Midazolam produces vasodilation by mixed endothelium-dependent and -independent mechanisms

Aortic rings were obtained from rat thoracic aorta and studied in vitro with and without functionally intact endothelium to determine whether "the mechanism" requires endothelium [or endothelium-derived relaxing factor (EDRF)]. In aortic rings precontracted with either phenylephrine (PE, 3 x 10(-8)-3 x 10(-7) mol/L) or KCl (40 mmol/L), midazolam produced concentration-dependent relaxation, with and without endothelium. Rings without endothelium demonstrated significantly less relaxation than those with endothelium regardless of whether they were precontracted with PE or KCl. With intact endothelium, midazolam produced greater relaxation in PE-contracted aortic rings than in KCl-contracted aortic rings; the midazolam concentration producing 50% relaxation from the contracted state (RC50) was 8.8 +/- 3.6 x 10(-7) mol/L for PE-contracted rings and 3.3 +/- 1.1 x 10(-6) mol/L for KCl-contracted rings (P < 0.05). In aortic rings with intact endothelium pretreated with NG-monomethyl-L-arginine (L-NMMA, 10(-4) mol/L), an inhibitor of nitric oxide (NO) synthesis, midazolam produced relaxation of similar magnitude to that seen in the denuded aortic rings except at the highest concentration (1 x 10(-5) mol/L). Pretreatment with the cyclooxygenase inhibitor, indomethacin (2.5 x 10(-5) mol/L), did not change the midazolam-induced relaxation in rings with intact endothelium as compared to untreated control aortic rings. In contrast to the intact endothelium state, when endothelium was removed, midazolam produced greater relaxation in the KCl-contracted aortic rings than in PE-contracted rings (RC50, 1.2 +/- 0.3 x 10(-5) mol/L vs 2.3 +/- 0.4 x 10(-5) mol/L, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)