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Possible mechanisms underlying the midazolam‐induced relaxation of the noradrenaline‐contraction in rabbit mesenteric resistance artery
Author(s) -
Shiraishi Yoshihisa,
Ohashi Masuo,
Kanmura Yuichi,
Yamaguchi Shunichiro,
Yoshimura Nozomu,
Itoh Takeo
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701230
Subject(s) - nicardipine , chemistry , isometric exercise , contraction (grammar) , depolarization , ryanodine receptor , egta , tonic (physiology) , membrane potential , muscle contraction , midazolam , biophysics , caffeine , vasodilation , endocrinology , medicine , calcium , anesthesia , intracellular , biochemistry , biology , organic chemistry , sedation
The mechanisms underlying the midazolam‐induced relaxation of the noradrenaline (NA)‐contraction were studied by measuring membrane potential, isometric force and intracellular concentration of Ca 2+ ([Ca 2+ ] i ) in endothelium‐denuded muscle strips from the rabbit mesenteric resistance artery. The actions of midazolam were compared with those of nicardipine, an L‐type Ca 2+ ‐channel blocker. Midazolam (30 and 100μ m ) did not modify either the resting membrane potential or the membrane depolarization induced by 10μ m NA. NA (10μ m ) produced a phasic, followed by a tonic increase in both [Ca 2+ ] i and force. Midazolam (10–100μ m ) did not modify the resting [Ca 2+ ] i , but attenuated the NA‐induced phasic and tonic increases in [Ca 2+ ] i and force, in a concentration‐dependent manner. In contrast, nicardipine (0.3μ m ) attenuated the NA‐induced tonic, but not phasic, increases in [Ca 2+ ] i and force. In Ca 2+ ‐free solution containing 2m m EGTA, NA (10μ m ) transiently increased [Ca 2+ ] i and force. Midazolam (10–100μ m ), but not nicardipine (0.3μ m ), attenuated this NA‐induced increase in [Ca 2+ ] i and force, in a concentration‐dependent manner. However, midazolam (10 and 30μ m ), had no effect on the increases in [Ca 2+ ] i and force induced by 10m m caffeine. In ryanodine‐treated strips, which have functionally lost the NA‐sensitive Ca 2+ ‐ storage sites, NA slowly increased [Ca 2+ ] i and force. Nicardipine (0.3μ m ) did not modify the resting [Ca 2+ ] i but partly attenuated the NA‐induced increases in [Ca 2+ ] i and force. In the presence of nicardipine, midazolam (100μ m ) lowered the resting [Ca 2+ ] i and further attenuated the remaining NA‐induced increases in [Ca 2+ ] i and force. The [Ca 2+ ] i ‐force relationship was obtained in ryanodine‐treated strips by the application of ascending concentrations of Ca 2+ (0.16–2.6m m ) in Ca 2+ ‐free solution containing 100m m K + . NA (10μ m ) shifted the [Ca 2+ ] i ‐force relationship to the left and enhanced the maximum Ca 2+ ‐induced force. Under these conditions, whether in the presence or absence of 10μ m NA, midazolam (10 and 30μ m ) attenuated the increases in [Ca 2+ ] i and force induced by Ca 2+ without changing the [Ca 2+ ] i ‐force relationship. It was concluded that, in smooth muscle of the rabbit mesenteric resistance artery, midazolam inhibits the NA‐induced contraction through its inhibitory action on NA‐induced Ca 2+ mobilization. Midazolam attenuates NA‐induced Ca 2+ influx via its inhibition of both nicardipine‐sensitive and ‐insensitive pathways. Furthermore, midazolam attenuates the NA‐induced release of Ca 2+ from the storage sites. This effect contributes to the midazolam‐induced inhibition of the NA‐induced phasic contraction.