INHIBITION BY MIDAZOLAM OF THE ADRENERGIC-FUNCTION IN THE ISOLATED CANINE MESENTERIC VEIN

Background: Midazolam has been reported to cause hypotension or to dep ress sympathetic activity following intravenous injection. However, li ttle information is available concerning the mechanism of these effect s. The aim of the present study was to determine the effects of midazo lam on release of noradrenaline (NA) at nerve terminals and on recepto rs in the venous smooth muscle. Methods: The effect of midazolam at ne rve terminals was examined by measuring the amount of NA release from superfused canine mesenteric Vein helical strips during electrical sti mulation (ES; 5 Hz, 2 ms, 9V). The NA was quantified by high-performan ce liquid chromatography with electrochemical detection; tension devel opment evoked by ES was also recorded simultaneously. In a separate se ries of experiments, ring preparations from the isolated vein were mou nted in Krebs-Ringer solution for isometric tension recording to asses s the effect of midazolam on alpha(2)-adrenoceptors. Results: Applicat ion of tetrodotoxin (10(-6) M) or replacement of superfusate with Ca2-free solution decreased both the release of NA and the tension develo pment evoked by ES. Yohimbine (5x10(-8) M) increased the ES-evoked rel ease of NA, whereas it decreased tension development in the vein strip s. 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 t he tension development (P<0.01) during ES; midazolam at 10(-5) M inhib ited 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 re sponses to NA (a mixed alpha(1)- and alpha(2)-adrenoceptor agonist, 10 (-8) to 10(-3) M), phenylephrine (the alpha(1)-adrenoceptor agonist, 1 0-8 to 10-3 M) and 5-bromo-6-[2-imidazolin-2yl-amino]-quinoxaline (UK1 4304; the alpha(2)-adrenoceptor agonist, 10(-7) to 10(-3) M) in a dose -dependent manner. Conclusion: The data obtained in the present study suggest that midazolam at 10(-4) M may reduce venous tone by inhibitin g the release of NA from sympathetic nerve endings and both alpha(1)- and alpha(2)-adrenoceptor mediated smooth muscle contractions. It is a lso postulated that a stage of the post-receptor transduction mechanis m linked to the venous smooth muscle contraction may be more sensitive to midazolam than the NA release mechanism at nerve terminals since m idazolam at the low concentration tested inhibited ES-evoked tension d evelopment with no effect on the release of NA.