POSSIBLE MECHANISMS UNDERLYING THE MIDAZOLAM-INDUCED RELAXATION OF THE NORADRENALINE-CONTRACTION IN RABBIT MESENTERIC RESISTANCE ARTERY

1 The mechanisms underlying the midazolam-induced relaxation of the no radrenaline (NA)-contraction were studied by measuring membrane potent ial, isometric force and intracellular concentration of Ca2+([Ca2+](i) ) in endothelium-denuded muscle strips from the rabbit mesenteric resi stance artery. The actions of midazolam were compared with those of ni cardipine, an L-type Ca2+-channel blocker. 2 Midazolam (30 and 100 mu M) did not modify either the resting membrane potential or the membran e depolarization induced by 10 mu M NA. 3 NA (10 mu M) produced a phas ic, followed by a tonic increase in both [Ca2+](i) and force. Midazola m (10-100 mu M) did not modify the resting [Ca2+](i), but attenuated t he NA-induced phasic and tonic increases in [Ca2+](i) and force, in a concentration-dependent manner. In contrast, nicardipine (0.3 mu M) at tenuated the NA-induced tonic, but not phasic, increases in [Ca2+](i) and force.4 In Ca2+-free solution containing 2 mM EGTA, NA (10 mu M) t ransiently increased [Ca2+](i) and force. Midazolam (10-100 mu M), but not nicardipine (0.3 mu M), attenuated this NA-induced increase in [C a2+](i) and force, in a concentration-dependent manner. However, midaz olam (10 and 30 mu M), had no effect on the increases in [Ca2+](i) and force induced by 10 mM caffeine. 5 In ryanodine-treated strips, which have functionally lost the NA-sensitive Ca2+-storage sites, NA slowly increased [Ca2+](i) and force. Nicardipine (0.3 mu M) did not modify the resting [Ca2+](i) but partly attenuated the NA-induced increases i n [Ca2+](i) and force. In the presence of nicardipine, midazolam (100 mu M) lowered the resting [Ca2+](i) and further attenuated the remaini ng NA-induced increases in [Ca2+](i) and force. 6 The [Ca2+](i)-force relationship was obtained in ryanodine-treated strips by the applicati on of ascending concentrations of Ca2+ (0.16-2.6 mM) in Ca2+-free solu tion containing 100 mM K+. NA (10 mu M) shifted the [Ca2+](i)-force re lationship to the left and enhanced the maximum Ca2+-induced force. Un der these conditions, whether in the presence or absence of 10 mu M NA , midazolam (10 and 30 mu M) attenuated the increases in [Ca2+](i) and force induced by Ca2+ without changing the [Ca2+](i)-force relationsh ip. 7 It was concluded that, in smooth muscle of the rabbit mesenteric resistance artery, midazolam inhibits the NA-induced contraction thro ugh its inhibitory action on NA-induced Ca2+ mobilization. Midazolam a ttenuates NA-induced Ca2+ influx via its inhibition of both nicardipin e-sensitive and -insensitive pathways. Furthermore, midazolam attenuat es the NA-induced release of Ca2+ from the storage sites. This effect contributes to the midazolam-induced inhibition of the NA-induced phas ic contraction.