Pentobarbital enhances GABAergic neurotransmission to cardiac parasympathetic neurons, which is prevented by expression of GABA(A) epsilon subunit.
BACKGROUND
Pentobarbital decreases the gain of the baroreceptor reflex on the order of 50%, and this blunting is caused nearly entirely by decreasing cardioinhibitory parasympathetic activity. The most likely site of action of pentobarbital is the gamma-aminobutyric acid type A (GABA(A)) receptor. The authors tested whether pentobarbital augments the inhibitory GABAergic neurotransmission to cardiac parasympathetic neurons, and whether expression of the GABA(A) epsilon subunit prevents this facilitation.


METHODS
The authors used a novel approach to study the effect of pentobarbital on identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the nucleus ambiguus were retrogradely prelabeled with a fluorescent tracer and were visually identified for patch clamp recording. The effects of pentobarbital on spontaneous GABAergic synaptic events were tested. An adenovirus was used to express the epsilon subunit of the GABA(A) receptor in cardiac parasympathetic neurons to examine whether this transfection alters pentobarbital-mediated changes in GABAergic neurotransmission.


RESULTS
Pentobarbital increased the duration but not the frequency or amplitude of spontaneous GABAergic currents in cardiac parasympathetic neurons. Transfection of cardiac parasympathetic neurons with the epsilon subunit of the GABA(A) receptor prevented the pentobarbital-evoked facilitation of GABAergic currents.


CONCLUSIONS
Pentobarbital, at clinically relevant concentrations, prolongs the duration of spontaneous inhibitory postsynaptic currents that impinge on cardiac parasympathetic neurons. This action would augment the inhibition of cardiac parasympathetic neurons, reduce parasympathetic cardioinhibitory activity, and increase heart rate. Expression of the GABA(A) receptor epsilon subunit in cardiac parasympathetic neurons renders the GABA receptors insensitive to pentobarbital.
Irnaten
Mustapha
M
Department of Pharmacology, George Washington University, Washington, DC 20037, USA.
Walwyn
Wendy M
WM
Wang
Jijiang
J
Venkatesan
Priya
P
Evans
Cory
C
Chang
Kyoung S K
KS
Andresen
Michael C
MC
Hales
Tim G
TG
Mendelowitz
David
D
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005822:Genetic Vectors; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital