Effect of a new Ca2(+)-calmodulin-dependent protein kinase II inhibitor on GABA release in cerebrospinal fluid of the rat.

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)