A Specific Chymase Inhibitor, 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), Suppresses Development of Abdominal Aortic Aneurysm in Hamsters

Abstract

In this study, we investigated the effect of a specific chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), in the development of abdominal aortic aneurysm in a hamster experimental model. The abdominal aortic aneurysm was induced by application of elastase onto the abdominal aorta in hamster. Each hamster was administered NK3201 (30 mg/kg/day p.o.) or placebo beginning 4 days before application of elastase and continuing through the experiments. Sham-operated hamsters received saline application onto the abdominal aorta. Two weeks after application of elastase, the aortic diameter in the placebo-treated group was significantly increased to 1.6-fold compared with the value for the sham-operated group, whereas that in the NK3201-treated group was significantly reduced. The chymase activities in the sham-operated and the placebo-treated groups were 0.35 Ϯ 0.01 and 3.44 Ϯ 0.62 mU/mg protein, respectively, and this difference was significant. NK3201 significantly reduced the chymase activity in the placebo-treated group. Here, we demonstrated for the first time that a chymase inhibitor prevented the development of abdominal aortic aneurysm in a hamster experimental model.

Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice

“…Chymase-positive mast cells were detected in the media and adventitia in human AAA (8). Pharmacological inhibition of chymase activity reduces AAA progression in hamsters (12). In addition to a unique set of proteases, mast cells also release proinflammatory cytokines (IFN-γ, TNF-α, and IL-4, -5, -6, and -13) and chemokines (monocyte chemoattractant protein-1 [MCP-1], IL-8, RANTES), all of which may directly or indirectly participate in AAA formation.…”

Effects of Angiotensin Receptor Blocker and Calcium Channel Blocker on Experimental Abdominal Aortic Aneurysms in a Hamster Model

“…It has also been reported that chymase activity was significantly increased in human AAA, and that accumulated chymase-positive mast cells were observed in the media and adventitia [19]. A specific chymase inhibitor, 2-(5-formyamino-6-oxo-2 phenyl-1, 6-dihydropyrmidine-1-yl) N-[{3, 4-dioxo-1-phenyl-7-} 2-pyridyloxy]}-2heptyl] acetamide (NK3201), has been shown to suppress the development of AAA in hamsters (Tsunemi et al, 2004) [16]. Meanwhile, Yokokura et al (2007) reported that a new calcium antagonist, azelnidipine, may act via an anti-inflammatory mechanism in a rat AAA model, thus resulting in inhibition of aortic expansion.…”

“…Angiotensin II plays an important role in the activation of inflammatory reactions in atherosclerosis (Miyazaki et al, 1999) [16][17]. Angiotensin II is generated from angiotensin I by two distinct types of angiotensin II-forming enzyme (ACE) and chymase in human cardiovascular tissues (Takai et al, 1999) [16][17].…”

“…Angiotensin II plays an important role in the activation of inflammatory reactions in atherosclerosis (Miyazaki et al, 1999) [16][17]. Angiotensin II is generated from angiotensin I by two distinct types of angiotensin II-forming enzyme (ACE) and chymase in human cardiovascular tissues (Takai et al, 1999) [16][17]. It has been reported that the ratio of chymase-dependent angiotensin II-forming activity to total angiotensin II-forming activity is significantly higher in aneurysmal aortas than in normal aortas (Ihara et al, 1999) [16,18].…”

“…Angiotensin II is generated from angiotensin I by two distinct types of angiotensin II-forming enzyme (ACE) and chymase in human cardiovascular tissues (Takai et al, 1999) [16][17]. It has been reported that the ratio of chymase-dependent angiotensin II-forming activity to total angiotensin II-forming activity is significantly higher in aneurysmal aortas than in normal aortas (Ihara et al, 1999) [16,18]. It has also been reported that chymase activity was significantly increased in human AAA, and that accumulated chymase-positive mast cells were observed in the media and adventitia [19].…”