Selective pharmacological inhibition of distinct nitric oxide synthase isoforms

被引:524
作者
Southan, GJ [1 ]
Szabo, C [1 ]
机构
[1] CHILDRENS HOSP,MED CTR,DIV CRIT CARE,CINCINNATI,OH 45229
关键词
nitric oxide; endothelium; macrophage; selectivity; L-arginine; N-G-nitro L-arginine; 7-nitroindazole; isothioureas; amidines; aminoguanidine; inflammation; shock; vascular effects;
D O I
10.1016/0006-2952(95)02099-3
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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-N-6-(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.
引用
收藏
页码:383 / 394
页数:12
相关论文
共 131 条
  • [71] INHIBITION OF NITRIC-OXIDE SYNTHESIS BY METHYLENE-BLUE
    MAYER, B
    BRUNNER, F
    SCHMIDT, K
    [J]. BIOCHEMICAL PHARMACOLOGY, 1993, 45 (02) : 367 - 374
  • [72] IDENTIFICATION OF N-IMINOETHYL-L-ORNITHINE AS AN IRREVERSIBLE INHIBITOR OF NITRIC-OXIDE SYNTHASE IN PHAGOCYTIC-CELLS
    MCCALL, TB
    FEELISCH, M
    PALMER, RMJ
    MONCADA, S
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 1991, 102 (01) : 234 - 238
  • [73] SUPPRESSION OF ARTHRITIS BY AN INHIBITOR OF NITRIC-OXIDE SYNTHASE
    MCCARTNEYFRANCIS, N
    ALLEN, JB
    MIZEL, DE
    ALBINA, JE
    XIE, QW
    NATHAN, CF
    WAHL, SM
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 178 (02) : 749 - 754
  • [74] PROKARYOTIC EXPRESSION OF THE HEME-BINDING AND FLAVIN-BINDING DOMAINS OF RAT NEURONAL NITRIC-OXIDE SYNTHASE AS DISTINCT POLYPEPTIDES - IDENTIFICATION OF THE HEME-BINDING PROXIMAL THIOLATE LIGAND AS CYSTEINE-415
    MCMILLAN, K
    MASTERS, BSS
    [J]. BIOCHEMISTRY, 1995, 34 (11) : 3686 - 3693
  • [75] NITRIC-OXIDE SYNTHASE INHIBITORS 7-NITROINDAZOLE AND 6-NITROINDAZOLE RELAX SMOOTH-MUSCLE IN-VITRO
    MEDHURST, AD
    GREENLEES, C
    PARSONS, AA
    SMITH, SJ
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1994, 256 (01) : R5 - R6
  • [76] REVERSAL OF HYPERDYNAMIC RESPONSE TO CONTINUOUS ENDOTOXIN ADMINISTRATION BY INHIBITION OF NO SYNTHESIS
    MEYER, J
    TRABER, LD
    NELSON, S
    LENTZ, CW
    NAKAZAWA, H
    HERNDON, DN
    NODA, H
    TRABER, DL
    [J]. JOURNAL OF APPLIED PHYSIOLOGY, 1992, 73 (01) : 324 - 328
  • [77] MILLER MJS, 1993, J PHARMACOL EXP THER, V264, P11
  • [78] SELECTIVE-INHIBITION OF THE INDUCIBLE NITRIC-OXIDE SYNTHASE BY AMINOGUANIDINE
    MISKO, TP
    MOORE, WM
    KASTEN, TP
    NICKOLS, GA
    CORBETT, JA
    TILTON, RG
    MCDANIEL, ML
    WILLIAMSON, JR
    CURRIE, MG
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1993, 233 (01) : 119 - 125
  • [79] MONCADA S, 1991, PHARMACOL REV, V43, P109
  • [80] CHARACTERIZATION OF THE NOVEL NITRIC-OXIDE SYNTHASE INHIBITOR 7-NITRO INDAZOLE AND RELATED INDAZOLES - ANTINOCICEPTIVE AND CARDIOVASCULAR EFFECTS
    MOORE, PK
    WALLACE, P
    GAFFEN, Z
    HART, SL
    BABBEDGE, RC
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 1993, 110 (01) : 219 - 224