Calmodulin antagonistic action of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4- ([4-(2-methoxyphenyl)-1-piperazinyl]methyl)isoquinoline.
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)
Nakajima
T
T
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
Okada
T
T
Kuruma
I
I
Yoshizaki
H
H
Satoh
T
T
Kuwahara
T
T
Nakamura
K
K
D000205:Actomyosin / Q000378:metabolism; D000779:Anesthetics, Local; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002645:Chickens; D004789:Enzyme Activation / Q000187:drug effects; D004907:Erythrocyte Deformability / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence
D000779:Anesthetics, Local; D002147:Calmodulin; D007546:Isoquinolines; D008054:Lipid Peroxides; C052931:Ro 22-4839; D000205:Actomyosin; D010727:Phosphoric Diester Hydrolases; D002118:Calcium