Biochemical and functional profile of a newly developed potent and isozyme-selective arginase inhibitor.
An increase in arginase activity has been associated with the pathophysiology of a number of conditions, including an impairment in nonadrenergic and noncholinergic (NANC) nerve-mediated relaxation of the gastrointestinal smooth muscle. An arginase inhibitor may rectify this condition. We compared the effects of a newly designed arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH), with the currently available N(omega)-hydroxy-L-arginine (L-HO-Arg), on the NANC nerve-mediated internal anal sphincter (IAS) smooth-muscle relaxation and the arginase activity in the IAS and other tissues. Arginase caused an attenuation of the IAS smooth-muscle relaxations by NANC nerve stimulation that was restored by the arginase inhibitors. L-HO-Arg but not ABH caused dose-dependent and complete reversal of N(omega)-nitro-L-arginine-suppressed IAS relaxation that was similar to that seen with L-arginine. Both ABH and L-HO-Arg caused an augmentation of NANC nerve-mediated relaxation of the IAS. In the IAS, ABH was found to be approximately 250 times more potent than L-HO-Arg in inhibiting the arginase activity. L-HO-Arg was found to be 10 to 18 times more potent in inhibiting the arginase activity in the liver than in nonhepatic tissues. We conclude that arginase plays a significant role in the regulation of nitric oxide synthase-mediated NANC relaxation in the IAS. The advent of new and selective arginase inhibitors may play a significant role in the discrimination of arginase isozymes and have important pathophysiological and therapeutic implications in gastrointestinal motility disorders.
Baggio
R
R
Department of Chemistry, University of Pennsylvania, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Emig
F A
FA
Christianson
D W
DW
Ash
D E
DE
Chakder
S
S
Rattan
S
S
D000596:Amino Acids / Q000494:pharmacology*; D000614:Aminocaproates; D001003:Anal Canal / Q000201:enzymology / Q000294:innervation / Q000502:physiology; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009893:Opossums; D012007:Rectum / Q000201:enzymology; D013379:Substrate Specificity
C121228:2-amino-6-boronohexanoic acid; D000596:Amino Acids; D000614:Aminocaproates; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019335:Nitroarginine; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase