The role of Ca2(+)-
calmodulin-dependent protein kinase II (
CaM kinase II) in the central nervous system has been studied with special reference to the effect of
CaM kinase II inhibitor on
gamma-aminobutyric acid (
GABA) release. We have used two different selective inhibitors of Ca2(+)-
calmodulin-dependent
enzymes such as a
calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), and a newly synthesized selective inhibitor of
CaM kinase II, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpipe raz ine (KN-62). N-[1-[P-(5-Isoquinolinesulfonyl)benzyl]-2-(4- phenylpiperazinyl)ethyl]-5-isoquinolinesulfonamide (KN-04), a derivative of
KN-62, which has a much lower inhibitory activity on the
enzyme, was also synthesized for use as a control. Although i.v. injection of the drugs did not produce any effect, infusion of
W-7 or
KN-62 into the 4th ventricle produce any effect, infusion of
W-7 or
KN-62 into the 4th ventricle of the rat caused
hypertension and
tachycardia, associated with the diminished rate of
GABA release in cerebrospinal fluid. The ability of
KN-62 to produce these effects was more potent than that of
W-7. Intracisternal infusion of
KN-04 influenced neither systemic blood pressure nor
GABA release at the concentration up to 100 microM. The same order of potencies of three agents (
KN-62 greater than
W-7 much greater than
KN-04) has been obtained in their effects on either in vitro
CaM kinase II activity, the in vivo autonomic nervous system or the rate of
GABA release.(ABSTRACT TRUNCATED AT 250 WORDS)