Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist.
Nitric oxide (NO) which is produced by activation of Ca2+/calmodulin-dependent NO synthase is known to induce neuronal damage. We examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT, a reverse transcriptase inhibitor), pentamidine (a therapeutic drug for Pneumocystis carinii pneumonia) and calmodulin antagonists such as trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on NO synthase activation. Although AZT had no effect on the activity of constitutive neuronal NO synthase, pentamidine inhibited the activation of neuronal NO synthase as did trifluoperazine and W-7. The inhibition by pentamidine was prevented by the addition of purified calmodulin. In addition, pentamidine inhibited calmodulin-dependent activation of neuronal NO synthase purified from rat cerebellum. From these results, it is suggested that pentamidine inhibits the neuronal NO synthase activation by probably acting as a calmodulin antagonist.
Kitamura
Y
Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Arima
T
T
Imaizumi
R
R
Sato
T
T
Nomura
Y
Y
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D000818:Animals; D000906:Antibodies; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002147:Calmodulin / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D019001:Nitric Oxide Synthase; D010419:Pentamidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014268:Trifluoperazine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000906:Antibodies; D002147:Calmodulin; D014268:Trifluoperazine; D015215:Zidovudine; D010419:Pentamidine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases