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Nitric oxide contributes to desipramine- induced hypotension in rats

Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, Departments of Medicine and Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA

W. Wananukul

Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

W. Scarlett

Department of Medicine, Hennepin County Medical Center, Minneapolis, MN

DE Keylerl

Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, University of Minnesota College of Pharmacy, Minneapolis, MN, USA

1 Anesthetized rats received the TCA desipramine (DMI) 60 mg kg^-1 i.p. Administration of the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester-(L-NAME) 15 min after DMI reversed hypotension within 5 min (P < 0.05). In contrast to its beneficial effect on blood pressure, L-NAME worsened DMI-induced prolongation of the electrocardiographic QRS interval. Dexamethasone, an inhibitor of NOS induction, did not prevent DMI-induced hypotension.

2 To study the effect of L-NAME on survival, DMI was administered to anesthetized rats as a continuous i.v. infusion until death. Despite initially improving blood pressure, L-NAME decreased the mean survival time by 33% (P < 0.01) compared to control treatment. Adminis tration of the nitric oxide (NO) donor 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 suggest that NO production attributable to constitutive NOS (cNOS) activity aggravates the hypoten sion associated with DMI toxicity in the anesthetized rat, and contributes to the pathophysiology of this overdose. The shortened survival time produced by both increasing and decreasing NO production suggests that cNOS activity during DMI overdose is regulated and adaptive. Ongoing cNOS activity also contributed to nitroprusside-induced hypotension, and may represent a feature common to other drug-induced hypotensive states.

Key Words: Tricyclic antidepressant • desipramine • toxicity • nitric oxide • nitroprusside • L-NAME (NG-nitro-L-arginine methyl ester- (L-NAME)

Human & Experimental Toxicology, Vol. 15, No. 4, 320-328 (1996)
DOI: 10.1177/096032719601500408


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