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 NG-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. Administration 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 hypotension 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.
Pentel
P R
PR
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
Wananukul
W
W
Scarlett
W
W
Keyler
D E
DE
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000633:toxicity*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003891:Desipramine / Q000633:toxicity*; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced*; D007262:Infusions, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin; D003891:Desipramine; D019331:NG-Nitroarginine Methyl Ester