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J Appl Physiol 87: 363-369, 1999;
8750-7587/99 $5.00
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Vol. 87, Issue 1, 363-369, July 1999

Tyrosine kinase inhibitors modulate the ventilatory response to hypoxia in the conscious rat

Marc A. Czapla1, Narong Simakajornboon1, Gregory A. Holt3, and David Gozal1,2

1 Departments of Pediatrics and Physiology, Constance S. Kaufman Pediatric Pulmonary Research Laboratory, and 2 Neuroscience Training Program, Tulane University School of Medicine, New Orleans, Louisiana 70112; and 3 Department of Cardiorespiratory Science, School of Allied Health, Florida A&M University, Tallahassee, Florida 32307

Tyrosine kinases (TKs) exert multiple regulatory roles in neuronal activity and synaptic plasticity and could be involved in modulation of cardiovascular and respiratory control mechanisms within the dorsocaudal brain stem. To study this issue, the cardioventilatory responses to 1-µl microinjection within the dorsocaudal brain stem of either vehicle (Veh), the inactive TK inhibitor analog tyrphostin A1 (A1; 1 mM), or the active TK inhibitors genistein (Gen; 10 mM) and tyrphostin A25 (A25; 1 mM) were assessed by whole body plethysmography in unrestrained Sprague-Dawley adult rats. No changes in minute ventilation, heart rate, or mean arterial pressure occurred with Veh, A1, Gen, or A25 during room air breathing (P not significant). However, Gen and A25 attenuated the peak hypoxic ventilatory responses (HVR) to 10% O2 (P < 0.006 vs. Veh), whereas A1 did not modify HVR (P not significant). HVR reductions by Gen and A25 were primarily due to diminished respiratory frequency enhancements (P < 0.002). No changes in heart rate or mean arterial pressure responses occurred during hypoxia with TK inhibition. In addition, increases in tyrosine phosphorylation of the NR2A/B subunits, but not of the NR2C subunit, of the N-methyl-D-aspartate receptor occurred at 5, 30, and 60 min of hypoxia in the dorsocaudal brain stem and returned to baseline values at 120 min. We conclude that hypoxia induces tyrosine phosphorylation of the N-methyl-D-aspartate glutamate receptor, and TK inhibition within the dorsocaudal brain stem attenuates components of HVR in conscious rats.

respiratory regulation; second messengers; dorsal brain stem; ventilation; tyrosine kinases; signal transduction pathways


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