Biochemical and functional profile of a newly developed potent and isozyme-selective arginase inhibitor

An increase in arginase activity has been associated with the pathophysiolo gy of a number of conditions, including an impairment in nonadrenergic and noncholinergic (NANC) nerve-mediated relaxation of the gastrointestinal smo oth muscle. An arginase inhibitor may rectify this condition. We compared t he effects of a newly designed arginase inhibitor, 2(S)-amino-6-boronohexan oic acid (ABH), with the currently available N-omega-hydroxy-L-arginine (L- HO-Arg), on the NANC nerve-mediated internal anal sphincter (IAS) smooth-mu scle relaxation and the arginase activity in the IAS and other tissues. Arg inase caused an attenuation of the IAS smooth-muscle relaxations by NANC: n erve 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-arg inine-suppressed IAS relaxation that was similar to that seen with L-argini ne. Both ABH and L-HO-Arg caused an augmentation of NANC nerve-mediated rel axation of the IAS. In the IAS, ABH was found to be approximate to 250 time s more potent than L-HO-Arg in inhibiting the arginase activity. L-HO-Arg w as found to be 10 to 18 times more potent in inhibiting the arginase activi ty in the liver than in nonhepatic tissues. We conclude that arginase plays a significant role in the regulation of nitric oxide synthase-mediated NAN C relaxation in the IAS. The advent of new and selective arginase inhibitor s may play a significant role in the discrimination of arginase Isozymes an d have important pathophysiological and therapeutic implications in gastroi ntestinal motility disorders.