Inhibition of protein kinase G activity protects neonatal mouse respiratory network from hyperthermic and hypoxic stress.

Abstract

In spite of considerable research attention focused on clarifying the mechanisms by which the mammalian respiratory rhythm is generated, little attention has been given to examining how this neuronal circuit can be protected from heat stress. Hyperthermia has a profound effect on neuronal circuits including the circuit that generates breathing in mammals. As temperature of the brainstem increases, respiratory frequency concomitantly rises. If temperature continues to increase respiratory arrest (apnea) and death can occur. Previous research has implicated protein kinase G (PKG) activity in regulating neuronal thermosensitivity of neuronal circuits in invertebrates. Here we examine if pharmacological manipulation of PKG activity in a brainstem slice preparation could alter the thermosensitivity of the fictive neonatal mouse respiratory rhythm. We report a striking effect following alteration of PKG activity in the brainstem such that slices treated with the PKG inhibitor KT5823 recovered fictive respiratory rhythm generation significantly faster than control slices and slices treated with a PKG activator (8-Br-cGMP). Furthermore, slices treated with 8-Br-cGMP arrested fictive respiration at a significantly lower temperature than all other treatment groups. In a separate set of experiments we examined if altered PKG activity could regulate the response of slices to hypoxia by altering the protective switch to fictive gasping. Slices treated with 8-Br-cGMP did not switch to the fictive gasp-like pattern following exposure to hypoxia whereas slices treated with KT5823 did display fictive gasping. We propose that PKG activity inversely regulates the amount of stress the neonatal mammalian respiratory rhythm can endure.

• Authors: Gary A B Armstrong, Juan J López-Guerrero, Ken Dawson-Scully, Fernando Peña, R Meldrum Robertson
• Journal: Brain research (Brain Res) Vol. 1311 Pg. 64-72 (Jan 22 2010) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 19945442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier B.V. All rights reserved.

Chemical References

• Carbazoles
• Protein Kinase Inhibitors
• KT 5823
• 8-bromocyclic GMP
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP

Topics

• Action Potentials
• Animals
• Animals, Newborn
• Brain Stem (drug effects, enzymology, physiopathology)
• Carbazoles (pharmacology)
• Cell Hypoxia (drug effects, physiology)
• Cyclic GMP (analogs & derivatives, pharmacology)
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Fever (drug therapy, enzymology, physiopathology)
• In Vitro Techniques
• Mice
• Mice, Inbred Strains
• Microelectrodes
• Neurons (drug effects, physiology)
• Periodicity
• Protein Kinase Inhibitors (pharmacology)
• Respiration (drug effects)
• Temperature