Peroxynitrite affects Ca2+ influx through voltage-dependent calcium channels.
The effect of peroxynitrite (OONO-) on voltage-dependent Ca2+ channels (VDCCs) was examined by measuring [45Ca2+] influx into mouse cerebral cortical neurones. OONO- time- and dose-dependently increased [45Ca2+] influx and this increase was abolished by manganese (III) tetrakis (4-benzoic acid) porphyrin, a scavenger for OONO-. Inhibition of cyclic GMP (cGMP) formation did not alter the OONO(-)-induced [45Ca2+] influx. OONO-, as well as 30 mm KCl, significantly increased fluorescence intensity of cell-associated bis-(1,3-dibutylbarbituric acid) trimethine oxonol (bis-oxonol). Tetrodotoxin and membrane stabilizers such as lidocaine dose-dependently suppressed OONO(-)-induced [45Ca2+] influx. Although each of 1 microM nifedipine and 1 microM omega-agatoxin VIA (omega-ATX) significantly inhibited the OONO(-)-induced [45Ca2+] influx and the concomitant presence of these agents completely abolished the influx, 1 microM omega-conotoxin GVIA (omega-CTX) showed no effect on the influx. On the other hand, OONO- itself reduced 30 mM KCl-induced [45Ca2+] influx to the level of [45Ca2+] influx induced by OONO- alone, and the magnitude of this reduction was as same as that of KCl-induced [45Ca2+] influx by omega-CTX. These results indicate that OONO- increases [45Ca2+] influx into the neurones through opening P/Q- and L-type VDCCs subsequent to depolarization, and inhibits the influx through N-type VDCCs.
Ohkuma
S
S
Department of Pharmacology, Kawasaki Medical School, Matsushima, Kurashiki, Japan. sohkuma@bcc.kawasaki-m.ac.jp
Katsura
M
M
Higo
A
A
Shirotani
K
K
Hara
A
A
Tarumi
C
C
Ohgi
T
T
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013858:Thiobarbiturates
D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D013858:Thiobarbiturates; D030421:Peroxynitrous Acid; D013779:Tetrodotoxin; C025284:bis(1,3-diethylthiobarbiturate)trimethineoxonol; D011189:Potassium Chloride; D006152:Cyclic GMP; D002118:Calcium