EFFECT OF CILOSTAZOL, A PHOSPHODIESTERASE TYPE-III INHIBITOR, ON HISTAMINE-INDUCED INCREASE IN [CA2-ARTERY OF THE RABBIT(](I) AND FORCE IN MIDDLE CEREBRAL)
Y. Shiraishi et al., EFFECT OF CILOSTAZOL, A PHOSPHODIESTERASE TYPE-III INHIBITOR, ON HISTAMINE-INDUCED INCREASE IN [CA2-ARTERY OF THE RABBIT(](I) AND FORCE IN MIDDLE CEREBRAL), British Journal of Pharmacology, 123(5), 1998, pp. 869-878
1 The effect of cilostazol, an inhibitor of phosphodiesterase type III
(PDE III), on the contraction induced by histamine was studied by mak
ing simultaneous measurements of isometric force and the intracellular
concentration of Ca2+ ([Ca2+](i)) in endothelium-denuded muscle strip
s from the peripheral part of the middle cerebral artery of the rabbit
. 2 High K+ (80 mM) produced a phasic, followed by a tonic increase in
both [Ca2+](i) and force. Cilostazol (10 mu M) did not modify the res
ting [Ca2+](i), but it did significantly decrease the tonic contractio
n induced by high K+ without a corresponding change in the [Ca2+](i) r
esponse. 3 Histamine (3 mu M) produced a phasic, followed by a tonic i
ncrease in both [Ca2+](i) and force. Cilostazol (3 and 10 mu M) signif
icantly reduced both the phasic and tonic increases in [Ca2+](i) and f
orce induced by histamine, in a concentration-dependent manner. 4 Rp-a
denosine-3':5'-cyclic monophosphorothioate (Rp-cAMPS, 0.1 mM), a PDE-r
esistant inhibitor of protein kinase A (and as such a cyclic AMP antag
onist), did not modify the increases in [Ca2+](i) and force induced by
histamine alone, but it did significantly decrease the cilostazol-ind
uced inhibition of the histamine-induced responses. 5 In Ca2+-free sol
ution containing 2 mM EGTA, both histamine (3 mu M) and caffeine (10 m
M) transiently increased [Ca2+](i) and force. Cilostazol (1-10 mu M) (
i) significantly reduced the increases in [Ca2+](i) and force induced
by histamine, and (ii) significantly reduced the increase in force but
not the increase in [Ca2+](i) induced by caffeine. 6 In ryanodine-tre
ated strips, which had functionally lost the histamine-sensitive Ca2storage sites, histamine (3 mu M) slowly increased [Ca2+](i) and force
. Cilostazol (3 and 10 mu M) lowered the resting [Ca2+](i), but did no
t modify the histamine-induced increase in [Ca2+](i), suggesting that
functional Ca2+ storage sites are required for the cilostazol-induced
inhibition of histamine-induced Ca2+ mobilization. 7 The [Ca2+](i)-for
ce relationship was obtained in ryanodine-treated strips by applying a
scending concentrations of Ca2+ (0.16-2.6 mM) in Ca2+-free solution co
ntaining 100 mM K+. Histamine (3 mu M) shifted the [Ca2+](i)-force rel
ationship to the left and increased the maximum Ca2+-induced force. Un
der the same conditions, whether in the presence or absence of 3 mu M
histamine, cilostazol (3-10 mu M) shifted the [Ca2+](i)-force relation
ship to the right without producing a change in the maximum Ca2+-induc
ed force. 8 It is concluded that, in smooth muscle of the peripheral p
art of the rabbit middle cerebral artery, cilostazol attenuates the hi
stamine-induced contraction both by inhibiting histamine-induced Ca2mobilization and by reducing the myofilament Ca2+ sensitivity. It is s
uggested that the increase in the cellular concentration of cyclic AMP
that will follow the inhibition of PDE III may play an important role
in the cilostazol-induced inhibition of the histamine-contraction.