Inhibition by midazolam of the adrenergic function in the isolated canine mesenteric vein.
BACKGROUND
Midazolam has been reported to cause hypotension or to depress sympathetic activity following intravenous injection. However, little information is available concerning the mechanism of these effects. The aim of the present study was to determine the effects of midazolam on release of noradrenaline (NA) at nerve terminals and on receptors in the venous smooth muscle.


METHODS
The effect of midazolam at nerve terminals was examined by measuring the amount of NA release from superfused canine mesenteric vein helical strips during electrical stimulation (ES; 5 Hz, 2 ms, 9 V). The NA was quantified by high-performance liquid chromatography with electrochemical detection; tension development evoked by ES was also recorded simultaneously. In a separate series of experiments, ring preparations from the isolated vein were mounted in Krebs-Ringer solution for isometric tension recording to assess the effect of midazolam on alpha-adrenoceptors.


RESULTS
Application of tetrodotoxin (10(-6) M) or replacement of superfusate with Ca(2+)-free solution decreased both the release of NA and the tension development evoked by ES. Yohimbine (5 x 10(-8) M) increased the ES-evoked release of NA, whereas it decreased tension development in the vein strips. Midazolam (10(-4) M) did not affect either the basal release of NA or the basal tension, but inhibited both the NA release (P < 0.01) and the tension development (P < 0.01) during ES; midazolam at 10(-5) M inhibited the tension development (P < 0.05) but had no effect on NA release. In the ring preparations, midazolam (10(-5) and 10(-4) M) attenuated responses to NA (a mixed alpha 1- and alpha 2-adrenoceptor agonist, 10(-8) to 10(-3) M), phenylephrine (the alpha 1-adrenoceptor agonist, 10(-8) to 10(-3) M) and 5-bromo-6-[2-imidazolin-2yl-amino]-quinoxaline (UK14304; the alpha 2-adrenoceptor agonist, 10(-7) to 10(-3) M) in a dose-dependent manner.


CONCLUSIONS
The data obtained in the present study suggest that midazolam at 10(-4) M may reduce venous tone by inhibiting the release of NA from sympathetic nerve endings and both alpha 1- and alpha 2-adrenoceptor mediated smooth muscle contractions. It is also postulated that a stage of the post-receptor transduction mechanism linked to the venous smooth muscle contraction may be more sensitive to midazolam than the NA release mechanism at nerve terminals since midazolam at the low concentration tested inhibited ES-evoked tension development with no effect on the release of NA.
Kobayashi
Y
Y
Department of Pharmacology, Kanagawa Dental College, Yokosuka, Japan.
Muldoon
S M
SM
Kiyose
M
M
Hagiwara
T
T
Kumasaka
S
S
Okabe
E
E
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004563:Electrochemistry; D005260:Female; D008297:Male; D008642:Mesenteric Veins / Q000187:drug effects* / Q000294:innervation; D008874:Midazolam / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000294:innervation; D009411:Nerve Endings / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D018674:Adrenergic Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D015016:Yohimbine; D013779:Tetrodotoxin; D000068438:Brimonidine Tartrate; D008874:Midazolam; D002118:Calcium; D009638:Norepinephrine