Selective pharmacological inhibition of distinct nitric oxide synthase isoforms

Garry J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

517 Citations (Scopus)

Abstract

Nitric oxide (NO) is produced in physiological and pathophysiological conditions by three distinct isoforms of NO synthase (NOS): endothelial NOS (ecNOS), inducible NOS (iNOS), and brain NOS (bNOS). Selective inhibition of iNOS may be beneficial in various forms of shock and inflammation, whereas inhibition of bNOS may protect against neuroinjury. This article surveys the enzymatic mechanism of NO production, lists the strategies and pharmacological tools for selective inhibition of distinct NOS isoforms, and considers the side-effects of the various approaches. Selective inhibition of NOS isoforms is achieved by: (a) targeting the differential co-factor (calmodulin or tetrahydrobiopterin) requirement of various NOS isoforms of NOS; (b) targeting the differential substrate requirements of cells expressing various isoforms of NOS (L-arginine uptake blockers or arginase); (c) the use of pharmacological agents that are selectively taken up by cells expressing various isoforms of NOS (7-nitroindazole); or (d) developing pharmacological NOS inhibitors with isoform specificity. The amino acid-based NOS inhibitor, N(G)-nitro-L-arginine, shows a preference for ecNOS and bNOS over iNOS, whereas L-N6-(1-iminoethyl)lysine is selective for iNOS over bNOS. Certain non-amino acid-based small molecules, such as aminoguanidine and certain S-alkylated isothioureas, also express selectivity towards iNOS and have anti-inflammatory and anti-shock properties. 7-Nitroindazole, a bNOS-selective inhibitor, protects in central nervous system injury. Clearly, there are a number of distinct approaches that are worthy of further research efforts in order to achieve even more selective targeting of various NOS isoforms.

Original languageEnglish (US)
Pages (from-to)383-394
Number of pages12
JournalBiochemical Pharmacology
Volume51
Issue number4
DOIs
StatePublished - Feb 23 1996
Externally publishedYes

Fingerprint

Nitric Oxide Synthase
Protein Isoforms
Pharmacology
Brain
Arginine
Shock
Nitric Oxide
Cells
Nervous System Trauma
Arginase
Nitric Oxide Synthase Type III
Neurology
Calmodulin
Anti-Inflammatory Agents
Central Nervous System
Inflammation
Amino Acids
Molecules
Acids

Keywords

  • 7-nitroindazole
  • amidines
  • aminoguanidine
  • endothelium
  • inflammation
  • isothioureas
  • L-arginine
  • macrophage
  • N(G)-nitro-L-argini ne
  • nitric oxide
  • selectivity
  • sh ock
  • vascular effects

ASJC Scopus subject areas

  • Pharmacology

Cite this

Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. / Southan, Garry J.; Szabo, Csaba.

In: Biochemical Pharmacology, Vol. 51, No. 4, 23.02.1996, p. 383-394.

Research output: Contribution to journalArticle

Southan, Garry J. ; Szabo, Csaba. / Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. In: Biochemical Pharmacology. 1996 ; Vol. 51, No. 4. pp. 383-394.
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