6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)
isoquinoline (Ro 22-4839) is a new cerebral circulation improver with vasospasmolytic properties. Preliminarily, Ro 22-4839-induced arterial relaxation was confirmed under the treatment of various constrictors and it was hardly overcome by addition of extra
calcium. In this study the mode and site of action of this agent were further explored.
Ro 22-4839 was found to more strongly inhibit the superprecipitation of chicken gizzard smooth muscle
actomyosin (IC50 = 2.0 mumol/l) than
trifluoperazine (38 mumol/l) and
W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide) (220 mumol/l), an in vitro model for relaxation-contraction coupling of the smooth muscle in which
calmodulin is known to play an important role through phosphorylation of
myosin light chain kinase. The
calmodulin antagonistic action of
Ro 22-4839 was also demonstrated in other
calmodulin-related reaction systems such as
phosphodiesterase and hydrophobic
fluorescent probe, but was very weak in Ca2+,
Mg2+-ATPase of rat erythrocyte membrane. Thus,
Ro 22-4839 was suggested to have a relative preference for smooth muscle contraction process unlike
trifluoperazine and
W-7. Moreover,
Ro 22-4839 prevented the decrease in erythrocyte deformability induced by hyperosmolarity or intracellular Ca2+ accumulation, like
trifluoperazine and
W-7. However,
Ro 22-4839 itself caused hardly an internal stomatocytic shape of erythrocytes in contrast to known
calmodulin antagonists. Further,
Ro 22-4839 inhibited erythrocyte membrane
rupture, platelet aggregation and lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)