Nifedipine inhibits the induction of nitric oxide synthase by bacterial lipopolysaccharide

Csaba Szabo, J. A. Mitchell, S. S. Gross, C. Thiemermann, J. R. Vane

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Abstract

We investigated the effect of the calcium channel antagonist nifedipine on the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in J774.2 macrophages, in cultured rat aortic smooth muscle cells and in a rat model of endotoxin shock. Stimulation by LPS for 24 hr increased nitrite accumulation in the supernatant of both cell types. NOS induction accounts for this nitrite accumulation, as both N(G)- methyl-L-arginine and cycloheximide reduced nitrite production in both cell types. Dexamethasone inhibited LPS-stimulated nitrite production in macrophages, but not in rat aortic smooth muscle cells. Nifedipine inhibited the production of nitrite in these LPS-treated cell types, with a more pronounced effect on macrophages. However, nifedipine did not inhibit the production of nitrite in J774.2 cells in which NOS had already been induced by prior exposure to LPS, and any possible further induction was inhibited by cycloheximide. In anesthetized rats subjected to LPS, pretreatment with nifedipine or dexamethasone ameliorated the fall in mean arterial blood pressure and the vascular hyporeactivity to norepinephrine at 180 min after LPS injection. At 180 min after LPS, an increase in a calcium-independent (induced) NOS activity was measured in lung homogenates. This induced NOS activity was reduced in lungs from rats treated with nifedipine or dexamethasone before LPS. Thus, nifedipine inhibits the induction of NOS in response to LPS in cultured cells in vitro and in the anesthetized rat.

Original languageEnglish (US)
Pages (from-to)674-680
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume265
Issue number2
StatePublished - 1993
Externally publishedYes

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Nifedipine
Nitrites
Nitric Oxide Synthase
Lipopolysaccharides
Dexamethasone
Macrophages
Cycloheximide
Endotoxins
Smooth Muscle Myocytes
Arterial Pressure
Lung
Calcium Channel Blockers
Blood Vessels
Arginine
Cultured Cells
Shock
Norepinephrine
Calcium
Injections

ASJC Scopus subject areas

  • Pharmacology

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Nifedipine inhibits the induction of nitric oxide synthase by bacterial lipopolysaccharide. / Szabo, Csaba; Mitchell, J. A.; Gross, S. S.; Thiemermann, C.; Vane, J. R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 265, No. 2, 1993, p. 674-680.

Research output: Contribution to journalArticle

Szabo, Csaba ; Mitchell, J. A. ; Gross, S. S. ; Thiemermann, C. ; Vane, J. R. / Nifedipine inhibits the induction of nitric oxide synthase by bacterial lipopolysaccharide. In: Journal of Pharmacology and Experimental Therapeutics. 1993 ; Vol. 265, No. 2. pp. 674-680.
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