Enhancement of hydralazine hypotension by low doses of isoniazid. Possible role of semicarbazide-sensitive amine oxidase inhibition.
The influence of pretreatment with 1 through 300 mg/kg ip of isoniazid (ISO) on blood pressure and heart rate responses to 0.1 mg/kg iv of hydralazine (HYD) was assessed in rats anesthetized with chloralose--urethane. HYD hypotension was significantly enhanced by ISO at doses between 3 and 300 mg/kg ip. Heart rate was not influenced by HYD in control or pretreated animals. Depressor responses to 0.2 mg/kg iv of pinacidil (PIN) were also potentiated by ISO at 100 and 300, but not at 30 mg/kg. Similarly, ISO decreased cerebral gamma-aminobutyric acid (GABA) at the two highest doses; 30 mg/kg was without effect. Pretreatment of rats with ISO at 1 through 300 mg/kg failed to influence HYD-induced relaxation of aortic rings. These results were interpreted as indicating that potentiation of HYD hypotension by high doses of ISO is not specific for that vasodilator and is related to decreased cerebral GABA, as postulated previously. Lower doses could specifically potentiate the HYD-induced hypotensive effect by inhibition of semicarbazide-sensitive amine oxidase (SSAO), since both ISO and HYD are potent inhibitors of this enzyme. In support of this hypothesis, the SSAO inhibitors, benserazide (100 mg/kg ip) and mexiletine (50 mg/kg ip), were also found to enhance HYD hypotension.
Vidrio
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H
Department of Pharmacology, School of Medicine, Universidad Nacional Autonoma de Mexico, Apartado Postal 70-297, 04510, D.F., Mexico, Mexico. vidrio@servidor.unam.mx
Medina
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M
Fernandez
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Lorenzana-Jimenez
M
M
Campos
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D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D006830:Hydralazine; D005680:gamma-Aminobutyric Acid; D006631:Amine Oxidase (Copper-Containing); D007538:Isoniazid