The influence of indomethacin on the ventilatory response to CO2 in newborn anaesthetized piglets.

Wolsink, J G; Berkenbosch, A.; DeGoede, J.; Olievier, C.N.

doi:10.1113/jphysiol.1994.sp020195

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…Such acute reductions in CBF-CO 2 sensitivity result in an elevation in V E-CO 2 sensitivity under steady-state testing conditions (221). Moreover, as recently discussed elsewhere (219,222), the direct influence of indomethacin on ventilation (32) (via inhibition of prostaglandins) or the carotid body (90,123,218) seems negligible, and recent findings at sea level indicate that indomethacin has no measurable effect on peripheral chemosensitivity in response to transient hypoxia, hypercapnia, or hyperoxia (P. N. Ainslie, unpublished data). This feature makes indomethacin an ideal tool for investigating the effect of CBF on the control of breathing in humans (see Fig.…”

Section: Integration Of Cerebrovascular Reactivity To Co2 and The Chementioning

confidence: 79%

Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Ainslie¹,

Duffin²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

489

513

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Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO(2) (Pa(CO(2))). This physiological response, termed cerebrovascular CO(2) reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO(2) from brain tissue, thereby attenuating the rise in central Pco(2), whereas hypocapnia causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of brain tissue Pco(2). Cerebrovascular reactivity and ventilatory response to Pa(CO(2)) are therefore tightly linked, so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO(2), primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupneic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, and exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO(2) that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude. In this review, we summarize the major factors that regulate CBF to emphasize the integrated mechanisms, in addition to Pa(CO(2)), that control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO(2). Next, we provide a detailed update on the integration of the role of cerebrovascular CO(2) reactivity and CBF in regulation of chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.

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Section: Integration Of Cerebrovascular Reactivity To Co2 and The Chementioning

confidence: 79%

Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Ainslie¹,

Duffin²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

489

513

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“…Our use of hyperoxia suppressed the peripheral chemoreceptor contribution to the ventilatory response to hypercapnia (Lahiri & DeLaney, 1975; Rodman et al 2001). Furthermore, indomethacin does not have a significant influence on the functional status of the carotid body (Wolsink et al 1994). Hence the finding that indomethacin also significantly increased the hyperoxic hypercapnic ventilatory response to about the same extent as with the normoxic CO 2 response indicates that the increased response was caused primarily by the effect of indomethacin on the environment of the central chemoreceptors.…”

Section: Discussionmentioning

confidence: 99%

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

Xie¹,

Skatrud

Morgan

et al. 2006

The Journal of Physiology

139

177

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An important determinant of [H(+)] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO(2) would lead to hyperventilation and an increased ventilatory responsiveness to CO(2). We used oral indomethacin to reduce the cerebrovascular reactivity to CO(2) and tested the steady-state hypercapnic ventilatory response to CO(2) in nine normal awake human subjects under normoxia and hyperoxia (50% O(2)). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 +/- 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05). Concomitantly, indomethacin administration also caused 40-60% increases in the slope of the mean ventilatory response to CO(2) in both normoxia (1.27 +/- 0.31 versus 1.76 +/- 0.37 l min(-1) mmHg(-1), P < 0.05) and hyperoxia (1.08 +/- 0.22 versus 1.79 +/- 0.37 l min(-1) mmHg(-1), P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO(2) is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.

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“…It has also been correlated with an increased number of central apneas in human neonates (18). Conversely, indomethacin, a drug that inhibits cyclooxygenase (COX) and thus prostaglandin synthesis, stimulates ventilation in both fetal and newborn animals (19,20).…”

mentioning

confidence: 99%

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

et al. 2003

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IL-1␤ has been proposed to be an important mediator linking infection, apnea, and sudden infant death syndrome. We hypothesized that IL-1␤ acts in this capacity by depressing brainstem respiratory neurons via a prostaglandin-dependent pathway. For studying the effects of IL-1␤ on respiration as well as the mechanism underlying its actions, 7-d-old rats received an initial injection (i.p.) of NaCl or a cyclooxygenase inhibitor (indomethacin, 10 mg/kg) followed by a second injection (i.p.) at 30 min of NaCl, recombinant rat IL-1␤ (10 g/kg), or lipopolysaccharide (LPS; 100 g/kg). Respiration during normoxia and in response to anoxia (100% N 2 ) was examined at 60 min after the second injection using flow and barometric plethysmography. Animals given IL-1␤ breathed more slowly and died more often after anoxia. LPS also reduced the rats' ability to autoresuscitate and survive an anoxic challenge. Indomethacin prevented the depressive effects during normoxia and the adverse effects on survival. For investigating drug-induced changes in central respiratory activity, IL-1␤ (1.0 or 1.25 ng/mL) and prostaglandin E 2 (5 or 20 g/L) was applied to the brainstem-spinal cord preparation of 0-to 4-d-old rats. Whereas IL-1␤ exerted no effect on respiration measured at the C4 ventral root during a 60-min period, prostaglandin E 2 reversibly inhibited respiratory activity. These findings suggest that IL-1␤ does not inhibit respiratory neurons directly but may depress breathing and hypoxic defense via a prostaglandin-mediated mechanism. Abbreviations BBB, blood-brain barrier COX-2, cyclooxygenase-2 f R , respiratory frequency LPS, lipopolysaccharide NTS, nucleus of the solitary tract PGE 2 , prostaglandin E 2 RVLM, rostral ventrolateral medulla Infection, hypoxia, and apnea each have been implicated in the pathogenesis of sudden infant death syndrome, and it has been postulated that the proinflammatory cytokine IL-1␤ may serve as the critical link between them (1, 2). IL-1␤ is released during an acute-phase immune response and subsequently induces multiple effects within the CNS, including the initiation of fever, sleep, and neuropeptide release [for review, see (3)]. Previous studies indicated that this immunomodulator may also alter respiration and autoresuscitation, yet the mechanism underlying such effects must be further elucidated (4 -7). Systemic administration of IL-1␤ has been shown to induce time-and dose-dependent expression of early immediate genes in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), both of which contain neurons important for respiratory control and the latter houses the central pattern generator for breathing (8,9). Because of its size and lipophilic properties, IL-1␤ does not diffuse readily across the blood-brain barrier (BBB) (10). However, IL-1␤ may still communicate with the brain across the BBB via active transport passage, through circumventricular organs, vagal afferent stimulation, and via second messenger induction at the BBB [for review, see (11)].We propose ...

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The influence of indomethacin on the ventilatory response to CO2 in newborn anaesthetized piglets.

Cited by 5 publications

References 15 publications

Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

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The influence of indomethacin on the ventilatory response to CO2 in newborn anaesthetized piglets.

Cited by 5 publications

References 15 publications

Integration of cerebrovascular CO2reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Integration of cerebrovascular CO2reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

IL-1β Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats

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Product

Resources

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Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Integration of cerebrovascular CO₂reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation