The effects of thiol compounds and ebselen on nitric oxide activity in rat aortic vascular responses.
1. Thiols have been implicated to play a role in a variety of aspects of nitric oxide (NO) generation and activity. Thiol dependence of nitric oxide synthase (NOS) has remained controversial and its mechanism is not clear. This study investigates possible mechanisms between thiol (SH group) and NOS activation, through thiol compounds (glutathione, dithiothreitol, N-acetyl-L-cysteine) and Ebselen [2-phenyl-1,2-benzisoselenazole-3(2H)-one] on rat aortic vascular responses. 2. In rat thoracic aorta, acetylcholine (10(-6)-10(-9) M) induced a relaxation of phenylephrine (PE) (10(-7) M)-induced tone, which was inhibited dose dependently by increasing concentration of ebselen (1-10 microM). 3. In rings of rat thoracic aorta, ebselen and NOS inhibitors (NG-monomethyl-L-arginine, NG-nitro-L-arginine methyl ester) produced an augmentation of phenylephrine (10(-7) M)- induced tone and acetylcholine induced a relaxation of PE (10(-7) M)-induced tone in rat thoracic aorta, which was inhibited by ebselen (10 microM) like NOS inhibitor. 4. The thiol compounds (glutathione, dithiothreitol, and N-acetyl-L-cysteine) alone did not change vascular tone in rat thoracic aorta. Pretreatment with thiol compounds before ebselen treatment, however, reversed the inhibitory effect of ebselen which acts like the NOS inhibitor in rat thoracic aorta. Posttreatment with thiol compounds after ebselen treatment did not reverse the inhibitory effect of ebselen by as much as pretreatment. 5. Calcium ionophore A23187 (10(-7) M)-induced vasodilation was inhibited in ebselen pretreated rat thoracic aorta, but sodium nitroprusside (SNP, 10(-7) M)-induced relaxation was not inhibited by ebselen. This suggests that NOS is involved in the inhibitory effect of ebselen on rat thoracic aorta relaxation. 6. These results suggest that ebselen exerts an inhibitory action on the nitric oxide synthesis in rat thoracic aorta by interacting with thiol groups.
Kim
H R
HR
Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea SungKyunKwan University, Suwon 440-746, Korea.
Kim
J W
JW
Park
J Y
JY
Je
H D
HD
Lee
S Y
SY
Huh
I H
IH
Sohn
U D
UD
D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation; D005260:Female; D007476:Ionophores / Q000494:pharmacology; D054833:Isoindoles; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D007476:Ionophores; D054833:Isoindoles; D016566:Organoselenium Compounds; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D000001:Calcimycin; C042986:ebselen; D019001:Nitric Oxide Synthase; D000109:Acetylcholine