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)
Ishikawa
N
N
Department of Pharmacology, Nagoya University School of Medicine, Japan.
Hashiba
Y
Y
Hidaka
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid / Q000378:metabolism*
D002147:Calmodulin; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014665:Vasodilator Agents; C065344:KN 04; D005680:gamma-Aminobutyric Acid; C063302:KN 62; C017967:W 7; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C