Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist

Nitric oxide (NO) which is produced by activation of Ca 2+/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.