Background : Histamine, released from mast cells in atheromatous plaque, has been
known to cause cardiac ischemia or sudden cardiac death in atherosclerosis patient.
Previous reports have suggested that histamine induced coronary vasoconstriction was
due to increase in IP3 and DAG, which induce release of
Ca2+ from SR and increase the Ca2+ sensitivity of contractile
element via activation of PKC. Recently, it was reported that application of histamine
cause depolarization of intestinal smooth muscle, which may contribute to
histamine-induced contraction via augmenting Ca2+ influx through
activation of Ca2+ channels. However, the underyling mechanism of
histamine-induced depolarization and its contribution to the magnitude of coronary
vasoconstriction are still uncertain.
Method : To elucidate the underlying mechanism of Ca2+ influx change
during histamine-induced vasoconstriction, we examined the effect of Ca2+
influx change during histamine-induced vasoconstriction, we examined the effect of
Ca2- channel antagonist and PKC blocker on histamine-induced
contractions, and then measured the effect of PKC antagonist on whole cell
K+ current using patch clamping method in rabbit coronary smooth muscle
cells.
Results : Application of histamine induced phasic and tonic constraction of coronary
rings via activation of H1 receptors. Pretreatment of Ca2+
channel antagonist (nifedipine, 1μM) or PKC blockers (10nM staurosporine and 10μM
Go6976) markedly inhibited histamine-induced tonic contraction, which suggest that the
magnitude of tonic contraction depend on the Ca2+ influx. Application of
4-AP, a blocker of voltage-dependent K+ channels, increased resting tone
of coronary rings, and combined treatment of nifedipine blocked this 4-AP induced
increase of resting tone. Application of active analogue of DAG (1,2-DiC8)
significantly inhibited the activity of voltage-dependent K+ current in
single smooth muscle cell, meanwhile the inactive analogue of DAG
(1,3-DiC8) has no apparent effect on the activity of voltage-dependent
K+ current. Furthermore, pretreatment of calphostin C (1μM), a blocker of
PKC, diminished the 1,2-DiC8-induced inhibition of K-
current.
Conclusions : PKC dependent inhibition of voltage-dependent K+ current
may be responsible for the maintaining of histamine-induced tonic contraction in rabbit
coronary artery.
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