Effects of a novel benzodiazepine derivative, JM-1232(-), on human gastroepiploic artery in vitro.
OBJECTIVE
To investigate the effects of JM-1232(-) on norepinephrine (10(-6) mol/L)- and high K(+) (40 mmol/L)-induced contractions in isolated human gastroepiploic arteries (GEA), and to compare them with the effects of midazolam and propofol. In addition, to investigate whether the benzodiazepine-receptor antagonist, flumazenil, or μ-opioid-receptor antagonist, naloxone, influenced the vascular effects of JM-1232(-).


METHODS
An in vitro experimental study.


METHODS
University laboratory.


METHODS
GEA segments were used from 69 patients undergoing coronary artery bypass graft surgery.


RESULTS
JM-1232(-) produced dose-dependent relaxation effects in the rings. Although these effects of JM-1232(-) were greater than those of midazolam and propofol at high concentrations (10(-5)-10(-4) mol/L), there were no significantly different relaxation effects at the clinical concentrations of 3 × 10(-6) mol/L JM-1232(-), 3 × 10(-6) mol/L midazolam, and 1 × 10(-5) mol/L propofol. In addition, all these effects were independent of the presence of a functional endothelium. Vasorelaxation induced by JM-1232(-) on norepinephrine-preconstricted GEA was inhibited by flumazenil, but not by naloxone.


CONCLUSIONS
These results indicate that JM-1232(-) dose-dependently relaxes smooth muscle in human GEA, this effect being independent of the endothelium. Within the ranges of plasma concentrations achieved in clinical practice, JM-1232(-) had similar vasorelaxation effects to midazolam and propofol. JM-1232(-)-induced vasorelaxation was inhibited by flumazenil, indicating that JM-1232(-)-induced vasorelaxation occurred via peripheral benzodiazepine receptor activation in the GEA.
Moriyama
Takahiro
T
Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, Kagoshima, Japan. moriyama@kxa.biglobe.ne.jp
Tsuneyoshi
Isao
I
Kanmura
Yuichi
Y
D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D024405:Gastroepiploic Artery / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D054833:Isoindoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008874:Midazolam / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D018757:GABA Modulators; D054833:Isoindoles; D009292:Narcotic Antagonists; D010879:Piperazines; D014662:Vasoconstrictor Agents; D009270:Naloxone; D005442:Flumazenil; D008874:Midazolam; D011188:Potassium; D009638:Norepinephrine; D015742:Propofol