ReviewIbuprofen blocks time-dependent increases in hypoxic ventilation in rats☆
Introduction
Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation during chronic sustained hypoxia (Powell et al., 1998). Several laboratories have demonstrated that this involves increased O2-sensitivity of carotid body chemoreceptors resulting in increased afferent input to ventilatory chemoreflexes for a given arterial after chronic hypoxia (reviewed by Powell, 2007). Additionally, we have shown time-dependent changes in the central nervous system (CNS) processing of carotid body chemoreceptor input resulting in a greater respiratory motor output for a given afferent input (Dwinell and Powell, 1999). Plasticity in the carotid body-ventilatory chemoreflex with chronic hypoxia involves changes in neurotransmitters and ion channels in the carotid bodies and CNS (reviewed by Powell, 2007), and changes in gene expression controlled by Hypoxia Inducible Factor 1, HIF-1 (Kline et al., 2002, Powell and Fu, 2008).
Recently, inflammatory processes have been shown to be important for the increased O2-sensitivity of carotid bodies with chronic sustained hypoxia (Liu et al., 2009). Using an in vitro rat carotid body preparation, these investigators showed that chronic sustained hypoxia increases the frequency of action potentials recorded in the carotid sinus nerve when is lowered in a solution superfusing the carotid body. They also found increased mRNA expression for inflammatory cytokines in carotid bodies from chronically hypoxic rats. The increased cytokine expression, as well as the increased carotid body neural response to acute hypoxia, was blocked by ibuprofen and dexamethasone treatment during the chronic hypoxia.
To test the physiological significance of these inflammatory signals for plasticity in chronically hypoxic carotid bodies, we studied the effects of a nonsteroidal anti-inflammatory drug, ibuprofen, on ventilatory acclimatization to hypoxia in conscious rats. Also, we measured the effects of chronic hypoxia and ibuprofen on cytokine expression in the CNS. Ibuprofen decreased ventilatory acclimatization to hypoxia and cytokine gene expression in the CNS, providing evidence that inflammatory signaling in the CNS contributes to ventilatory acclimatization to hypoxia.
Section snippets
Experimental animals
Adult, male rats (Sprague–Dawley, Charles River) were housed in standard rat cages in a vivarium, with a 12:12-h light–dark cycle and fed a standard rat diet ad libitum. All experiments were approved by the University of California, San Diego, Animal Care and Use Committee. The experiments conformed to national standards for the care and use of experimental animals as well as the American Physiological Society's “Guiding Principles in the Care and Use of Animals.” At the end of an experiment,
Ventilatory response to hypoxia
In normoxic rats, ibuprofen had no effect on ventilation () or its components, frequency and tidal volume (fR and VT, respectively), breathing normoxic or hypoxic gas (Fig. 1). Chronic hypoxia increased in saline treated rats breathing normoxic and hypoxic gas, as expected for ventilatory acclimatization to sustained hypoxia. Ibuprofen had no effect on the persistent hyperventilation in chronically hypoxic rats breathing normoxic gas but ibuprofen blocked the increase in breathing
Discussion
The results showed an effect of ibuprofen on ventilation during hypoxia in chronically hypoxic rats but not normoxic rats (Fig. 1). However, there were no significant effects of ibuprofen on ventilation in rats breathing normoxic or hypercapnic gas before or after acclimatization to chronic hypoxia. Hence, the data indicate that the previously demonstrated effect of ibuprofen to block the time-dependent increase in carotid body discharge with chronic hypoxia (Liu et al., 2009) is
Acknowledgments
This study was supported by RO1 HL 081823, 1P01 HL 098053 and White Mountain Research Station. The authors would like to thank Drs. Moh Malek and Sue Hopkins, for their assistance with statistical analysis and Drs. Kechun Tang and Ellen Breen for their assistance with the ctyokine expression measurements.
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2020, Respiratory Physiology and NeurobiologyCitation Excerpt :Among the similarities, neonatal rats exhibited greater mass-specific ventilation after their return to normoxia. Persistent hyperpnea / hyperventilation in normoxia is also a hallmark of ventilatory acclimatization in adult mammals (Teppema and Dahan, 2010), including in adult rats exposed to normobaric or hypobaric CH (e.g., (Olson and Dempsey, 1978; Popa et al., 2011)). However, mass-specific ventilation is typically increased at all inspired Po2 in adult mammals after CH and the acute HVR (i.e., the slope of the response) tends to be increased as well (Teppema and Dahan, 2010; Pamenter and Powell, 2016); these changes are obvious after one week of CH in adult rats (Olson and Dempsey, 1978; Popa et al., 2011).
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This paper is part of a special issue entitled “Inflammation and Cardio-Respiratory Control”, guest-edited by Frank L. Powell and Yu Ru Kou.