia coli Endotoxin Infusion on the Ventilatory Response to Hypoxia in Unanesthetized Newborn Piglets

Thromboxane A 2 -Induced Inhibition of Voltage-Gated K + Channels and Pulmonary Vasoconstriction

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Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction