Drug interaction with gamma-aminobutyric acid/benzodiazepine receptors at the ventral surface of the medulla results in pronounced changes in cardiorespiratory activity.
Studies were carried out in chloralose-anesthetized cats while monitoring respiratory (tidal volume and respiratory rate) and cardiovascular (arterial pressure and heart rate) activity. Midazolam applied bilaterally to the intermediate area of the ventral surface of the medulla in doses of 0.75, 7.5 and 75 micrograms/side reduced tidal volume by -6 +/- 3, -10 +/- 1 and -11 +/- 1 ml, respectively. A dose of 250 micrograms/side produced apnea in each animal tested. Corresponding changes in arterial pressure were -35 +/- 9, -44 +/- 6, -43 +/- 9 and -64 +/- 17 mm Hg, respectively. Larger doses of chlordiazepoxide (e.g., 1000 micrograms/side) were required to produce similar effects. Intravenous administration of midazolam in doses of 1.5 to 150 micrograms had no significant effect on cardiorespiratory activity. However, larger doses of midazolam given i.v. produced cardiorespiratory depression that was similar to that observed with centrally applied drug. Pretreatment or treatment with centrally applied flumazenil or bicuculline counteracted the cardiorespiratory effects of centrally applied midazolam. Most importantly, ventral surface application of flumazenil counteracted the cardiorespiratory depressant effects of i.v. midazolam. Central administration of ethyl-beta-carboline-3-carboxylate produced cardiorespiratory effects opposite to those seen with midazolam, and these stimulatory effects were also counteracted by centrally applied flumazenil. These results indicate that alterations in cardiorespiratory activity can be produced by drugs interacting with gamma-aminobutyric acid/benzodiazepine receptors at the ventral surface of the medulla.
Gillis
R A
RA
Department of Pharmacology, Georgetown University Medical Center, Washington, District of Columbia.
Namath
I J
IJ
Easington
C
C
Abrahams
T P
TP
Guidotti
A
A
Quest
J A
JA
Hamosh
P
P
Taveira da Silva
A M
AM
D000494:Allosteric Regulation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology; D002415:Cats; D002707:Chlordiazepoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects*; D008874:Midazolam / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects*; D013618:Tachyphylaxis
D002243:Carbolines; D011963:Receptors, GABA-A; D002707:Chlordiazepoxide; D008874:Midazolam