Carboxyebselen a potent and selective inhibitor of endothelial nitric oxide synthase

• Published in: Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Vol. 45; no. 1; pp. 55 - 67
• Main Authors: Hatchett, R J, Gryglewski, R J, Młochowski, J, Zembowicz, A, Radziszewski, W
• Format: Journal Article
• Language: English
• Published: Poland 01.03.1994
• Subjects: Acetylcholine - pharmacology; Acetylcysteine - pharmacology; Amino Acid Oxidoreductases - antagonists & inhibitors; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Azoles - antagonists & inhibitors; Azoles - pharmacology; Cattle; Cerebellum - enzymology; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Female; Glutathione - pharmacology; Glutathione Peroxidase - metabolism; In Vitro Techniques; Male; Mice; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Nitric Oxide Synthase; Organoselenium Compounds - antagonists & inhibitors; Organoselenium Compounds - pharmacology; Rabbits; Spleen - enzymology; Sulfhydryl Compounds - metabolism; Swine
• ISSN: 0867-5910

Ebselen (Ebs) a glutathione peroxidase like agent has been recently described as an inhibitor of nitric oxide synthase (NOS). Presently, we report that carboxyebselen (HOOC-Ebs), a hydrophyllic derivative of Ebs inhibits NOS present in enzymatic preparations from bovine endothelium, porcine cerebella, and murine spleen, however, it is both more potent and more selective for the constitutive endothelial NOS than Ebs. Unlike Ebs, HOOC-Ebs (0.1-30 microM) causes a concentration-dependent endothelium-independent relaxations of rings of rabbit aorta. The mechanism of this relaxation remains unknown and it is attenuated by glutathione (GSH, 30-300 microM) and N-acetyl-L-cysteine (NAC, 30-300 microM). The vasorelaxant activity of acetylcholine (Ach, 0.1-1 microM) in aortic rings exposed to low concentrations of HOOC-Ebs (0.1-1 microM) or rings exposed to 10 microM HOOC-Ebs after their pretreatment with GSH or NAC (30-300 microM) remained unchanged. The lack of activity of HOOC-Ebs as a NOS inhibitor in intact endothelial cells contrasts the effectiveness of Ebs in this respect.