NITRIC-OXIDE CONTRIBUTES TO DESIPRAMINE-INDUCED HYPOTENSION IN RATS

1 Anesthetized rats received the TCA desipramine (DMI) 60 mg kg(-1) i. p. Administration of the nitric oxide synthase (NOS) inhibitor N-G-nit ro-L-arginine methyl ester-(L-NAME) 15 min after DMI reversed hypotens ion within 5 min (P < 0.05). In contrast to its beneficial effect on b lood pressure, L-NAME worsened DMI-induced prolongation of the electro cardiographic QRS interval. Dexamethasane, an inhibitor of NOS inducti on, did not prevent DMI-induced hypotension. 2 To study the effect of L-NAME on survival, DMI was administered to anesthetized rats as a con tinuous i.v. infusion until death. Despite initially improving blood p ressure, L-NAME decreased the mean survival time by 33% (P < 0.01) com pared to control treatment. Administration of the nitric oxide (NO) do nor nitroglycerine to rats during DMI infusion likewise decreased the mean survival time. 3 L-NAME partially reversed the hypotensive effect of nitroprusside in both anesthetized and awake rats. 4 These data su ggest that NO production attributable to constitutive NOS (cNOS) activ ity aggravates the hypotension associated with DMI toxicity in the ane sthetized rat, and contributes to the pathophysiology of this overdose . The shortened survival time produced by both increasing and decreasi ng NO production suggests that cNOS activity during DMI overdose is re gulated and adaptive. Ongoing cNOS activity also contributed to nitrop russide-induced hypotension, and may represent a feature common to oth er drug-induced hypotensive states.